Volume 10, Issue 11, Supplement 20 November 2012
Highlights in NSCLC From the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology
September 6–8, 2012 • Chicago, Illinois
Special Reporting on:
• Weekly nab-Paclitaxel in Combination With Carboplatin as First-Line Therapy For Advanced Non-Small Cell Lung Cancer
• Results of a Global Phase II Study With Crizotinib in Advanced ALK-Positive Non-Small Cell Lung Cancer (NSCLC)
• A Randomized, Open-label, Phase 3, Superiority Study Of Pemetrexed (Pem)+Carboplatin (Cb)+Bevacizumab (B) Followed By Maintenance Pem+B Versus Paclitaxel (Pac)+Cb+B Followed By Maintenance B In Patients (pts) With Stage IIIB Or IV Non-squamous Non-small Cell Lung Cancer (NS-NSCLC)
• The Select Study: a Multicenter Phase II Trial of Adjuvant Erlotinib in Resected Epidermal Growth Factor Receptor (EGFR) Mutation-Positive Non-Small Cell Lung Cancer (NSCLC)
• Clinical Activity and Safety of Anti-PD-1 (BMS-936558, MDX-1106) in Patients (Pts) With Advanced Non-Small-Cell Lung Cancer (NSCLC)
• Clinical Activity of Crizotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring ROS1 Gene Rearrangement
• LUX-Lung 3: A Randomized, Open-Label, Phase III Study of Afatinib vs Pemetrexed and Cisplatin as First-Line Treatment For Patients With Advanced Adenocarcinoma of the Lung Harboring EGFR-Activating Mutations (Subgroup Analysis)
PLUS Meeting Abstract Summaries
With Expert Commentary by:
Corey J. Langer, MD, FACP
Professor of Medicine
University of Pennsylvania
Every effort has been made to ensure that drug usage and other information are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Millennium Medical Publishing, Inc, and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation.
©2012 Millennium Medical Publishing, Inc., 611 Broadway, Suite 310, New York, NY 10012. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.
Weekly nab-Paclitaxel in Combination With Carboplatin as First-Line Therapy For Advanced Non-Small Cell Lung Cancer
This phase III trial of nab-paclitaxel randomized 1,052 patients with untreated, stage IIIB/IV non–small cell lung cancer (NSCLC) to receive carboplatin and either nab-paclitaxel or solvent-based paclitaxel on 21-day cycles until disease progression or unacceptable toxicity.
Patient-reported neuropathy, neuropathic pain in the hands and feet, and hearing loss were significantly less for patients treated with nab-paclitaxel compared with those treated with solvent-based paclitaxel.1 Using the functional assessment of cancer therapy (FACT)-Taxane version 4.0 subscales, neuropathy, pain, and hearing were assessed at baseline, on day 1 of each 21-day cycle, and upon completing treatment. A total of 1,031 patients completed FACT-Taxane at baseline, and 987 patients (94%) completed it during follow-up or at the completion of treatment.
The nab-paclitaxel arm was favored for patient-reported neuropathy (P<.001), neuropathic pain in the hands and feet (P<.001), and hearing loss (P=.002) over the solvent-based paclitaxel arm. Physician assessments of neuropathy outcomes were consistent with patient-reported outcomes. The physician-assessed rates of neuropathy were lower with nab-paclitaxel than solvent-based paclitaxel for all grades (46% vs 62%; P<.001) and grade 3/4 (3% vs 12%; P<.001). Grade 4 peripheral sensory neuropathy was not reported by any patients in the nab-paclitaxel arm. Peripheral neuropathy took 38 days to improve from grade 3 or higher to grade 1 in the nab-paclitaxel arm, compared with 104 days in the solvent-based paclitaxel arm (P=.238).
Among the 1,052 NSCLC patients in the phase III study who were randomized to receive carboplatin and either nab-paclitaxel or solvent-based paclitaxel, 15% were aged 70 years or older (74 patients in the nab-paclitaxel arm and 82 patients in the solvent-based paclitaxel arm). Most of these elderly patients were white (71%) and male (72%), had Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores of 1 (73%) and stage IV disease (83%), and were current or former smokers (72%). Patients’ baseline characteristics and demographics are summarized in Table 1.
First-line nab-paclitaxel for elderly patients (older than 70 years) was well tolerated and led to improved overall response rates (ORR; 34% vs 24% for solvent-based paclitaxel; P=.196; response rate [RR] ratio=1.385) and progression-free survival (PFS; median 8.0 vs 6.8 months for solvent-based paclitaxel; P=.134; hazard ratio [HR]=0.687).2 Overall survival (OS) was significantly longer with nab-paclitaxel (median, 19.9 months) than with solvent-based paclitaxel (median, 10.4 months; P=.009; HR=0.583; Figure 1) in elderly patients with advanced NSCLC.
The adverse events (AEs) were comparable among patients aged 70 years or older and patients younger than 70 years. When the nab-paclitaxel and solvent-based paclitaxel arms were compared, the nab-paclitaxel arm had less grade 3 or 4 neutropenia (54% vs 74%; P<.05) and neuropathy (7% vs 23%; P<.05), and increased thrombocytopenia (23% vs 14%; P=not significant) and anemia (23% vs 10%; P<.05). These rates in elderly patients were similar to those observed in the intent-to-treat (ITT) population. Among the 99% of elderly patients who completed the FACT-Taxane assessment at baseline, significant treatment effects occurred that favored nab-paclitaxel over solvent-based paclitaxel for neuropathy (P<.001), pain in hands and feet (P<.001), hearing loss (P=.022), and edema (P=.004).
Among the 1,052 randomized patients in the phase III study, 518 had adenocarcinoma histology, 450 had squamous cell carcinoma (SCC) histology, and 84 patients had either large cell carcinoma (LCC) or carcinoma that was not otherwise specified (NOS).3 The patients with SCC had a higher ORR with nab-paclitaxel (41%) than with solvent-based paclitaxel (24%; P<.001; RR ratio=1.680). Both arms of patients with SCC had similar PFS (5.6 vs 5.7 months; P=.245; HR=0.865). Nab-paclitaxel trended toward prolonging OS by more than 1 month (10.7 vs 9.5 months; P=.284; HR=0.890).
Among patients with LCC or NOS-NSCLC, the nab-paclitaxel arm had a higher ORR (26%) than the solvent-based paclitaxel arm (15%; P=.208; RR ratio=1.729), longer PFS (6.4 vs 4.2 months; P=.061; HR=0.565), and similar OS (10.5 vs 11.2 months; P=.702; HR=1.100). Among patients with adenocarcinoma, nab-paclitaxel was as effective as solvent-based paclitaxel for ORR (26% vs 27%; P=.814; RR ratio=0.966), PFS (6.9 months in both arms; P=.944; HR=0.991), and OS (13.9 vs 13.6 months; P=.639; HR=0.949). Like the ITT population, nab-paclitaxel treatment resulted in lower rates of grade 3 or 4 neuropathy and higher rates of anemia and thrombocytopenia than solvent-based paclitaxel in these histologic groups. Grade 3 or 4 neutropenia was lower with nab-paclitaxel than with solvent-based paclitaxel in patients with SCC (43% vs 51%; P=.103) and adenocarcinoma (49% vs 64%; P<.001), but not LCC or NOS (62% vs 53%; P=.500) histology.
Baseline patient characteristics and clinical treatment preferences differ by geographic region in large, international trials of advanced NSCLC. An analysis by region of this phase III trial included data from 1,038 patients.4 The patients were from Russia/Ukraine (n=724; 69%), North America (n=165; 16%), and Japan (n=149; 14%). Compared with the cohort from Russia/Ukraine, the cohorts from North America and Japan were generally older (median age, 65 years vs 58 years in Russia/Ukraine), had primarily nonsquamous histology (56% in North America, 77% in Japan, and 44% in Russia/Ukraine), and had a history of smoking (91% in North America, 76% in Japan, and 68% in Russia/Ukraine). More elderly patients (aged 70 years or older) were included in the North American (33%) and Japanese (21%) cohorts than the Russian/Ukrainian (9%) cohort.
For all 3 regions, ORR favored nab-paclitaxel over solvent-based paclitaxel in North America (25% vs 22%; RR ratio=1.125; P=.675), Japan (35% vs 27%; RR ratio=1.318; P=.263), and Russia/Ukraine (34% vs 26%; RR ratio=1.327; P=.014). Response rates were not affected by region, according to multivariate analysis.
Region did affect OS. For nab-paclitaxel versus solvent-based paclitaxel, median OS was 12.7 versus 9.8 months (P=.008) in North America, 11.0 versus 11.1 months (P=.834) in Russia/Ukraine, and 16.7 versus 17.2 months (P=.814) in Japan. The regions had variation in the number of treatment cycles (5 in North America, 4 in Japan, and 6 in Russia/Ukraine) and in the proportion of patients receiving 6 or fewer cycles of nab-paclitaxel (86% in North America, 89% in Japan, and 60% in Russia/Ukraine). Japan had the highest use of second-line therapy (85%), followed by North America (69%) and Russia/Ukraine (44%).
The safety and efficacy of nab-paclitaxel was analyzed among the 53 patients whose creatine clearance was less than or equal to 50 mL/min at baseline (n=26 in the nab-paclitaxel arm and n=27 in the solvent-based paclitaxel arm).5 These patients had a median age of 70 years in both treatment arms. The rates of grade 1 creatinine elevation were lower in patients receiving nab-paclitaxel (0%) than in those receiving solvent-based paclitaxel (7%; P=.161). The rates of grade 3 or higher AEs were lower for the patients receiving nab-paclitaxel (62%) than for those receiving solvent-based paclitaxel (81%). The patients in the nab-paclitaxel arm did not experience any grade 3 or higher sensory neuropathy, although 19% of patients in the solvent-based paclitaxel arm did (P=.051). The nab-paclitaxel arm had a lower rate of grade 3 or higher neutropenia (44%) than the solvent-based paclitaxel arm (77%; P=.023). Notably, grade 3 or higher anemia and thrombocytopenia were higher in the nab-paclitaxel arm (32% and 28%) than in the solvent-based paclitaxel arm (15% and 4%; P=.193 and P=.022, respectively). The rates of grade 3 or higher fatigue were lower in the nab-paclitaxel arm (8%) than in the solvent-based paclitaxel arm (22%; P=.250).
Among the patients with renal impairment, those in the nab-paclitaxel arm had a median paclitaxel dose intensity of 83.33 mg/m2/week and a median of 4 cycles, while those in the solvent-based paclitaxel arm had a median dose of 60.43 mg/m2/week and a median of 5 cycles. The nab-paclitaxel arm had a higher ORR of 31% versus 19% for the solvent-based paclitaxel arm (RR ratio=1.662; P=.300). The nab-paclitaxel arm had a longer median PFS than the solvent-based paclitaxel arm (6.0 months vs 4.7 months; HR=0.607; P=.238), and a longer median OS (9.7 months vs 9.3 months; HR=0.824; P=.576).
1. Hirsh V, Okamoto I, Hon JK, et al. Weekly nab®-paclitaxel in combination with carboplatin as first-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC): analysis of patient-reported neuropathy and taxane-associated symptoms. Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract 108.
2. Socinski MA, Langer CJ, Okamoto I, et al. Weekly nab®-paclitaxel in combination with carboplatin as first-line therapy in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC). Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract 109.
3. Renschler MF, Okamoto I, Hon JK, et al. Safety and efficacy by histology of weekly nab®-paclitaxel in combination with carboplatin as first-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC). Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract 110.
4. Socinski M, Okamoto I, Hon JK, et al. nab®-Paclitaxel in combination with carboplatin as first-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC): analysis of pt characteristics and clinical treatment patterns by region. Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract 183.
5. Hon JK, Okamoto I, Hirsh V, et al. Weekly nab®-paclitaxel in combination with carboplatin as first-line therapy in pts (pts) with advanced non-small cell lung cancer (NSCLC): analysis of safety and efficacy in pts with renal impairment. Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract 189.
A Randomized Phase II Study of Pazopanib or Placebo in Combination With Erlotinib in Patients With Advanced Non-Small-Cell Lung Cancer
Pazopanib plus erlotinib improved PFS when compared with erlotinib plus a placebo (median 2.60 vs 1.81 months; HR=0.59; 95% CI, 0.43–0.83; P=.0016) in this randomized, placebo-controlled, phase II study of previously treated patients with stage IIIB or IV NSCLC and ECOG PS of 0 or 1 (Abstract 13). The trial met its goal of a 50% improvement in PFS. Unfortunately, treatment with pazopanib did not improve OS (6.8 months vs 6.7 months with placebo and erlotinib; HR=1.1; 95% CI, 0.77–1.55; P=.61). Several biomarker-defined subgroups did have PFS advantages when treated with pazopanib and erlotinib. Grade 3/4 hematologic toxicity was less than 4% in both arms. Severe nonhematologic AEs were diarrhea (15% with pazopanib vs 9% with placebo), fatigue (21% with pazopanib vs 15% with placebo), and proteinuria (5% with pazopanib vs 0% with placebo). Pazopanib was associated with a greater frequency of elevated hepatic enzymes (occurring in up to 5% of patients), and this condition reversed when therapy was stopped.
Results of a Global Phase II Study With Crizotinib in Advanced ALK-Positive Non-Small Cell Lung Cancer (NSCLC)
In lung adenocarcinomas, the most common mutations involve KRAS and EGFR, although approximately 35% of lung adenocarcinomas have unknown mutations. Gene rearrangements of anaplastic lymphoma kinase (ALK) have been identified in approximately 3–5% of NSCLCs, and these occur most frequently in adenocarcinomas. Crizotinib (PF-02341066) is an oral ALK inhibitor that demonstrated a 61% response rate and 10-month median PFS in a phase I study.1
Updated data from the subsequent phase II study of crizotinib in patients with previously treated, advanced ALK-positive NSCLC (NCT0032451) were presented.2 This phase II, single-arm, multicenter study has enrolled approximately 1,100 patients, and enrollment is ongoing. The key eligibility criteria are ALK-positive NSCLC, as determined by the central laboratory; ECOG PS of 0–3; and history of 1 or more prior lines of chemotherapy. Patients with stable or controlled brain metastases are allowed to enroll. Enrolled patients receive continuous dosing with oral crizotinib 250 mg twice daily. The primary endpoints are ORR and safety/tolerability. Of the 259 patients who were evaluable for response, 4 (2%) had a complete response (CR), 151 (58%) had a partial response (PR), 69 (27%) had stable disease (SD), and 19 (7%) had progressive disease (PD). The median PFS was 8 months (95% CI, 7–10 months), and 28% of patients were in follow-up for progression. Figure 2 shows the best response of indicator lesions in 240 response-evaluable patients, excluding those with early death, indeterminate response, and non-measurable disease.
A total of 18 patients with asymptomatic, non-irradiated brain metastases were evaluable for both brain and systemic disease. Of these 18 patients, 2 (11%) had a CR, 2 (11%) had a PR, 12 (67%) had SD, and 2 patients (11%) had PD.
The most frequent treatment-related AEs, which were mostly grade 1 and 2, were visual effects (50%), nausea (46%), vomiting (39%), and diarrhea (35%). Treatment-related serious AEs were reported for 29 patients (6.6%). They included dyspnea and pneumonitis (4 patients each, 0.9%), as well as febrile neutropenia and renal cysts (2 patients each, 0.5%).
The researchers concluded that crizotinib treatment led to a response rate of 60% and median PFS of
8 months. Crizotinib continued to show a good safety profile in patients with previously treated ALK-positive advanced NSCLC. The researchers noted that clinically meaningful improvement was observed in global quality of life, and in such lung cancer symptoms as fatigue, cough, dyspnea, and chest pain. The data are consistent with the efficacy and safety findings previously reported. The data further support the use of crizotinib in patients with ALK-positive lung cancer, and provide strong evidence for its use as standard of care for advanced ALK-positive NSCLC.
1. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13:1011-1019.
2. Riely GJ, Evans TL, Salgia R, et al. Results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC). Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract 3.
A Randomized, Open-label, Phase 3, Superiority Study Of Pemetrexed (Pem)+Carboplatin (Cb)+Bevacizumab (B) Followed By Maintenance Pem+B Versus Paclitaxel (Pac)+Cb+B Followed By Maintenance B In Patients (pts) With Stage IIIB Or IV Non-squamous Non-small Cell Lung Cancer (NS-NSCLC)
Platinum-based chemotherapy combinations are recommended for first-line treatment of advanced NSCLC.1 For patients with nonsquamous NSCLC in the United States, 2 regimens are widely used because they improve survival. The regimen of paclitaxel, carboplatin, and bevacizumab, followed by bevacizumab maintenance, improves response rates, PFS, and OS, and it is approved for first-line treatment of nonsquamous NSCLC.2 The other regimen, cisplatin and pemetrexed, is preferred because of its non-inferiority to cisplatin and gemcitabine and its improved toxicity profile.3 The regimen of cisplatin and pemetrexed followed by continuation maintenance therapy with pemetrexed also led to improvements in PFS and OS.4,5 Finally, the previously reported phase II single-arm study that combined pemetrexed, carboplatin, and bevacizumab for 6 cycles, followed by maintenance with pemetrexed and bevacizumab, demonstrated a promising OS of 14.1 months and PFS of 7.8 months.6
These findings led to the PointBreak (A Randomized, Open-label, Phase 3, Superiority Study Of Pemetrexed [Pem]+Carboplatin [Cb]+Bevacizumab [B] Followed By Maintenance Pem+B Versus Paclitaxel [Pac]+Cb+B Followed By Maintenance B In Patients [pts] With Stage IIIB Or IV Non-squamous Non-small Cell Lung Cancer [NS-NSCLC]) trial, which was designed as a superiority study to compare a treatment arm of pemetrexed, carboplatin, and bevacizumab followed by maintenance with pemetrexed and bevacizumab (the pemetrexed arm) to an arm with paclitaxel, carboplatin, and bevacizumab followed by bevacizumab maintenance (the paclitaxel arm).7 Patients were randomized 1:1 to the 2 study arms. The study was conducted in the United States at 147 sites. It was designed to compare survival from time of initial therapy for patients with stage IIIB or IV nonsquamous NSCLC, as defined by the American Joint Committee on Cancer’s sixth edition of their staging manual.8 Importantly, patients with stable, treated brain metastases were allowed to enroll. Other inclusion criteria were no prior systemic therapy for lung cancer, PS of 0 or 1, and stage IIIB or IV nonsquamous NSCLC. Exclusionary criteria were pre-existing neuropathy of grade 1 or higher, along with uncontrolled pleural effusions.
Survival was calculated from the time of randomization through induction, maintenance, and onward. The primary objective was to demonstrate a 20% improvement in survival for patients treated in the pemetrexed arm compared with the paclitaxel arm. This objective required 676 events in 900 patients for 80% power and a 1-sided error of 0.025.
The trial was also designed to evaluate PFS, time to PD, ORR, safety, and patient-reported outcomes. (The patient-reported outcomes will be presented at a forthcoming meeting.) The prespecified but exploratory analyses were OS, PFS in the maintenance population, and PFS without grade 4 toxicity. For the endpoint of PFS without grade 4 toxicity, an event was defined as either PD or the occurrence of grade 4 toxicity.
Enrollment in the study began on December 30, 2008, and the database log occurred on May 17, 2012. A total of 1,259 patients enrolled so that 939 patients could be randomized, which eventually resulted in 292 patients on maintenance with pemetrexed and bevacizumab and 298 patients on maintenance with bevacizumab alone. The vast majority of patients who discontinued the study did so because of PD.
Treatment arms were well balanced. Median age was 75.0 years in the pemetrexed arm and 72.4 years in the paclitaxel arm. Notably, African-American enrollment was 10% across the entire study, which aligns well with US census data and differs from the 5% representation among the current trials reported at the 2012 meeting of the American Society of Clinical Oncology (ASCO).
From the time of randomization to initial therapy, PFS was improved in the pemetrexed arm (median 6.0 months in the pemetrexed arm vs 5.6 months in the paclitaxel arm; HR=0.83; P=.012). Both arms had similar response rates (34.1% with pemetrexed and 33.0% with paclitaxel), which were consistent with previously recorded results. Almost all subgroups slightly favored pemetrexed, although the 172 patients with other or indeterminate histology had PFS that appeared to favor paclitaxel (HR=1.19), without reaching significance.
From the time of randomization in the ITT population, the Kaplan-Meier OS curves are superimposable for the 2 arms (Figure 3). The HR is 1.00 (95% CI, 0.86–1.16; P=.949). The pemetrexed arm did not have improvement. Similarly, OS was not affected by subgroup, although the small number of patients with large cell histology seemed to have improved OS with pemetrexed (HR=0.53), and those with other or indeterminate histologies seemed to have improved OS with paclitaxel (HR=1.36).
Although the trial was designed to evaluate OS improvements in the ITT populations from the time of randomization prior to induction therapy, a prespecified and exploratory analysis of PFS in the maintenance population was also planned. Patients who had at least stable or responsive disease during the 4 cycles of induction demonstrated PFS of 8.6 months in the pemetrexed arm (n=292) and 6.9 months in the paclitaxel arm (n=298). This population had demographics that were very similar to the ITT population. For patients who received maintenance therapy, the OS was 17.7 months in the pemetrexed arm and 15.7 months in the paclitaxel arm. Among the group of patients who did not go on to receive maintenance—largely because of PD or toxicity—the median OS was only 4.6 months in the pemetrexed arm and 6.1 months in the paclitaxel arm.
Toxicities related to the study drugs were evaluated among patients who received at least 1 dose of the study drug. Both regimens were tolerable overall. However, the toxicity parameters had significant differences. Pemetrexed was associated with significantly more anemia (grade 1/2, 31.0% for pemetrexed vs 24.4% for paclitaxel; grade 3/4, 14.5% vs 2.7%, respectively) and thrombocytopenia (grade 1/2, 17.9% vs 17.2%, respectively; grade 3/4, 23.3% vs 5.6%, respectively), whereas paclitaxel was associated with more neutropenia (grade 3/4, 40.6% for paclitaxel vs 25.8% for pemetrexed) and febrile neutropenia (grade 3/4, 4.1% vs 1.4%, respectively). A total of 18 grade 5 AEs occurred. Importantly, none of the grade 5 hemorrhages were related to grade 3 or 4 thrombocytopenia, which is a complication of post-discontinuation therapies (treatment at second-line or progression and beyond). Only 53% of patients in the pemetrexed arm went on to receive second-line therapies or beyond, whereas 59% of patients in the paclitaxel arm went on to receive second-line therapies or beyond.
In conclusion, the primary endpoint of superior OS was not met in this trial. The HR was 1, and the lines were superimposable. The efficacy, response rates, and survival were similar to previously published data for paclitaxel, carboplatin, and bevacizumab followed by bevacizumab maintenance.2 Patients who received pemetrexed, carboplatin, and bevacizumab followed by maintenance therapy had superior PFS compared with those who received paclitaxel, carboplatin, and bevacizumab followed by maintenance therapy
(6.0 months vs 5.6 months). In a prespecified, exploratory, noncomparative analysis of the maintenance population, OS was 17.7 months in the pemetrexed arm and 15.7 months in the paclitaxel arm. The regimens have different toxicity profiles, but both are considered tolerable.
1. Azzoli CG, Baker S Jr, Temin S, et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol. 2009;27:6251-6266.
2. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542-2550.
3. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543-3551.
4. Paz-Ares L, de Marinis F, Dediu M, et al. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012;13:247-255.
5. Paz-Ares L, De Marinis F, Dediu M, et al. PARAMOUNT: final overall survival (OS) results of the phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo (plb) plus BSC immediately following induction treatment with pem plus cisplatin (cis) for advanced nonsquamous (NS) non-small cell lung cancer (NSCLC). J Clin Oncol. 2012;30: Abstract LBA7507.
6. Patel JD, Hensing TA, Rademaker A, et al. Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer. J Clin Oncol. 2009;27:3284-3289.
7. Patel JD, Socinski MA, Garon EB, et al. A randomized, open-label, phase III, superiority study of pemetrexed (Pem) + carboplatin(Cb) + bevacizumab(Bev) followed by maintenance Pem + Bev versus paclitaxel (Pac)+Cb+Bev followed by maintenance Bev in patients with stage IIIB or IV non-squamous non-small cell lung cancer (NS-NSCLC). Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract LBPL1.
8. Greene F, Page D, Fleming I, eds. Lung. In: AJCC Cancer Staging Manual. Sixth edition. Chicago, Illinois: American Joint Committee on Cancer; 2002.
Dacomitinib (D) Versus Erlotinib (E) in Patients (pt) With EGFR-Mutated (mu) Advanced Non-Small Cell Lung Cancer (NSCLC): Analyses From a Randomized, Phase 2 Trial
Among EGFR-mutated advanced NSCLC patients receiving second- or third-line treatment, dacomitinib had superior PFS compared with erlotinib (HR=0.46; 95% CI, 0.18–1.18; 2-sided P=.098). Both arms had a median PFS of 32 weeks (95% CI, 17–80 weeks for dacomitinib and 11–48 weeks for erlotinib). This subset analysis is the first to compare a pan-HER tyrosine-kinase inhibitor, which acts irreversibly across the kinase-active members of the HER family, to a selective, reversible EGFR tyrosine-kinase inhibitor (Abstract 2). Among the 188 patients enrolled in this randomized, phase II trial, EGFR mutations occurred in 19 patients receiving dacomitinib and in 11 patients receiving erlotinib. The ORR was 58% (95% CI, 33.5–79.7) for patients treated with dacomitinib and 36% (95% CI, 10.9–69.2) for patients treated with erlotinib (P=.26). Among the patients with mutations in exon 19 of EGFR (8 in each arm of the trial), the PFS HR (dacomitinib vs erlotinib) was 0.27 (95% CI, 0.076–0.94; 2-sided P=.028). These patients had a median PFS of 77 weeks (95% CI, 32.3–NA) with dacomitinib and 24 weeks (95% CI, 11.4–NA) with erlotinib. The small sample size does not allow definitive conclusions regarding whether mutations in exon 19 are predictive of treatment effects. The most frequently reported AEs were diarrhea, acneiform dermatitis, stomatitis, decreased appetite, mucosal inflammation, and paronychia. These events were mostly grade 1/2, and they were manageable with standard supportive care. One grade 4 treatment-related AE occurred with dacomitinib, which was increased blood creatinine.
Accuracy of Fine Needle Aspiration and Core Lung Biopsies to Predict Histology in Patients With Non Small Cell Lung Cancer
Although treatment decisions in NSCLC are guided by histologic diagnosis, the overall concordance rate between preoperative and final histologic subtype is only 67.2% (80/119 patients with NSCLC). Such data guide the treatment of patients with nonsquamous NSCLC, who are treated exclusively with pemetrexed and bevacizumab. This retrospective review of 295 lobectomies in 117 patients at the University of Arkansas between 2002 and 2011 sought to determine how accurately the histologic subtype of primary NSCLC can be determined by fine needle aspiration and core lung biopsies (Abstract LBOA2). The included histologic subtypes were squamous, nonsquamous, and adenosquamous. Patients had a final diagnosis of primary NSCLC and a preoperative biopsy performed by bronchoscopy or computed tomography (CT) guidance. From preoperative to final histologic subtype, the nonsquamous histology increased from 43% to 56%, squamous from 31% to 36%, and adenosquamous from 2% to 8%. A total of 29 preoperative biopsies did not specify a histologic subtype, and 10 preoperative biopsies changed histologic subtype. The most common change from preoperative subtype to final histologic subtype was from NSCLC to nonsquamous (11 patients). Data on pemetrexed for nonsquamous NSCLC were first presented at the 2007 ASCO annual meeting, but concordance rates were not significantly different before and after pemetrexed data were presented and published. Further, concordance rates did not have statistically significant differences based on tumor location (P=.630), type of biopsy procedure (P=.773), preoperative stage (P=.995), postoperative stage (P=.443), or differentiation (P=.061). No factors have been identified to predict which patients are at higher risk for an inaccurate histologic diagnosis.
The Select Study: a Multicenter Phase II Trial of Adjuvant Erlotinib in Resected Epidermal Growth Factor Receptor (EGFR) Mutation-Positive Non-Small Cell Lung Cancer (NSCLC)
Adjuvant chemotherapy for NSCLC results in modest improvements, with an OS benefit of approximately 5–10% seen at 5 years, which is predominantly in stage II and III NSCLC. However, many patients still relapse after treatment with adjuvant chemotherapy.1
In the metastatic setting, tumors with mutations activating epidermal growth factor receptor (EGFR) are very sensitive to EGFR inhibitors.2,3 A retrospective cohort study showed a 2-year disease-free survival (DFS) of 89% in patients whose EGFR-mutant tumors were treated with erlotinib or gefitinib versus 72% in untreated patients.4 The Select study of adjuvant erlotinib was a single-arm, phase II study in patients with surgically resected, stage I–III NSCLC whose tumors harbored EGFR mutations.5 Patients received adjuvant erlotinib 150 mg daily for 2 years. They were scanned by CT every 6 months for 3 years, and then annually for years 4 and 5 during the observation period. The primary endpoint was DFS, and the 2-year target was 86%. The secondary endpoints were OS, safety, and tolerability.
The characteristics among the 36 enrolled patients were as expected for a trial that selected patients with EGFR-mutant tumors. Most patients were women (75%), never-smokers (56%), and non-Asian (89%), since the trial was conducted in the United States. More than half of patients had stage I disease (53%; stage IB, 39%; stage IA, 14%). Disease stages II and III were less prevalent (19% and 28%, respectively).
Mutation analysis found that 22 patients had EGFR exon 19 deletions (61%), 13 patients had L858R mutations (36%), and 1 patient had the L861Q mutation (3%). All types of EGFR-sensitizing mutations were allowed in the study, except for such mutations as exon 20 insertions or T790.
After a median follow-up of 2.7 years, the DFS rate was 94% (95% CI, 80–90%). Only 2 patients died of recurrent disease, and all other patients remained alive.
The AEs were as expected for adjuvant erlotinib and predominantly included rash (89%), diarrhea (78%), and fatigue (61%). Dose reductions occurred due to rash, transaminitis, diarrhea, fatigue, hyperbilirubinemia, and urticaria. Doses were reduced to 100 mg daily for 8 patients (22%) and 50 mg daily for 5 patients (14%). A total of 69% of patients completed more than 90% of the full 2 years of treatment. A total of 11 patients (31%) discontinued before they had been treated for 2 years. Among the patients who stopped the study, some did so because of toxicities (n=6), which were mainly diarrhea, rash, or fatigue. Other reasons for going off study were patient preference (n=3), travel, and, for 1 patient, the development of incidental prostate cancer. One patient came off study due to recurrence.
Among the 12 patients who had progressed to date, some completed 2 years of therapy and some did not. Only 1 patient progressed while on adjuvant therapy. The remainder progressed 3–24 months after finishing treatment with adjuvant erlotinib. Sites of progression varied, with some patients having a solitary recurrence in the brain, lung, or bone. Others had multifocal recurrence in a metastatic fashion. Among evaluated patients who received erlotinib after they progressed, all responded and all remained on erlotinib at the time of the study presentation, which ranged from 4 months
to 26 months after recurrence.
Treatment with adjuvant erlotinib was feasible for patients with EGFR-mutated NSCLC. Many patients required a dose reduction or discontinued treatment. The primary endpoint of 2-year DFS was met at a rate of 94%. Adjuvant erlotinib seems to have, at the very least, a cytostatic effect on micrometastatic disease, as only 1 patient recurred during treatment. Although patients recurred at various times after treatment, a possible genetic mechanism of resistance was identified in only 2 of the 8 recurrent tumors. All evaluable patients who restarted erlotinib for metastatic disease had a response.
This trial has subsequently expanded from 36 patients to a total of 100 patients in order to permit subgroup analysis by stage. Enrollment is complete, and final results of the subgroup analysis are expected within a few years.
1. Arriagada R, Dunant A, Pignon JP, et al. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant Cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010;28:35-42.
2. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129-2139.
3. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957.
4. Janjigian YY, Park BJ, Zakowski MF, et al. Impact on disease-free survival of adjuvant erlotinib or gefitinib in patients with resected lung adenocarcinomas that harbor EGFR mutations. J Thorac Oncol. 2011;6:569-575.
5. Neal JW, Pennell NA, Govindan R, et al. The Select study: a multicenter phase II trial of adjuvant erlotinib in resected epidermal growth factor receptor (EGFR) mutation-positive nonsmall cell lung cancer (NSCLC). Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract 16.
Evaluation of VeriStrat in the Randomized, Placebo-Controlled, Phase II Trial of Erlotinib and High-Dose Celecoxib in Advanced Non-Small Cell Lung Cancer
VeriStrat is a commercially available, pretreatment serum test that classifies NSCLC patients as likely to have “Good” or “Poor” outcomes after treatment with erlotinib. A limited population of patients with NSCLC receives a significant benefit from EGFR inhibitor therapy. When EGFR is activated, COX-2 expression is upregulated, which can increase the expression of EGFR ligands. This study enrolled 107 patients with stage IIIB or IV NSCLC. Patients were randomized to receive erlotinib and high-dose celecoxib or erlotinib and placebo, and 96 samples were classified by VeriStrat (Abstract LBOA1). The correlation between
VeriStrat classification and durable clinical response was significant in the combined arms (P=.010) and in the arm of patients receiving erlotinib and high-dose celecoxib (P=.008). ORR was significantly correlated with VeriStrat status in the combined arm (P=.002). VeriStrat classification was not significantly correlated with mutation status. Patients whose VeriStrat classification was Good had a longer PFS (P<.0001) and OS (P<.0001) in the erlotinib and high-dose celecoxib arm, and a longer OS (P=.001) in the erlotinib and placebo arm. When VeriStrat Good status was stratified by EGFR mutation status, patients with wild-type EGFR had improved PFS from the addition of high-dose celecoxib, while those with EGFR mutations did not likely benefit from the high-dose celecoxib. VeriStrat may be useful to identify NSCLC patients with Good classification who will benefit from combining high-dose celecoxib with erlotinib.
Ablative Local Therapy Extends the Clinical Benefit of Crizotinib in ALK-Positive Lung Cancer
Among ALK-positive NSCLC patients treated with crizotinib who had oligoprogression, treatment with ablative local therapy caused minimal toxicity and allowed patients to gain 9 months of additional clinical benefit from crizotinib, along with improved OS (Abstract 21). Oligoprogression was defined as the emergence of 5 or fewer sites of disease that were resistant to crizotinib and outside the central nervous system. This approach of treating disease that is oligoprogressive and crizotinib-resistant departs from the traditional method of changing systemic therapy at the first sign of progression. The study enrolled 38 patients with metastatic ALK-positive NSCLC. The patients were followed by surveillance scans every 6–8 weeks. When oligoprogression was found, ablative local therapy was performed through either hypofractionated radiotherapy or surgery. If the patient was still receiving clinical benefit, crizotinib was continued. Clinical benefit was defined as sustained control of other disease sites outside the central nervous system and minimal toxicity. Disease progression in the central nervous system was treated with local therapy. Crizotinib was discontinued if toxicity was unacceptable or if the disease progressed beyond oligoprogression. Patients were followed for a median of 19.6 months (range, 2–32 months). Of the 10 patients who experienced oligoprogression, it occurred at a median of 6.5 months (range, 2–24 months) after crizotinib was initiated. The clinical benefit from crizotinib was extended by ablative local therapy by 9.2 months. Among the 10 patients who received ablative local therapy, the median time on crizotinib was 17.4 months, while the other 28 patients received crizotinib for a median of 12.6 months. Additionally, the 1-year actuarial OS was 100% for the patients who received crizotinib and ablative local therapy, compared with 70% for those who received crizotinib alone (P=.002).
Clinical Activity and Safety of Anti-PD-1 (BMS-936558, MDX-1106) in Patients (Pts) With Advanced Non-Small-Cell Lung Cancer (NSCLC)
The programmed death-1 (PD-1) pathway is important in T-cell activation, and its role in NSCLC requires further study. Expression of PD-1 on tumor infiltrating lymphocytes decreases cytokine production and effector function.1,2 The expression of PD-L1 has been noted in NSCLC.3 Increased PD-1 expression on tumor cells is correlated with an increased number of tumor-infiltrating lymphocytes in the same region.4
Activated T cells express the PD-1 co-inhibitory receptor, which is blocked by the fully human, monoclonal antibody BMS-936558.5 This interim analysis demonstrated that BMS-936558 mediates anti-tumor activity in heavily pretreated patients with advanced NSCLC.6 The analysis was conducted in a large, phase I, multi-dose study that administered the antibody intravenously once every 2 weeks for an 8-week treatment cycle. The doses were 0.1, 1, 3, or 10 mg/kg during the dose escalation and cohort expansion phases. The study included patients with advanced melanoma, renal cell cancer, NSCLC, colorectal cancer, and prostate cancer. These patients had PD and were heavily pretreated with up to 5 prior regimens. Patients received 4 doses of treatment per cycle for up to 12 cycles. Patients remained on study if they had a response, SD, or even progression or clinical stability; treatment lasted for up to 96 weeks. Patients went off study if they had unacceptable toxicity, confirmed PD, or complete response. The primary objective was to assess safety and tolerability when the antibody was administered once every 2 weeks. Secondary objectives included assessing anti-tumor activity and evaluating pharmacodynamics. The initial activity observed in the dose-escalation portion of the study (particularly in NSCLC) led to enrolling the expansion cohorts at 3 different dose levels. Equal numbers of patients with NSCLC were randomized between
3 dose levels of 1, 3, or 10 mg/kg, for a total of 32 patients on each dose level. The study enrolled equal numbers of patients with squamous and nonsquamous histology. A total of 122 patients with NSCLC were followed for safety, and 76 patients with NSCLC were followed for clinical activity. This analysis included patients treated through February 2012 who had been evaluated or followed for at least 6 months.
The safety population of 120 new patients had a mean age of 65 years, and most were men (61%). Patients were divided between squamous cell histology (39%) and nonsquamous cell histology (60%). Most patients had good ECOG PS (0 for 34 patients, 1 for 83 patients, 2 for 2 patients, and not reported for 3 patients). The number of prior therapies was 1 for 18 patients, 2 for 31 patients, 3 for 27 patients, and 4 or more for 40 patients. Platinum-based therapies had been administered in 94% of patients, and 34% had received a prior tyrosine kinase inhibitor.
BMS-936558 was generally well tolerated. AEs occurred in 64% of NSCLC patients. The maximum tolerated dose was not found. At the doses of up to 10 mg/kg included in this study, no relationship was apparent between dose and AE frequency. In the NSCLC patients, the common drug-related AEs were fatigue (18%), decreased appetite (10%), anemia (8%), nausea (7%), pyrexia (6%), and diarrhea (6%). Such events were consistent with the immunogenic activity of BMS-936558. Grade 3–5 related AEs occurred in 8% of the NSCLC patients. In patients with NSCLC, fatigue was the most common grade 3/4 toxicity (2% of patients). Grade 1/2 pneumonitis occurred in 6 (2%) patients, including 4 (3%) NSCLC patients. Among the patients with pneumonitis, 3 drug-related deaths occurred (2 patients with NSCLC and 1 with colorectal cancer).
Among the 76 patients with NSCLC who were evaluable for clinical activity, the ORR was 18% (Table 2). There were 14 cases of PR, which occurred at doses of 1 (1 of 18 patients), 3 (6 of 19 patients), and 10 mg/kg (7 of 39 patients), resulting in response rates of 6%, 32%, and 18%, respectively. Two additional NSCLC patients who had received the antibody at a dose of 10 mg/kg were awaiting a confirmatory scan, and thus had unconfirmed PRs.
The anti-PD-1 antibody was active in both squamous and nonsquamous NSCLC histologies. Responses occurred in 6 of the 18 patients with squamous histology (33%) and in 7 of the 56 patients with nonsquamous histology (12.5%). All 14 of the responding patients began treatment more than 24 weeks before the analysis, and 8 of these patients had a response that lasted 24 weeks or longer. Further, 3 patients had a persistent decrease in overall tumor burden in the presence of new lesions, so they were not classified as responders.
BMS-936558 can be administered safely in heavily pretreated NSCLC patients in an outpatient setting. BMS-936558 is well tolerated. The clinical activity of BMS-936558 in patients with previously treated, advanced NSCLC is encouraging and warrants further development of this agent in patients with advanced NSCLC.
1. Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114:1537-1544.
2. Zhang Y, Huang S, Gong D, Qin Y, Shen Q. Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer. Cell Mol Immunol. 2010;7:389-395.
3. Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol. 2011;28:682-688.
4. Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res. 2004;10:5094-5100.
5. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167-3175.
6. Brahmer JR, Horn L, Antonia SJ, et al. Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in patients (Pts) with advanced non-small-cell lung cancer (NSCLC). Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract 4.
Clinical Behavior of Lung Cancers Harboring EGFR Exon 20 Insertions
While patients with EGFR exon 20 insertions have similar clinical characteristics as other patients with EGFR mutations, they tend to do poorly on tyrosine kinase inhibitors and have a shorter survival. The subset of EGFR exon 20 insertions is the third most common family of EGFR mutations in NSCLC, representing 9% of EGFR-mutant lung cancers. Patients with EGFR exon 20 insertions are an attractive population for trials of new targeted therapies. This study reviewed an institutional database of 951 patients with NSCLC who underwent EGFR sequencing (Abstract 10). Of these, 233 patients had an EGFR mutation, and 25 (11%, or 2.6% of all patients) had an insertion in exon 20. The patients with insertions in exon 20 and those with other EGFR mutations were more often never-smokers (56% and 53%) and Asian (16% and 12%) than the patients with wild-type EGFR (21% never-smokers, P<.001 for both subgroup comparisons; 3.8% Asian, P=.02 vs exon 20 insertions and P<.001 vs other EGFR mutations). Among patients with insertions in exon 20 of EGFR who had evaluable disease, the greatest activity occurred with platinum-based chemotherapy (mean time to progression, 6.3 months; range, 1.5–19 months; n=17; P=.001), compared with 3.1 months on initial exposure to erlotinib or gefitinib (range, 1–4.1 months, n=9). Among 22 patients with exon 20 insertions, median survival for advanced disease was 19 months, which was shorter than the 31-month median survival observed in 166 patients with other EGFR mutations (P=.002) and similar to the 21-month median survival of the 561 patients with wild-type EGFR.
Clinical Activity of Crizotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring ROS1 Gene Rearrangement
A new molecular subset of NSCLC is defined by chromosomal rearrangements of the ROS1 receptor tyrosine kinase gene.1,2 The ROS1 gene encodes a tyrosine kinase receptor, and ROS1 is most closely related to other tyrosine kinases in the insulin receptor super-family. Rearrangements of ROS1 in cell lines lead to expression of ROS1 fusion kinases and sensitivity to the inhibition of ROS kinase.3 The primary mechanism that activates ROS1 in lung cancer and other cancers is chromosomal rearrangement, and a number of ROS1 rearrangements can occur in nonsquamous lung cancer. These rearrangements lead to aberrant expression of ROS1 and constitutive activation of its tyrosine kinase.
Rearrangements of ROS1 are rare in nonsquamous NSCLC, occurring in only approximately 1% of patients.4 Lung cancer patients who have ROS1 rearrangements tend to be younger in age and light or never-smokers, and almost all have adenocarcinoma histology.2 In general, ROS1 rearrangements are mutually exclusive with other oncogenic drivers.5
Crizotinib is a small-molecule tyrosine kinase inhibitor of MET, ALK, and ROS1. Crizotinib was originally developed as a potent tyrosine kinase inhibitor of c-MET, and was subsequently found to inhibit other tyrosine kinases, including ALK and ROS1.3 More than 600 cell lines were screened for sensitivity to TAE684, a very potent ALK inhibitor.6 Among the top 10 most sensitive cell lines, 8 had known alterations in ALK. Interestingly, 1 of the sensitive lines was HCC-78, a nonsquamous NSCLC cell line that harbors a ROS1 rearrangement. This cell line screen showed that an ALK inhibitor could have activity in ROS1.
The phase I study of crizotinib included a dose-escalation phase followed by dose expansion. The molecular cohorts were specified, with a molecular expansion cohort included for ROS1 patients. Patients were screened for ROS1 by break-apart fluorescence in situ hybridization (FISH) assay. This study examined the efficacy and safety of crizotinib in patients with advanced, ROS1-rearranged NSCLC.7 As of April 2012, 15 ROS1-positive patients had received crizotinib, 12 patients were receiving ongoing crizotinib treatment, and 3 patients had discontinued due to disease progression. Data were presented on 14 of the 15 patients who were evaluated for a response (Figure 4). The ROS1-positive patients had a median age of 54 years (range, 31–72 years), and all but 1 were never-smokers. All patients had adenocarcinoma histology. All but 2 of these patients had been previously treated with chemotherapy.
To date, 8 of 12 patients had confirmed CR or PR. Two patients were characterized with SD, and 2 with PD. In 1 of the patients with PD, crizotinib had been discontinued for 6 weeks. He received a scan for unrelated bowel obstruction during the time crizotinib was discontinued. When he went back on crizotinib, his tumor was reduced to approximately 60%. The other patient with PD was initially characterized as ROS1-positive and did have progression on the first scans. When the molecular pathologist revisited his tumor, it was found to have an atypical ROS1 FISH, and he was in fact ROS1-negative.
Typical examples of responses to crizotinib in ROS1-positive patients include a 40-year-old never-smoker who had extensive disease when she started on the trial. She was treated with crizotinib and had a dramatic response after just 4 weeks. Her symptoms also improved greatly, and her disease remained under control for approximately 12 months. Another patient also had extensive disease when he started on the trial; after just 3 months of crizotinib, his disease completely resolved.
The ORR of the 14 ROS1-positive patients treated with crizotinib was 57%. The median duration of treatment was close to 26 weeks. The treatment-related AEs and safety profile of crizotinib were almost identical to what has been seen in ALK-positive patients.
In summary, ROS1 rearrangement does seem to define a new, distinct molecular subset of lung cancer. Crizotinib has marked anti-tumor activity in patients with advanced, ROS1-positive lung cancer. These results are the first to validate ROS1 as a therapeutic target in lung cancer.
1. Janne PA, Meyerson M. ROS1 rearrangements in lung cancer: a new genomic subset of lung adenocarcinoma. J Clin Oncol. 2012;30:878-879.
2. Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012;18:378-381.
3. Cui JJ, Tran-Dube M, Shen H, et al. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem. 2011;54:6342-6363.
4. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30:863-870.
5. Rimkunas VM, Crosby KE, Li D, et al. Analysis of receptor tyrosine kinase ROS1-positive tumors in non-small cell lung cancer: identification of a FIG-ROS1 fusion. Clin Cancer Res. 2012;18:4449-4457.
6. McDermott U, Iafrate AJ, Gray NS, et al. Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res. 2008;68:3389-3395.
7. Shaw AT, Camidge D, Clark JW, et al. Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract 15.
LUX-Lung 3: A Randomized, Open-Label, Phase III Study of Afatinib vs Pemetrexed and Cisplatin as First-Line Treatment For Patients With Advanced Adenocarcinoma of the Lung Harboring EGFR-Activating Mutations (Subgroup Analysis)
Afatinib is an irreversible ErbB family blocker that prevents the homodimerization and heterodimerization of the ErbB family receptor.1,2 Afatinib has known efficacy in lung adenocarcinoma patients with EGFR mutations.3 This study was designed to compare afatinib with the now commonly prescribed combination of pemetrexed and cisplatin. Enrollment included 345 patients with stage IIIB or IV advanced lung adenocarcinoma and proven EGFR mutations, as determined in a central screening facility using the TheraScreen polymerase chain reaction (PCR)-based test. Patients were randomized 2:1 to receive afatinib 40 mg daily continuous dosing or chemotherapy with cisplatin and pemetrexed at standard doses every 21 days for up to 6 cycles. The primary endpoint was PFS, as determined by independent review, and secondary endpoints included ORR, time to deterioration in cancer-related symptoms, and safety. A subgroup analysis was planned among patients with common mutations (Del19/L858R). The median PFS for all patients receiving afatinib was 11.1 months, which was more favorable than the 6.9-month PFS for patients receiving chemotherapy with pemetrexed and cisplatin (HR=0.58 [95% CI, 0.43–0.78]; P=.0004; Table 3). The ORR was higher with afatinib (56% vs 23%; P<.0001). Patients receiving afatinib had a significant delay in the time to deterioration of cancer-related symptoms of cough (HR=0.60; P=.0072) and dyspnea (HR=0.68; P=.0145) compared with chemotherapy. The most common drug-related AEs seen with afatinib were diarrhea (95%), rash (89%), and paronychia (57%). Nausea (66%), decreased appetite (53%), and vomiting (42%) were the most common AEs related to chemotherapy. Treatment was discontinued due to drug-related AEs in 8% of patients receiving afatinib and in 12% of patients receiving chemotherapy with pemetrexed and cisplatin.
Subgroup analyses found that 49% (n=170) of patients had the Del19 mutation and 40% (n=138) had L858R. All of the patients with these 2 common mutations benefited from afatinib treatment compared with chemotherapy (HR=0.47; P<.0001). Among the 72% of patients who were Asian, afatinib provided a strong benefit compared with chemotherapy (HR=0.44; 95% CI, 0.30–0.63). Asian patients may have had a modestly greater benefit with a slightly longer median PFS and lower HR compared with non-Asian patients.
The distribution of diarrhea, rash, and acneiform rash associated with afatinib treatment was fairly similar across races. However, Asians had higher incidences of paronychia, dry skin, and decreased appetite with afatinib than non-Asians. Among patients treated with chemotherapy, side effects again differed by race, with decreased appetite, vomiting, neutropenia, and leukopenia being more common for Asians than for non-Asians.
Among patients with common EGFR mutations, afatinib offered significant benefit in terms of relieving lung cancer–related symptoms like cough, dyspnea, and pain, with statistical significance for cough and dyspnea. Pain trended in the same direction but did not reach statistical significance.
In summary, LUX-Lung 3 is the largest global prospective trial involving EGFR mutation-positive NSCLC patients to date. It is the first trial to compare a genotype-directed strategy against one of the most commonly used chemotherapy regimens, cisplatin and pemetrexed. It is also the first clinical trial of this design to be performed in both Asian and non-Asian patients. LUX-Lung 3 met its primary endpoint of PFS by independent radiology review, and it showed a consistent efficacy across all patient subgroups. The efficacy was particularly notable in the largest subset of patients, which included those with the common mutations Del19 and L858R. The safety profile is consistent with previous afatinib trials. Interestingly, toxicity appears to be milder in non-Asian patients. Therefore, afatinib is a first-line treatment option for patients with EGFR-mutated NSCLC.
1. Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008;27:4702-4711.
2. Solca F, Dahl G, Zoephel A, et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther. 2012;343:342-350.
3. Yang JC, Shih JY, Su WC, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 2012;13:539-548.
Corey J. Langer, MD, FACP
Professor of Medicine Hematology-Oncology Division University of Pennsylvania Philadelphia, Pennsylvania
For those of us treating patients with advanced non–small cell lung cancer (NSCLC), we have embarked on a new era of personalized therapy dictated by both the unique histology and the molecular fingerprints of the tumor under scrutiny. Our customized strategies have largely replaced the “one size fits all” approach to which we previously defaulted. Recent advances in NSCLC were highlighted in a number of provocative presentations at the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology.
Histology is a critical component in individualizing treatment for patients with NSCLC. The presentation by Robertson1 and associates addressed the issue of specimen adequacy. Of particular interest was the relatively low overall concordance rate between preoperative and final histologic subtype of 67.2% (80/119 patients with NSCLC). This is concerning, as we are frequently forced to deal with a relatively small specimen at initial diagnosis. Trying to do more with less has been the preferred method, but this observational analysis underscores the hazard of such an approach. It is clear that initial histologic analysis may lead us down the wrong path. Newer treatment strategies are more complex; certain novel therapeutics are restricted to specific histologic or molecular subtypes. This requires more precise classification and performance of molecular testing for actionable biomarkers, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations. This problem may be exacerbated in advanced NSCLC, where fine needle aspiration is likely to be inadequate in obtaining sufficient tissue for histologic and molecular analysis. A diagnostic strategy for small biopsies lacking differentiation criteria relies on immunohistochemical (IHC) markers that lead to a speciﬁc diagnosis in more than 80% of small biopsies. The focus, however, should not be on using an excessive number of IHC stains, but instead on conserving tissue for molecular analysis. Our philosophy has changed in the last 5–7 years; it should take relatively few stains to differentiate adenocarcinoma from squamous cell carcinoma in questionable cases that defy ready histologic identification. TTF-1 is often sufficient to declare adenocarcinoma, and the majority of squamous cell tumors are positive for p63 or p40.
The Eastern Cooperative Oncology Group (ECOG) 4599 trial2 established a role for bevacizumab in combination with carboplatin and paclitaxel in nonsquamous cell carcinoma of the lung, resulting in a statistically significant response rate (RR), progression-free survival (PFS), and overall survival (OS) advantage when compared to chemotherapy alone. More recently, a phase II trial by Patel and colleagues3 demonstrated a median OS that exceeded 14 months and an RR of 55% in treatment-naïve, bevacizumab-eligible, advanced NSCLC patients receiving carboplatin, pemetrexed, and bevacizumab. Given the favorable toxicity profile of pemetrexed compared to paclitaxel, many clinicians adopted this regimen in the absence of phase III data. In a plenary session at the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology, Patel and coworkers provided the first glimpse of results from the landmark PointBreak trial,4 which compared the ECOG 4599 approach (carboplatin/paclitaxel/bevacizumab) to the strategy piloted by Patel and colleagues (carboplatin/pemetrexed/bevacizumab). Patients without disease progression on the control arm went on to maintenance therapy with bevacizumab alone, while those on the experimental arm received maintenance therapy with combination pemetrexed and bevacizumab. Unfortunately, but unsurprisingly, the pemetrexed-containing regimen offered no therapeutic advantage, with the exception of reduced toxicity. The primary endpoint of improved survival was not met.
A landmark analysis of those patients able to make it onto maintenance therapy suggested a possible advantage for the combination pemetrexed/bevacizumab approach. Adding pemetrexed to bevacizumab was demonstrated to be somewhat better than bevacizumab alone (median OS, 17.7 vs 15.7 months, respectively); however, P values and hazard ratios (HRs) were not provided. Similar findings were shown in the AVAPERL (A Study of Avastin [Bevacizumab] With or Without Pemetrexed as Maintenance Therapy After Avastin in First Line in Patients With Non-Squamous Non-Small Cell Lung Cancer) trial,5 which had an identical comparison in the maintenance setting. However, to date, there is insufficient evidence to fully recommend the combination of pemetrexed and bevacizumab over bevacizumab alone in the maintenance setting, particularly when we factor in cost. The results of this study reinforce the need to complete the ongoing ECOG 5508 maintenance trial,6 in which patients who exhibit no disease progression after 4 cycles of combination paclitaxel/carboplatin/bevacizumab are randomized to either continuation maintenance with bevacizumab alone (the standard arm), switch maintenance with pemetrexed, or a hybrid approach employing both bevacizumab and pemetrexed. This trial is slated to enroll 1,236 patients, and anticipates randomization of 864 subjects. OS is the primary endpoint.
Unlike paclitaxel injection, nab-paclitaxel does not require the steroid premedication that can be challenging for many patients. In the original report by Socinski and coworkers published in the Journal of Clinical Oncology,7 patients with squamous NSCLC who received nab-paclitaxel appeared to benefit, with a significant improvement in RR (41% vs 24% in the carboplatin/nab-paclitaxel vs carboplatin/solvent-based paclitaxel arms, respectively). There was no difference in PFS or survival between the 2 arms.
However, survival in the nab-paclitaxel arm was significantly longer in the subset of patients aged 70 years or older (median OS, 19.9 vs 10.4 months)8 and in enrolled patients from North America (12.7 vs 9.8 months).9 Additionally, patients treated with nab-paclitaxel experienced less neuropathy.10 Whether these benefits occurred due to the drug or to the schedule remains unclear. This is a major issue that must be addressed in future studies. A more cogent and relevant comparison that would address the issue of schedule versus drug effect might have been weekly therapy with nab-paclitaxel versus weekly therapy with standard cremophor-based paclitaxel at identical or similar doses. There is tremendous interest in performing a formal, prospective, randomized, phase III trial comparing weekly paclitaxel/carboplatin to weekly nab-paclitaxel in elderly patients with NSCLC.
Riely and coworkers presented a mature update of a phase II trial that evaluated crizotinib in patients with advanced, ALK-positive NSCLC.11 Of the 261 patients enrolled, 94% had adenocarcinoma, 67% were never smokers, 53% had received 3 or more prior regimens, and 17% of patients had performance scores of 2 or 3. The 60% overall response rate (ORR) matched that observed in the phase I study. The PFS was approximately 8 months at the time of presentation, and median survival has not been reached. Overall, crizotinib demonstrated a very reasonable safety profile. Based on the Lung Cancer Symptom Scale, crizotinib produced improvements in fatigue, cough, dyspnea, and chest pain, as well as quality of life.
A phase III trial comparing crizotinib to combination pemetrexed and cisplatin in treatment-naïve, ALK-positive, NSCLC patients is ongoing.12 There is also a separate phase III trial in the second-line setting comparing crizotinib to standard chemotherapy with either docetaxel or pemetrexed.13 PFS is the primary endpoint. A press release of the results documented a significant improvement in PFS for crizotinib.14
Sequist and associates presented updates from the LUX-Lung 3 trial, which compared afatinib to cisplatin and pemetrexed in the first-line setting of treatment-naïve patients with advanced adenocarcinoma of the lung harboring EGFR mutations.15 Afatinib demonstrated superiority with respect to RR and PFS, and these benefits were even more pronounced in patients whose tumors harbored activating mutations in exons 19 and 21. A number of other trials have examined erlotinib and gefitinib in the identical therapeutic setting. These studies have consistently shown a statistically significant and clinically meaningful benefit with regard to RR and PFS. However, the afatinib trial is distinguished by a variety of factors: 1) it is the largest trial in the first-line, EGFR-mutant setting; 2) it is the first to use a second-generation irreversible EGFR tyrosine kinase inhibitor (TKI); 3) it employs a state-of-the-art comparator (pemetrexed and cisplatin); 4) it integrates quality of life evaluation into outcome analysis; and 5) it is a global registration trial. It was a rather bold move to include resistance mutations in this study, as this might have sabotaged the entire trial. However, despite such inclusion, the data were still positive. Afatinib is now available in the United States through expanded access programs. I presume it will be formally approved by the US Food and Drug Administration in the next several months. Whether it displaces erlotinib in use remains to be seen.
A randomized phase II trial recently reported by Ramalingam and colleagues in the Journal of Clinical Oncology16 suggests that dacomitinib may have greater activity than erlotinib in advanced NSCLC. The study compared dacomitinib with erlotinib as second-line therapy in an unselected population. Median PFS favored dacomitinib (2.86 vs 1.91 months), with an HR of 0.66. There was a similar prevalence of EGFR mutations (16%) and KRAS mutations (16.4%) between groups. However, there was an imbalance in the number of EGFR-mutant patients receiving dacomitinib (20.2%) versus those receiving erlotinib (11.7%). Ramalingam and coworkers presented efficacy analyses in the subgroup of patients with EGFR mutations.17
Roughly 1 out of every 5 patients had unknown EGFR mutation status. The standard formula used for estimating sample size assumed a homogeneous population. However, the accuracy of such an estimate is questionable when the population is a heterogeneous mix of patients with and without EGFR mutations. This is especially true when the impact of an EGFR TKI is significantly different between the 2 groups. Even slight differences must be interpreted with caution due to the lack of certainty of equality in the incidence of EGFR mutation between the 2 study arms. Nevertheless, it was found that the KRAS wild-type subgroup had a greater benefit from dacomitinib. The small sample size precludes definitive conclusions regarding whether mutations in exon 19 are predictive of treatment effects. Toxicities were more common in the dacomitinib group. Nonetheless, dacomitinib produced clinically meaningful improvements in disease symptoms, including cough, dyspnea, and chest pain.
Historically, immunotherapies have not offered any significant improvements in therapeutic outcome in advanced NSCLC. Brahmer and associates presented the preliminary results of an ongoing phase I/II trial evaluating the activity and safety of BMS-936558 in patients with advanced NSCLC.18 BMS-936558 is a fully human IgG4 antibody that blocks the programmed death-1 (PD-1) protein, overcoming immune resistance and mediating tumor regression. This was part of a much larger phase I/II trial involving multiple cancer types.19 The threshold dose for therapeutic activity was 3 mg/kg intravenously every 2 weeks. There was an ORR of 18%, which rivals that observed with conventional cytotoxics. Responses, when they occurred, were relatively durable. Preferential activity, it seems, was observed in squamous cell carcinoma. In the 13 patients with squamous cell carcinoma receiving either 3 or 10 mg/kg, the RR was 46%. It remains unclear whether this advantage in squamous cell carcinoma is real or serendipitous. At present, there is no known reliable marker for activity. However, it has been suggested that the absence of programmed death ligand 1 expression may correlate with an absence of clinical benefit. Accordingly, phase II trials involving immunologic and molecular-marker correlates are under way,20,21 and phase III studies of anti-PD–1 antibodies for the treatment of NSCLC, melanoma, and renal cell carcinoma are being developed.
Dr. Langer has served on advisory boards for BMS, BI, and Genentech.
1. Robertson WW, Steliga M, Arnaoutakis K. Accuracy of fine needle aspiration and core lung biopsies to predict histology in patients with non small cell lung cancer. Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract LBOA2.
2. Patel JD, Hensing TA, Rademaker A, et al. Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer. J Clin Oncol. 2009;27:3284-3289.
3. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542-2450.
4. Patel JD, Socinski MA, Garon EB, et al. A randomized, open-label, phase III, superiority study of pemetrexed (Pem) + carboplatin(Cb) + bevacizumab(Bev) followed by maintenance Pem + Bev versus paclitaxel (Pac)+Cb+Bev followed by maintenance Bev in patients with stage IIIB or IV non-squamous non-small cell lung cancer (NS-NSCLC). Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract LBPL1.
5. Barlesi F, de Castro J, Dvornichenko V, et al. AVAPERL (MO22089): final efficacy outcomes for patients (pts) with advanced non-squamous non-small cell lung cancer (nsNSCLC) randomised to continuation maintenance (mtc) with bevacizumab (bev) or bev+pemetrexed (pem) after first-line (1L) bev-cisplatin (cis)-pem treatment (Tx). Paper presented at: the 2011 European Multidisciplinary Cancer Congress; September 23-27, 2011; Stockholm, Sweden.
6. www.ClinicalTrials.gov. Bevacizumab or Pemetrexed Disodium Alone or In Combination After Induction Therapy in Treating Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer. http://clinicaltrials.gov/show/NCT01107626. Identifier: NCT01107626.
7. Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012;30:2055-2062.
8. Socinski MA, Langer CJ, Okamoto I, et al. Weekly nab®-paclitaxel in combination with carboplatin as first-line therapy in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC). Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract 109.
9. Socinski M, Okamoto I, Hon JK, et al. nab®-Paclitaxel in combination with carboplatin as first-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC): analysis of pt characteristics and clinical treatment patterns by region. Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract 183.
10. Hirsh V, Okamoto I, Hon JK, et al. Weekly nab®-paclitaxel in combination with carboplatin as first-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC): analysis of patient-reported neuropathy and taxane-associated symptoms. Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract 108.
11. Riely GJ, Evans TL, Salgia R, et al. Results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC). Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract 3.
12. www.ClinicalTrials.gov. Phase 3, Randomized, Open-Label Study Of The Efficacy And Safety Of Crizotinib Versus Pemetrexed/Cisplatin Or Pemetrexed/Carboplatin In Previously Untreated Patients With Non-Squamous Carcinoma Of The Lung Harboring A Translocation Or Inversion Event Involving The Anaplastic Lymphoma Kinase (ALK) Gene Locus. http://clinicaltrials.gov/ct2/show/NCT00932893. Identifier: NCT01154140.
13. www.ClinicalTrials.gov. Phase 3, Randomized, Open-Label Study Of The Efficacy And Safety Of PF-02341066 Versus Standard Of Care Chemotherapy (Pemetrexed Or Docetaxel) In Patients With Non-Small Lung Cancer Harboring A Translocation Or Inversion Event Involving The Anaplastic Lymphoma Kinase (ALK) Gene Locus. http://clinicaltrials.gov/ct2/show/NCT00932893. Identifier: NCT00932893.
14. European Society for Medical Oncology. Phase III trial shows crizotinib superior to single-agent chemotherapy for ALK-positive advanced NSCLC. September 30, 2012. Vienna, Austria. http://www.esmo.org/events/vienna-2012-congress/congress-news/view.html?tx_ttnews%5Btt_news%5D=1632&tx_ttnews%5BbackPid%5D=2580&cHash=39e1ce5cb6. Accessed November 19, 2012.
15. Sequist L, Schuler M, Yamamoto N, et al. LUX-Lung 3: a randomized, open-label, phase III study of afatinib vs pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations (subgroup analysis). Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract 1.
16. Ramalingam SS, Blackhall F, Krzakowski M, et al. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2012;30:3337-3344.
17. Ramalingam S, Blackhall F, Rosell R, et al. Dacomitinib (D) versus erlotinib (E) in patients (pt) with EGFR-mutated (mu) advanced non-small cell lung cancer (NSCLC): analyses from a randomized, phase 2 trial. Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract 2.
18. Brahmer JR, Horn L, Antonia SJ, et al. Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in patients (Pts) with advanced non-small-cell lung cancer (NSCLC). Paper presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, IL. Abstract 4.
19. Topalian SL, Brahmer JR, Hodi FS, et al. Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: clinical activity, safety, and a potential biomarker for response. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30: Abstract CRA2509.
20. www.ClinicalTrials.gov. BMS-936558 (MDX-1106) In Subjects With Advanced/Metastatic Clear-Cell Renal Cell Carcinoma (RCC). http://clinicaltrials.gov/show/NCT01354431. Identifier: NCT01354431.
21. www.ClinicalTrials.gov. Phase I Biomarker Study (BMS-936558). http://clinicaltrials.gov/show/ NCT01358721. Identifier: NCT01358721.