A Review of Selected Presentations From the 2018 American Society of Clinical Oncology Gastrointestinal Cancers Symposium • January 18-20, 2018 • San Francisco, California
Dose Modifications of Liposomal Irinotecan + 5-Fluorouracil/Leucovorin in NAPOLI-1: Impact on Efficacy
In the phase 3 NAPOLI-1 trial (Nanoliposomal Irinotecan), the addition of nanoliposomal irinotecan to 5-fluorouracil (5-FU) and leu-covorin improved overall survival as compared with 5-FU/leucovorin alone among patients with metastatic pancreatic cancer previously treated with gemcitabine-based therapy.1 The median overall survival was 6.1 months with nanoliposomal irinotecan, 5-FU, and leucovorin vs 4.2 months with 5-FU and leucovorin (HR, 0.67; 95% CI, 0.49-0.92; P=.012). The protocol for the NAPOLI-1 study permitted up to 2 dose reductions for nanoliposomal irinotecan and 5-FU, as well as a dose delay of up to 3 weeks, in cases of toxicity-related adverse events.1 Dr Andrea Wang-Gillam and colleagues presented data from an exploratory analysis of NAPOLI-1, which sought to determine whether overall survival was impacted by dose reductions or dose delays used to manage an adverse event within the first 6 weeks of the study. A dose reduction was defined as any decrease in the scheduled dose from the initial administered dose. A dose delay was defined as a dose that was given more than 3 days after the scheduled date.2
In NAPOLI-1, patients were randomly assigned to a 6-week treatment regimen consisting of nanoliposomal irinotecan alone (120 mg/m2 every 3 weeks); 5-FU (2000 mg/m2 weekly for 4 weeks) and leucovorin (200 mg/m2 weekly for 4 weeks); or nanoliposomal irinotecan (80 mg/m2 every 2 weeks) plus 5-FU (2400 mg/m2 weekly every 2 weeks) and leucovorin (400 mg/m2 every 2 weeks).1
More patients in the nanoliposomal irinotecan plus 5-FU and leucovorin combination arm experienced adverse events that required dose delays and/or dose reductions vs the 5-FU and leucovorin-alone arm (62% vs 33%).1 In the exploratory post hoc analysis, a dose modification during the first 6 weeks of treatment was required for 53 patients (45%) treated with nanoliposomal irinotecan plus 5-FU and leucovorin. Of these, 49 patients required a dose delay and 34 patients required a dose reduction. Four patients who received a dose reduction did not require a dose delay.2
The most common grade 3/4 adverse events reported in patients who required a dose delay in the first 6 weeks of treatment with nanoliposomal irinotecan plus 5-FU and leucovorin were white blood cell decrease (n=11), neutrophil count decrease (n=9), neutropenia (n=8), diarrhea (n=6), and platelet count decrease (n=5). Among patients who required a dose reduction, the most common grade 3/4 adverse events were neutrophil count decrease (n=7), neutropenia (n=5), and white blood cell decrease (n=5).2
An analysis of overall survival compared outcomes with and without the addition of nanoliposomal irinotecan. Overall survival was prolonged in the nanoliposomal irinotecan plus 5-FU and leucovorin arm, regardless of the type of dose modification. Among patients who required a dose delay, the median overall survival was 8.44 months in the nanoliposomal irinotecan plus 5-FU and leucovorin arm vs 4.17 months in the 5-FU and leucovorin arm (hazard ratio [HR], 0.66; 95% CI, 0.46-0.95; Figure 1). Among patients with a dose reduction, the median overall survival was 9.36 months with nanoliposomal irinotecan vs 4.17 months without (HR, 0.58; 95% CI, 0.38-0.88; Figure 2).2
Within the cohort of patients treated with nanoliposomal irinotecan plus 5-FU and leucovorin, the median overall survival was 9.4 months in the 34 patients who had a dose reduction vs 5.4 months in the 83 patients who did not (HR, 0.66; 95% CI, 0.43-1.02). This difference did not reach statistical significance. A similar, nonsignificant trend was seen with dose delays. The median overall survival was 8.4 months among the 49 patients who had a dose delay vs 5.6 months in the 68 patients who did not (HR, 0.84; 95% CI, 0.57-1.23).2 This exploratory analysis suggested that an appropriate dose modification of nanoliposomal irinotecan, consisting of a dose reduction or a dose delay during the first 6 weeks of treatment, can be made without adversely affecting a patient’s survival.2
References
1. Wang-Gillam A, Li CP, Bodoky G, et al; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-557.
2. Wang-Gillam A, Hubner R, Mirakhur B, et al. Dose modifications of liposomal irinotecan (nal-IRI) + 5-fluorouracil/leucovorin (5-FU/LV) in NAPOLI-1: impact on efficacy [ASCO GI abstract 388]. J Clin Oncol. 2018;36(suppl 4S).
A Phase IB/II Randomized Study of mFOLFIRINOX + Pegylated Recombinant Human Hyaluronidase Versus mFFOX Alone in Patients With Good Performance Status Metastatic Pancreatic Adenocarcinoma: SWOG S1313 (NCT #01959139)
Hyaluronan is overexpressed in more than 80% of pancreatic cancers, and accumulating hyaluronan is associated with the development of high interstitial fluid pressure and drug resistance. Expression of hyaluronan is linked to disease progression and poor prognosis. Pegylated recombinant human hyaluronidase (PEGPH20) has demonstrated activity in a mouse pancreatic cancer model, by decreasing stromal expression of hyaluronan, normalizing the interstitial fluid pressure, and re-expanding the microvasculature.1 When combined with gemcitabine, PEGPH20 depleted the tumor microenvironment and improved survival.2
At the 2018 American Society of Clinical Oncology Gastrointestinal Cancers (ASCO GI) symposium, Dr Ramesh Ramanathan presented results from the SWOG S1313 study, which evaluated the activity of PEGPH20 in combination with a modified regimen of oxaliplatin, irinotecan, leucovorin, and 5-FU (mFOLFIRINOX) among patients with metastatic pancreatic cancer.3 Importantly, this study did not select patients according to hyaluronan expression.
Patients ages 75 years and younger were eligible for enrollment into SWOG S1313 if they had metastatic and measurable disease and had not received prior treatment for their metastatic disease. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and adequate organ function. The study criteria excluded patients previously treated with warfarin, those with a previous cerebrovascular accident or a transient ischemic attack, and those with preexisting carotid artery disease requiring intervention.3
The SWOG S1313 study was initiated in January 2014 and terminated in March 2017 at the interim futility analysis. A phase 1b dose-finding cohort of mFOLFIRINOX plus PEGPH20 was followed by a phase 2 portion, in which patients were randomly assigned to treatment with mFOLFIRINOX plus PEGPH20 (n=55) or mFOLFIRINOX alone (n=56). The study was amended to include use of prophylactic low-molecular weight heparin in the combination arm, based on an increase in thromboembolic events. The primary study endpoint was overall survival, with a null median overall survival of 10 months and an alternative of 15 months. Planned correlative studies included analysis of pretreatment biopsy samples for hyaluronan expression, as well as measurement of serum levels of hyaluronic acid at baseline and throughout the course of treatment.3
The phase 1b dose-escalation portion of the study established a dose of 3 µg/kg of PEGPH20 on day 1 of 2-week cycles for further phase 2 study. mFOLFIRINOX was fixed at 85 mg/m2 of oxaliplatin, 180 mg/m2 of irinotecan, 400 mg/m2 of leucovorin, and 2400 mg/m2 of 5-FU administered intravenously throughout 46 hours.3
At baseline, the median patient age was 63.9 years in the combination arm and 60.5 years in the mFOLFIRINOX arm. The combination arm included fewer men (44% vs 55%). In both arms, most patients had an ECOG performance status of 0 (58% vs 55%).3
During the phase 2 portion of the trial, the rate of grade 3 to 5 adverse events was increased in the mFOLFIRINOX plus PEGPH20 arm vs the mFOLFIRINOX-alone arm (HR, 2.7). Grade 3/4 events reported at a higher frequency in the combination arm vs the mFOLFIRINOX-alone arm included nausea (25% vs 15%), diarrhea (24% vs 19%), vomiting (22% vs 13%), and fatigue (20% vs 11%). In the combination arm, the rate of all-grade thromboembolic events decreased from 18% to 9% with the introduction of prophylactic low-molecular-weight heparin.3
An interim futility analysis, triggered when 35 deaths occurred in 113 patients, demonstrated that the addition of PEGPH20 to mFOLFIRINOX did not show benefit over mFOLFIRINOX alone. The study therefore met the criteria to halt enrollment. The median overall
survival was 7.7 months with PEGPH20 plus mFOLFIRINOX vs 14.4 months with mFOLFIRINOX alone (HR, 0.50; 95% CI, 0.31-0.81; P<.01). The median progression-free survival (PFS) showed a similar lack of benefit, at 4.3 months with PEGPH20 plus mFOLFIRINOX vs 6.2 months with mFOLFIRINOX alone (HR, 0.61; 95% CI, 0.40-0.93; P=.02; Figure 3). There was no benefit in the response rate, which was 33% (95% CI, 21%-47%) in the combination arm vs 45% (95% CI, 31%-59%) in the monotherapy arm.3
The authors concluded that the addition of PEGPH20 to mFOLFIRINOX not only increased toxicity, but also appeared to be detrimental to patient survival and response outcomes. The authors speculated that this detrimental effect might have been caused by lower exposure to mFOLFIRINOX treatment in the combination arm vs the mFOLFIRINOX-alone arm (median of 4 cycles vs 8 cycles, respectively), which in turn was attributed to higher toxicity in the combination arm. The results obtained in the SWOG S1313 trial are contradictory to the more favorable results reported in the HALO 202 phase 3 study with the combination of PEGPH20 plus gemcitabine/nab-paclitaxel.4 More study is needed.
References
1. Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21(3):418-429.
2. Jacobetz MA, Chan DS, Neesse A, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2013;62(1):112-120.
3. Ramanathan RK, McDonough S, Philip PA, et al. A phase IB/II randomized study of mFOLFIRINOX (mFFOX) + pegylated recombinant human hyaluronidase (PEGPH20) versus mFFOX alone in patients with good performance status metastatic pancreatic adenocarcinoma (mPC): SWOG S1313 (NCT #01959139) [ASCO GI abstract 208]. J Clin Oncol. 2018;36
(suppl 4S).
4. Hingorani SR, Zheng L, Bullock AJ, et al. HALO 202: randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma. J Clin Oncol. 2018;36(4):359-366.
Subgroup Analysis by Baseline Pain and Weight Among Patients in the NAPOLI-1 Trial
Dr Teresa Macarulla Mercadé and colleagues presented the results from subgroup analyses of the NAPOLI-1 trial.1 Outcome was evaluated according to patients’ baseline pain intensity and analgesic use2 and baseline weight-associated parameters.3 These analyses were post hoc, and therefore the reported P values are descriptive.
Baseline pain intensity and analgesic use were calculated based on the average value throughout the 7-day period before the first dose of the study drug. Pain was evaluated daily, and pain intensity during the previous 24 hours was recorded on a visual analog scale. Patients recorded analgesic consumption in a daily diary. Analgesic consumption was also tracked based on prescriptions and reported in the patient medical records. Patients’ analgesic needs were evaluated and converted to morphine equivalents (mg/day) for standardization.2
Numerical differences emerged in the patient demographics and baseline characteristics among the baseline pain intensity and analgesic use subgroups. For example, sex and ethnicity varied across baseline pain intensity and analgesic use subgroups compared with the corresponding overall intent-to-treat populations. There was variability in the Karnofsky performance scale distribution across the subgroups for baseline pain intensity and use of analgesics compared with the corresponding overall intent-to-treat populations, which was expected. Among 417 patients in the intent-to-treat population, 295 had data for baseline pain intensity and 299 had data for baseline analgesic use. The median baseline pain intensity was 25.0 on the visual analogue scale, and median baseline analgesic use was 8.1 mg/day.2
There was an increase in the mortality risk for patients with more baseline pain or analgesic use (Table 1). Median overall survival was also lower in these patients (Table 2).2
The safety profiles for nanoliposomal irinotecan plus 5-FU and leucovorin within the baseline pain intensity and analgesic use subgroups were consistent with the overall NAPOLI-1 population. There were no clinically important differences between the subgroups with high vs low baseline pain intensity and analgesic use, except for a higher incidence of abdominal pain in the subgroups of patients with lower baseline pain intensity and analgesic use. Drug discontinuations owing to treatment-emergent adverse events were increased among patients with higher rates of pain and analgesic use.2
The data from this post hoc analysis support the use of nanoliposomal irinotecan plus 5-FU and leucovorin in patients previously treated with gemcitabine-based therapy regardless of baseline pain intensity or analgesic use. The authors concluded that higher baseline pain intensity and analgesic use might be useful prognostic parameters for patients with metastatic pancreatic cancer who have received previous treatment with gemcitabine-based therapy.2
The weight-based analysis by Dr Mercadé and colleagues focused on the effect of baseline body surface area, body mass index (BMI), and weight on outcome.3 Baseline weight parameters were available for all patients in the intent-to-treat population (N=417). At baseline, the median body surface area was 1.71 m2, the median BMI was 22.9 kg/m2, and the median baseline weight was 63.6 kg.3
The mortality risk did not significantly differ among patients with baseline weight characteristics that were less than vs greater than or equal to the median values (Figure 4). The authors of this post hoc subgroup analysis concluded that the 3 baseline patient weight parameters considered—body surface area, BMI, and baseline weight—did not provide prognostic evidence for patient mortality or disease progression in this group of patients. Patients in both high and low baseline weight parameter subgroups showed a general improvement in overall survival when treated with nanoliposomal irinotecan plus 5-FU and leucovorin compared with 5-FU and leucovorin alone.3
Drug-related adverse events of grade 3 or higher occurred at a higher rate in lower-weight parameter subgroups (with the exception of BMI), and were more frequent in patients treated with nanoliposomal irinotecan plus 5-FU and leucovorin. Dose discontinuations occurred in similar numbers of patients in all baseline weight subgroups.3 The data from this post hoc analysis support the use of nanoliposomal irinotecan plus 5-FU and leucovorin in patients previously treated with gemcitabine-based therapy regardless of their baseline weight parameter values.2
References
1. Wang-Gillam A, Li CP, Bodoky G, et al; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-557.
2. Mercadé TM, Siveke JT, Dean AP, et al. Subgroup analysis by baseline pain intensity (BPI) and analgesic use (BAU) in NAPOLI-1: a phase III study of liposomal irinotecan (nal IRI)±5-fluorouracil/leucovorin (5-FU/LV) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy [ASCO GI abstract 379]. J Clin Oncol. 2018;36(suppl 4S).
3. Mercadé TM, Hubner R, Blanc J-F, et al. Subgroup analysis by baseline (BL) weight-associated parameters: a phase III study of liposomal irinotecan (nal‑IRI)±5‑fluorouracil/leucovorin 5‑FU/LV) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based (gem) therapy [ASCO GI abstract 410]. J Clin Oncol. 2018;36(suppl 4S).
Phase II LAPACT Trial of Nab-Paclitaxel Plus Gemcitabine for Patients With Locally Advanced Pancreatic Cancer
Nab-paclitaxel combined with gemcitabine showed efficacy as a treatment for patients with metastatic pancreatic cancer in an exploratory analysis of the phase 3 MPACT trial (Metastatic Pancreatic Adenocarcinoma Clinical Trial).1 This combination was associated with an approximate 3-fold greater median percentage reduction in the primary pancreatic tumor burden vs gemcitabine alone. Notably, this combination has a category 2A recommendation in guidelines from the National Comprehensive Cancer Network for treatment of patients with locally advanced pancreatic cancer and good performance status, based on extrapolation of data from the MPACT study.2
At the 2018 ASCO GI meeting, Dr Pascal Hammel and colleagues presented results of the LAPACT trial (Phase 2 Nab-Paclitaxel [Abraxane] Plus Gemcitabine in Subjects With Locally Advanced Pancreatic Cancer), which prospectively evaluated this treatment combination as induction therapy in patients with newly diagnosed, locally advanced pancreatic cancer.3 Patients with treatment-naive, locally advanced pancreatic cancer were treated with up to 6 cycles of induction therapy with nab-paclitaxel (125 mg/m2 weekly for 3 of 4 weeks) plus gemcitabine (1000 mg/m2 for 3 of 4 weeks). Surgical intervention was allowed prior to the completion of the 6 treatment cycles, if the disease was deemed operable by the treating medical team. After completion of induction, patients without disease progression or unacceptable toxicity proceeded to treatment according to the investigator’s choice: either continued nab-paclitaxel plus gemcitabine, chemoradiation (concurrent capecitabine or gemcitabine plus radiation according to the institutional practice), or surgical resection. The primary study endpoint was the time to treatment failure. Secondary endpoints included the disease control rate, overall response rate, PFS, overall survival, safety, and quality of life. Additionally, a post hoc evaluation of the resection rate and quality was planned.3
The intent-to-treat population consisted of 107 patients, of whom 106 received induction therapy and 61 completed treatment. Among these 61 patients, 45 went on to receive the investigator’s choice of therapy, with 12 patients continuing nab-paclitaxel plus gemcitabine, 17 patients receiving chemoradiation, and 16 patients undergoing surgical resection. In the intent-to-treat population, the median age was 65.0 years (range, 42-85 years), and 59% were female. Patients had an ECOG performance status of 0 (46.7%) or 1 (53.3%). The median sum of the longest diameter of pancreatic tumor target lesions was 44.0 mm (range, 17-130 mm).3
The median time to treatment failure was 8.8 months (90% CI, 6.67-9.82; Figure 5). This duration exceeded the protocol-specified median time to treatment failure target of 6.6 months. Median PFS was 10.8 months (90% CI, 9.26-11.63). The estimated 12-month overall survival rate was 72% (90% CI, 64.5-78.9). In the intent-to-treat population, the overall response rate was 32.7%; all of the responses were partial. Most patients showed some measurable decrease in the sizes of their lesions. The disease control rate, defined as stable disease for 24 or more weeks, was 65.4%. Among the 16 patients (15%) who were able to undergo surgery after induction therapy, the resection margin status was R0 in 7 and R1 in 9.3
The median number of induction cycles was 5 (range, 1-6). Approximately half of patients required at least 1 dose delay of each drug, and approximately two-thirds of patients required at least 1 dose reduction of each drug.3
Among the 106 patients who received induction therapy, the most common all-grade nonhematologic treatment-emergent adverse events were fatigue (50.0%), diarrhea (46.2%), and asthenia (34.9%). Additional all-grade adverse events of special interest included peripheral sensory neuropathy, occurring in 23.6%, and peripheral neuropathy, occurring in 22.6%. The most frequent all-grade hematologic treatment-emergent adverse events included neutropenia (58.5%), anemia (47.2%), and thrombocytopenia (41.5%). The grade 3/4 hematologic adverse events included neutropenia (41.5%), anemia (11.3%), and thrombocytopenia (7.5%). During induction therapy, patients’ overall quality of life was maintained throughout the 6 cycles of treatment.3
References
1. Kunzmann V, Ramanathan RK, Goldstein D, et al. Tumor reduction in primary and metastatic pancreatic cancer lesions with nab-paclitaxel and gemcitabine: an exploratory analysis from a phase 3 study. Pancreas. 2017;46(2):203-208.
2. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Pancreatic adenocarcinoma. Version 3.2017. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. pdated September 11, 2017. Accessed February 15, 2018.
3. Hammel P, Lacy J, Portales F, et al. Phase II LAPACT trial of nab-paclitaxel (nab-P) plus gemcitabine (G) for patients with locally advanced pancreatic cancer (LAPC) [ASCO GI abstract 204]. J Clin Oncol. 2018;36(suppl 4S).
Subgroup Analysis by Measurable Metastatic Lesion Number and Selected Lesion Locations at Baseline in NAPOLI-1: A Phase III Study of Liposomal Irinotecan ±5-Fluorouracil/Leucovorin in Patients With Metastatic Pancreatic Ductal Adenocarcinoma Previously Treated With Gemcitabine-Based Therapy
Dr Jens Siveke and colleagues presented results of a post hoc subgroup analysis of the NAPOLI-1 study, focusing on the baseline number of measurable metastatic lesions and lesion locations.1,2 The reported P values are descriptive.
The study analyzed investigator-assessed baseline measurement of the number of metastatic lesions (either 1, 2, 3, or >3), and primary and metastatic lesion locations (in either the pancreas, liver, distant/regional lymph nodes, lung, peritoneum, or other areas) among patients with measurable or nonmeasurable disease (per version 1.1 of the Response Assessment in Solid Tumors criteria). Patients with more than 1 lesion location were counted once for each location. Additionally, lesion locations were categorized into different subgroups: patients with metastatic lesions in a specific location only (location only), patients with metastatic lesions other than that location only (no location only), patients with lesions in that and other locations (any location) and patients without lesions in that location (no location).2
At baseline, 354 of the 417 patients in the intent-to-treat population had measurable metastatic lesions, and 1080 lesion locations were recorded. There were differences in the patient demographics and baseline characteristics between the metastatic lesion and lesion location baseline subgroups, which was likely further influenced by the variable patient numbers. Sex, ethnicity, and Karnofsky performance scale score distribution all differed numerically across baseline metastatic lesion and lesion location subgroups compared with the corresponding overall intent-to-treat populations.2
In the overall intent-to-treat population, patients with 1 selected metastatic lesion at baseline had a lower risk of mortality (Figure 6). The median overall survival was 6.1 months (95% CI, 4.2-8.0) for those with 1 lesion vs 4.6 months (95% CI, 4.2-5.1) for those with 2 lesions (HR, 1.59; P=.003). Patients with a liver lesion at baseline had a significantly increased risk of mortality vs patients without a liver lesion at baseline. The median overall survival was 4.3 months vs 6.8 months, respectively (HR, 1.68; 95% CI, 1.31-2.16; P<.001; Figure 7). The location of the lesion did not impact median overall survival in patients with lesions in the lung or peritoneum. Additionally, the lung only (n=9) and peritoneal only (n=18) groups contained too few patients to present as separate subgroups.2
The study authors concluded that this post hoc analysis suggested that the presence of lesions in the liver and, to some degree, the number of measurable metastatic lesions at baseline could potentially be used as prognostic indicators for mortality. A benefit to treatment with nanoliposomal irinotecan plus 5-FU and leucovorin vs 5-FU and leucovorin alone was observed in most baseline metastatic lesions and lesion location subgroups. However, the differences did not reach statistical significance in all groups, possibly owing to the low patient numbers in many of the subgroups. The data from this post host subgroup analysis support the use of nanoliposomal irinotecan plus 5-FU and leucovorin regardless of the number of measurable metastatic lesions or lesion locations at baseline.
References
1. Wang-Gillam A, Li CP, Bodoky G, et al; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-557.
2. Siveke JT, Hubner R, Macarulla TM, et al. Subgroup analysis by measurable metastatic lesion (ML) number and selected lesion locations (LL) at baseline (BL) in NAPOLI-1: a phase III study of liposomal irinotecan (nal-IRI)±5-fluorouracil/leucovorin (5-FU/LV) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy [ASCO GI abstract 460]. J Clin Oncol. 2018;36(suppl 4S).
Mapping the Immune Landscape in Pancreatic Cancer
The keynote lecture at the 2018 ASCO GI symposium was delivered by Dr Steven Leach, who focused on the changing treatment landscape in pancreatic cancer with emerging immunotherapies.1 One of the first points Dr Leach made was that optimal use of immunotherapy in pancreatic cancer will require an individualized approach to ensure optimal biomarker-driven selection. He noted that this requirement is not unique to immunotherapy, but that patients treated with molecular therapy and even chemotherapy would benefit from individualized selection. The approach in pancreatic cancer has been to identify subsets of patients predicted to maximally benefit from a given therapy, converting a one-size-fits-all approach to a strategy individualized according to a patient’s biomarkers. As one example, Dr Leach described the use of a BRCA mutation to identify patients who may be particularly sensitive to platinum-based chemotherapy, especially when combined with inhibitors of poly (ADP-ribose) polymerase (PARP).2 The targeting of metastatic pancreatic cancers with evidence of BRCA mutations was successful in a phase 1 clinical study, which reported substantial activity with the addition of the PARP inhibitor veliparib to gemcitabine and cisplatin chemotherapy.3 Based on promising results seen with targeting pancreatic cancers with BRCA mutations, current research is focused on identifying those pancreatic adenocarcinomas with a BRCAness phenotype, resulting in impaired DNA repair.
Expanding upon the idea of identifying particular molecular aberrations, Dr Leach discussed some of the barriers to identifying novel molecular targets in pancreatic cancer. Chief among these is the lack of a substantial tumor biopsy specimen with which to perform whole genome sequencing. Generally, pancreatic cancers are biopsied using fine needle aspiration, which typically does not provide a sufficient sample for detailed molecular analysis (particularly when it is considered that pancreatic tumors exhibit low cellularity). As research studies begin to focus on developing a molecular signature for pancreatic cancer, it is becoming increasingly important to design clinical trials that adequately target identified mutations. This approach is more difficult in pancreatic cancer than in other solid tumors, such as breast cancer and lung cancer, which often segregate into a few dominant molecular subtypes. In contrast, pancreatic tumors tend to exhibit a “smear” of mutations and aberrations across a wide variety of genes and pathways, with many showing a typical frequency of just a few percentage points. This challenge was recently exemplified by the finding that fewer than 2% of patients who had their pancreatic tumors molecularly profiled were able to enter a clinical trial targeting their identified mutation, even at a large institution like Memorial Sloan Kettering Cancer Center, which has a robust clinical trials portfolio.4
Dr Leach discussed immunotherapies and their potential impact in pancreatic adenocarcinoma. He noted that immunotherapies have revolutionized the treatment of patients with multiple solid tumor types. Much of this advancement has been driven by the identification and targeting of immune checkpoints. Microsatellite instability (MSI) status has emerged as a major biomarker predicting response to immune checkpoint therapy, but many patients with microsatellite-stable disease will also respond to immunotherapy. Dr Leach made the comparison to identifying tumors with a BRCAness phenotype, stating it was now necessary to define the full spectrum of “MSIness” in order to predict response to immune checkpoint inhibitors.
There has simultaneously been a great deal of interest in identifying which characteristics of pancreatic cancer define its characteristic resistance to immunotherapy. Pancreatic adenocarcinoma has classically been considered a nonimmunogenic tumor, with a low burden of somatic mutations.5 Recent sequencing efforts, including one pursued at Memorial Sloan Kettering Cancer Center involving laser capture microdissected material, have suggested that pancreatic cancer may have a rate of 2 mutations per megabase and therefore generate a regular, frequent immune response. Because there appears to be several mutations present creating an environment of regular neoantigen formation, these tumors should be well-targeted by immune checkpoint inhibitors. Alternative explanations are therefore needed to explain why pancreatic cancer may be largely resistant to checkpoint inhibitors. To address this question, Dr Vinod Balachandran and colleagues evaluated a cohort of pancreatic adenocarcinoma survivors with a particularly long survival time.6 The median survival of these patient was 6 years, and several patients had survived for more than 10 years. The study demonstrated that long-term survivors display enhanced intratumor immunity with a 12-fold increase in cytolytic CD8+ T cells, an immunogenic environment, and a polyclonal tumor-specific T-cell repertoire (Figure 8). Whole-genome sequencing had identified putative neoantigens in pancreatic adenocarcinoma, and a combination of neoantigen burden and activated T cells seemed to define patients with the longest survival times. The quality (but not the quantity) of the neoepitopes within these neoantigens also contributed to their prognostic significance. Tumor neoepitopes with known homology to epitopes from microbial pathogens are associated with an increased immune response and long-term survival.
References
1. Leach SD. Mapping the immune landscape in pancreatic cancer. Keynote lecture presented at: the 2018 American Society of Clinical Oncology Gastrointestinal Cancers Symposium; January 18-20, 2018; San Francisco, CA.
2. Lowery MA, Kelsen DP, Stadler ZK, et al. An emerging entity: pancreatic adenocarcinoma associated with a known BRCA mutation: clinical descriptors, treatment implications, and future directions. Oncologist. 2011;16(10):1397-1402.
3. O’Reilly EM, Lee JW, Lowery MA, et al. Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma [published online January 16, 2018]. Cancer. doi:10.1002/cncr.31218.
4. Lowery MA, Jordan EJ, Basturk O, et al. Real-time genomic profiling of pancreatic ductal adenocarcinoma: potential actionability and correlation with clinical phenotype. Clin Cancer Res. 2017;23(20):6094-6100.
5. Alexandrov LB, Nik-Zainal S, Wedge DC, et al; Australian Pancreatic Cancer Genome Initiative; ICGC Breast Cancer Consortium; ICGC MMML-Seq Consortium; ICGC PedBrain. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415-421.
6. Balachandran VP, Łuksza M, Zhao JN, et al; Australian Pancreatic Cancer Genome Initiative; Garvan Institute of Medical Research; Prince of Wales Hospital; Royal North Shore Hospital; University of Glasgow; St Vincent’s Hospital; QIMR Berghofer Medical Research Institute; University of Melbourne, Centre for Cancer Research; University of Queensland, Institute for Molecular Bioscience; Bankstown Hospital; Liverpool Hospital; Royal Prince Alfred Hospital, Chris O’Brien Lifehouse; Westmead Hospital; Fremantle Hospital; St John of God Healthcare; Royal Adelaide Hospital; Flinders Medical Centre; Envoi Pathology; Princess Alexandria Hospital; Austin Hospital; Johns Hopkins Medical Institutes; ARC-Net Centre for Applied Research on Cancer. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature. 2017;551(7681):512-516.
Nomogram for Predicting Overall Survival in Patients Treated With Liposomal Irinotecan ± 5-Fluorouracil/Leucovorin in Metastatic Pancreatic Ductal Adenocarcinoma Previously Treated With Gemcitabine-Based Therapy in NAPOLI-1
In a post hoc exploratory analysis of the NAPOLI-1 study, Dr Andrea Wang-Gillam and colleagues evaluated baseline patient characteristics and other variables in an effort to develop a nomogram to predict overall survival in patients with metastatic pancreatic adenocarcinoma after disease progression following gemcitabine-based therapy.1,2 Because the analysis was based on data from the NAPOLI-1 study, the nomogram was developed to predict 6-month and 12-month overall survival after treatment with nanoliposomal irinotecan plus 5-FU and leucovorin.2
Both univariate and multivariate analyses were performed to identify factors within the NAPOLI-1 clinical study that were significantly predictive of overall survival. The univariate analysis identified 21 independent factors that contributed to overall survival. Clinically relevant variables found to be significantly (or nearly significantly) associated with overall survival were used in the multivariate analysis. They included a baseline Karnofsky performance scale score of 90 or higher, baseline albumin of 4 g/dL or higher, a neutrophil-to-lymphocyte ratio greater than 5, the presence of liver metastases, a baseline CA19-9 level at or greater than the median (1542 U/mL), stage IV disease at diagnosis, treatment with nanoliposomal irinotecan plus 5-FU and leucovorin, and a BMI greater than 25 kg/m2. After the multivariate analysis, a multivariate Cox regression analysis was repeated using various stratification criteria to ensure clinical relevance.2
In the resulting nomogram, Karnofsky performance scale status contributed the largest number of points to the predicted overall survival, followed by the presence of liver metastasis and the randomized treatment arm. Each clinical factor is assigned a numerical value point by drawing a line upward from the observed value through to the points line. After this is performed for each of the clinical factors, the total sum of points is tabulated and plotted on the total points line. The corresponding predictions for 6-month and 12-month survival probability can then be determined by drawing a vertical line straight down. Larger values of total points on the nomogram correspond to a greater 6- and 12-month survival probability.2
When this nomogram was applied to the nanoliposomal irinotecan plus 5-FU and leucovorin arm of NAPOLI-1, it was able to discern lower (n=131), intermediate (n=137), and higher (n=131) risk groups corresponding to median overall survival values of 8.5 months, 5.3 months, and 2.9 months, respectively (Figure 9). The investigators concluded that this nomogram may have utility for distinguishing among patient risk groups to aid in clinical decision making. The study authors acknowledged that this exploratory analysis was limited, in that the nomogram was not validated against an external patient population.2
References
1. Wang-Gillam A, Li CP, Bodoky G, et al; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-557.
2. Wang-Gillam A, Hubner R, Mirakhur B, et al. Nomogram for predicting overall survival (OS) in patients (pts) treated with liposomal irinotecan (nal-IRI) ± 5-fluorouracil/leucovorin (5-FU/LV) in metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy in NAPOLI-1 [ASCO GI abstract 459]. J Clin Oncol. 2018;36(suppl 4S).
Genomics-Driven Precision Medicine for Advanced Pancreatic Ductal Carcinoma: Early Results From the COMPASS Trial (NCT02750657)
The ongoing COMPASS trial (Study of Changes and Characteristics of Genes in Patients With Pancreatic Cancer for Better Treatment Selection) was designed to obtain a biopsy of a primary tumor from patients with locally advanced or metastatic pancreatic cancer at baseline, and to then perform genomic analysis prior to starting the first-line chemotherapy.1,2 After biopsy, tumor specimens underwent whole-genome sequencing and whole transcriptome sequencing. Patients were then treated with standard first-line chemotherapy consisting of either mFOLFIRINOX or nab-paclitaxel as palliative treatment, or combination treatment with mFOLFIRINOX or nab-paclitaxel, with or without other investigational agents, within a clinical trial as first-line palliative treatment. After progression, patients received second-line therapy. The primary study endpoint was to determine the feasibility of reporting results from whole-genome sequencing prior to the first disease assessment at the first 8-week computed tomography scan. A secondary endpoint was the discovery of patient subsets with predictive mutational and transcriptional signatures to guide therapy.
At the time of the report, 71 patients were enrolled, of whom 63 safely underwent a baseline biopsy. Whole-genome sequencing was successful in 62 of the 63 biopsies (98%). The median time to reporting the whole-genome sequencing results was 35 days (range, 19-52 days). Therefore, the primary study endpoint was met. The main genomic drivers in advanced pancreatic cancer were similar to those already identified for earlier-stage disease, and included KRAS, TP53, CDKN2A, and SMAD4. Germline BRCA mutations were identified in 2 patients; one had somatic loss of heterozygosity and the other did not. Three patients had unstable genomic subtypes, as indicated by the presence of more than 200 structural variants. Among these 3 patients, 2 had a duplication signature without any pathogenic germline mutations, and the third had a BRAF mutation and numerous translocations. Potentially actionable somatic alterations were identified in 16 patients (25%), and included ARID1A mutation (n=5), PIK3CA mutation (n=4), PTEN mutation (n=3), CDK4/6 amplification (n=3), and BRAF mutation (n=1).1
RNA sequencing for whole transcriptome sequencing demonstrated that 24% of the tumor specimens had basal-like RNA signatures, whereas the remaining 76% had a classical signature. Subsequent RNA in situ hybridization showed that GATA6 expression was higher among patients with a classical signature vs a basal-like signature, which is consistent with prior reports.1
There were statistically significant differences in tumor response by RNA subtype among the 50 evaluable patients. More patients with the classical signature achieved tumor responses and partial responses compared with the basal-like signature (34% vs 8%; P=.0002). The mean percent change was increased in the basal-like signature (+17%) and decreased in the classical signature (–19.5%; P=.004). Among the 3 patients with unstable genomes, 2 achieved a partial response, and the third patient had tumor shrinkage of 20%. These tumor responses translated into survival differences. Both median PFS and median overall survival were prolonged in patients with a classical RNA signature. The median PFS was 6.4 months in patients with a classical signature vs 2.3 months in patients with a basal-like signature (HR, 0.28; 95% CI, 0.14-0.57; P<.001). Similarly, the median overall survival was 10.4 months vs 6.3 months, respectively (HR, 0.33; 95% CI, 0.15-0.7; P=.004).1
The authors concluded that obtaining a prospective genomic profile in advanced pancreatic cancer is safe and feasible, with a clinically meaningful turnaround time. Genomic characteristics may help to identify patients who might respond better to chemotherapy. Further study is needed to validate the prognostic and predictive value of these genomic biomarkers and to develop better patient selection treatment strategies.1
References
1. Aung KL, Fischer S, Denroche R, et al. Genomics-driven precision medicine for advanced pancreatic ductal carcinoma (PDAC): early results from the COMPASS trial (NCT02750657) [ASCO GI abstract 211]. J Clin Oncol. 2018;36(suppl 4S).
2. ClinicalTrials.gov. Study of changes and characteristics of genes in patients with pancreatic cancer for better treatment selection (COMPASS). https://clinicaltrials.gov/ct2/show/NCT02750657. Identifier: NCT02750657. Accessed March 5, 2018.
Highlights in Pancreatic Cancer From the 2018 American Society of Clinical Oncology Gastrointestinal Cancers Symposium: Commentary
Tanios Bekaii-Saab, MD
Professor, Mayo Clinic College of Medicine and Science
Program Leader, GI Program, Mayo Clinic Cancer Center
Senior Associate Consultant, Mayo Clinic
Phoenix, Arizona
Many presentations focusing on pancreatic cancer at the 2018 American Society of Clinical Oncology Gastrointestinal Cancers (ASCO GI) symposium helped further our knowledge of this deadly disease. Data from clinical trials, such as subanalyses from the NAPOLI-1 study (Nanoliposomal Irinotecan), focused on refining our understanding of which groups of patients are more likely to benefit from second-line therapy with nanoliposomal irinotecan. Further data from clinical trials provided insight into the potential successes and failures of pegylated hyaluronidase (PEGPH20), durvalumab, and olaparib.
Nanoliposomal Irinotecan
Dr Andrea Wang-Gillam and colleagues evaluated data from the NAPOLI-1 trial to see whether dose modifications of nanoliposomal irinotecan, in combination with 5-fluorouracil (5-FU), impacted efficacy.1 The randomized phase 3 NAPOLI-1 trial enrolled patients with metastatic pancreatic cancer previously treated with gemcitabine-based therapy. The study showed that the addition of nanoliposomal irinotecan to 5-FU increased survival to 6.1 months, vs 4.2 months with 5-FU alone (hazard ratio, 0.67; P=.012).2 The study was positive for its primary endpoint of overall survival, as well as for the secondary endpoints, such as progression-free survival and response rate. The study by Dr Wang-Gillam was an exploratory analysis to evaluate whether dose reductions or delays secondary to adverse events impacted overall survival.1 As expected, patients treated with nanoliposomal irinotecan, 5-FU, and leucovorin experienced more adverse events that required dose reductions or delays, at 62% vs 33%. Interestingly, among patients treated with nanoliposomal irinotecan, 5-FU, and leucovorin, the median overall survival was numerically, but not significantly, higher in patients who had a dose reduction or a dose delay. This analysis therefore shows that in patients treated with nanoliposomal irinotecan, 5-FU, and leucovorin, dose modifications related to toxicities do not significantly impact overall survival. Even when the dose of nanoliposomal irinotecan was reduced, survival remained better than with 5-FU and leucovorin alone.
This study is important because in clinical practice, there is always the concern that a reduced dose will decrease benefit. This analysis of NAPOLI-1 suggested that patients treated with nanoliposomal irinotecan, 5-FU, and leucovorin do equally well, and perhaps slightly better, than patients treated with 5-FU and leucovorin, regardless of dose delays and dose reductions. These data emphasize the importance of modifying the dose of nanoliposomal irinotecan when needed for adverse events, since this strategy does not adversely impact outcomes.
Another analysis of the NAPOLI-1 trial by Dr Wang-Gillam looked at whether a nomogram could be established to help predict survival in patients treated with nanoliposomal irinotecan.3 The study included both univariate and multivariate analysis to identify factors that might predict for overall survival. The model was created using several factors that were assigned points equal to the weight sum of relative significance of each valuable. A C-index was then evaluated by internal bootstrap validation. There were data from 417 patients for the univariate analysis and 399 patients for the multivariate analysis (in 18 patients, baseline data were missing). Positive predictors of overall survival included treatment with nanoliposomal irinotecan, 5-FU, and leucovorin; Karnofsky performance status of 90 or higher; a neutrophil-to-lymphocyte ratio of more than 5; and an albumin level of
4 g/dL or higher. Negative predictors of survival included the presence of liver metastases, CA-99 levels higher than the median of the study (1542 U/mL), and stage 4 at diagnosis. This analysis matched findings from all other studies in pancreatic cancer
This nomogram may help to stratify patients and inform decisions. In clinical practice, however, the factors used to select treatment are performance status, comorbidities, and patient/physician preferences. The nomogram helps us understand that there are different risk groups. Future studies should aim to identify the molecular and genetic differences that may lead to the various risk profiles. Currently, there are rough clinical characteristics that may or may not provide a clear picture to the best approach in managing this challenging disease.
Modified FOLFIRINOX Plus Pegylated Hyaluronidase
Dr Ramesh Ramanathan presented results from a phase 1b/2 randomized study of PEGPH20 plus modified FOLFIRINOX in patients with metastatic pancreatic cancer and a good performance status.4 PEGPH20 degrades hyaluronan, a major component of the stroma. Preclinical models suggest that the degradation of hyaluronan will increase delivery of chemotherapy and potentially prolong survival.5 Many ongoing and recently published studies include patients selected for tumor hyaluronan.6 The study by Dr Ramanathan did not select for these patients, although it did collect for tissue and will include a retrospective analysis to determine whether hyaluronan expression had any impact. The trial started as a phase 1b run-in study, and then randomly assigned patients to FOLFIRINOX plus PEGPH20 vs FOLFIRINOX alone. The planned analysis included 138 patients. The study was closed when a preplanned interim analysis showed futility with the addition of PEGPH20 to FOLFIRINOX. As expected, PEGPH20 increased the risk of clotting. Ultimately, all patients in the PEGPH20 arm were treated with low-molecular-weight heparin after an amendment was put in place.
Surprisingly, the survival differential favored the control arm, FOLFIRINOX. The median survival was 14.4 months with FOLFIRINOX alone and only 7.7 months with PEGPH20 plus FOLFIRINOX. Progression-free survival was also lower among patients treated with PEGPH20. These outcomes contrast with more favorable results that were reported for the combination of gemcitabine and nab-paclitaxel with PEGPH20.6 Previous studies that have included stromal modifiers, such as the hedgehog inhibitors, added to chemotherapy have also yielded results that were either nonsuperior or even inferior to chemotherapy alone.7 The cumulative data raise the question of whether stroma is a friend or a foe. Some data suggest that, in pancreatic cancer, the stroma may protect against the development of early metastases. At the same time, the stroma also exerts some negative immunosuppressive elements. The question remains about how to optimally target the stroma without negatively impacting outcome. The negative results from the PEGPH20 study, with a nearly 50% detrimental effect on survival, are very concerning.4 An ongoing study with gemcitabine nab-paclitaxel with or without PEGPH20 is selecting patients for high hyaluronan stains, and results should hopefully provide more insight.8
Durvalumab
Dr Eileen O’Reilly presented results of a study evaluating the combination of durvalumab, a programmed death ligand 1 inhibitor, and tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibitor, in patients with pancreatic ductal adenocarcinoma.9 These agents are active across multiple tumor types.10,11 Individually, they have not had much activity in pancreatic cancer. It was thought that the combination might synergistically increase the level of blockade and improve outcome in patients with previously treated metastatic pancreatic cancer. This study randomly assigned 65 patients to durvalumab alone or durvalumab plus tremelimumab. (One patient in the durvalumab-alone arm died before treatment began.) Among the 64 patients who received treatment, all experienced at least 1 adverse event thought to be treatment-related. None of the toxicities were fatal. The safety profiles were typical for these agents. Among the patients treated with durvalumab plus tremelimumab, 1 patient had a confirmed partial response, which lasted more than 12 months. The disease control rate was 9.4% in the combination arm. With durvalumab alone, there were 2 patients with unconfirmed partial responses, and the disease control rate was a meager 6.1%. In both arms, the median progression-free survival was 1.5 months. The median overall survival was 3.1 months with the combination vs 3.6 months with the monotherapy. These results were disappointing, and this regimen had no meaningful activity in the second-line setting for unselected patients with metastatic pancreatic cancer. Immune-based strategies continue to be very disappointing in pancreatic cancer, and further developments in this field remain challenging.
Olaparib
Dr Talia Golan presented results from a study evaluating olaparib in patients with pancreatic cancer who have the BRCAness phenotype.12 Among patients with pancreatic ductal adenocarcinoma, those with DNA damage repair from BRCA1/2 have a somewhat more favorable prognosis and tend to be sensitive to platinum analogs and poly(ADP-ribose) polymerase (PARP) inhibitors. Olaparib and rucaparib each have single-agent activity in patients with pancreatic cancer with these alterations.13,14 Veliparib, on the other hand, seems to be relatively inactive, including in highly selected patient populations. The study by Dr Golan enrolled patients with DNA damage repair deficiency without BRCA mutations (BRCAness). Approximately 10% to 15% of patients with pancreatic cancer are expected to fit this phenotype, and studies in ovarian cancer have shown benefit from PARP inhibitors in this group.15
The presentation by Dr Golan provided results of two parallel, ongoing phase 2 studies, one in Israel and the other in the United States.12 BRCAness was defined as a negative germline BRCA1/2 mutation, but a personal or family history of a BRCA-related cancer, loss of ATM, and genetic aberrations associated with homologous recombination deficiency. DNA damage repair genomic analyses identified ATM, PALB2, BRCA somatic, FANCB, PTEN, and CCNE1.
The study in Israel enrolled 21 patients, and the one in the United States included 11 patients. The Israeli study had only 5 patients with stable disease lasting for more than 4 months. In the US trial, which primarily enrolled platinum-sensitive patients, 2 patients had a partial response, and 6 had stable disease. The progression-free survival was 14 weeks in the Israeli study and 25 weeks in the US study.
This small study shows encouraging initial anti-tumor activities in platinum-sensitive germline, BRCA-negative patients with pancreatic ductal adenocarcinoma.12 The study is interesting, as it shows a potential benefit from PARP inhibitors in this BRCAness phenotype that includes up to 20% of all patients with pancreatic cancer.
Predictive Mutational Transcriptional Features
The ongoing, prospective COMPASS trial (Study of Changes and Characteristics of Genes in Patients With Pancreatic Cancer for Better Treatment Selection), from the Princess Margaret Cancer Centre in Toronto, is evaluating the predictive mutational transcriptional features in advanced pancreatic cancer.16 The goal is to improve patient stratification and treatment selection. The trial prospectively recruited patients with advanced pancreatic cancer before they started treatment. Patients underwent whole genome sequencing and RNA sequencing. Fresh tumor tissue was acquired from the patients. The tissue underwent laser capture microdissection and high genomic analysis. The primary endpoint of the study was feasibility—whether it was possible to report results from whole genome sequencing before the first disease assessment. This study, performed between 2016 and 2017, provided data for 63 patients. The genomic analyses were successful in more than 95% of the patients. The genomic results were available 35 days after biopsy, which was considered acceptable in Canada and met the primary feasibility endpoint. An unstable genomic subtype was identified in 3 patients, all of whom responded well to modified FOLFIRINOX. For these 3 patients, the predictive value of the genomic test led them to FOLFIRINOX, and all had a good response. Among 2 patients who had the same germline BRCA2 mutations, one responded to chemotherapy with loss of heterozygosity, which is a genomic hallmark of double-stranded break repair deficiency. A basal-like RNA expression signature was identified in 25% of the tumors. These patients were resistant to chemotherapy, and those that exhibited the classical RNA type had tumor shrinkage. This finding is interesting. In the clinic, we do not usually distinguish between basal-like RNA and classical RNA because these tests are not routine.
The COMPASS study provided several important insights. Close examination of the RNA sequencing reveals that 24% of patients had a basal-like RNA expression signature. These patients do not appear to respond to chemotherapy as well. The remaining 76% of patients, who have the classical RNA subtype, tend to respond better to chemotherapy. It is often thought to be difficult to find any actionable mutagenic alterations in pancreatic cancer. The COMPASS trial, however, showed that 30% of patients had potentially actionable genetic alterations. This finding is important because pancreatic cancer has been largely omitted from research in genomics and immunotherapy. This study continues to highlight the importance of precision medicine in cancer.
Disclosure
Dr Bekaii-Saab has no real or apparent conflicts of interest to report.
References
1. Wang-Gillam A, Hubner R, Mirakhur B, et al. Dose modifications of liposomal irinotecan (nal-IRI) + 5-fluorouracil/leucovorin (5-FU/LV) in NAPOLI-1: impact on efficacy [ASCO GI abstract 388]. J Clin Oncol. 2018;36(suppl 4S).
2. Wang-Gillam A, Li CP, Bodoky G, et al; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-557.
3. Wang-Gillam A, Hubner R, Mirakhur B, et al. Nomogram for predicting overall survival (OS) in patients (pts) treated with liposomal irinotecan (nal-IRI) ± 5-fluorouracil/leucovorin (5-FU/LV) in metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy in NAPOLI-1 [ASCO GI abstract 459]. J Clin Oncol. 2018;36(suppl 4S).
4. Ramanathan RK, McDonough S, Philip PA, et al. A phase IB/II randomized study of mFOLFIRINOX (mFFOX) + pegylated recombinant human hyaluronidase (PEGPH20) versus mFFOX alone in patients with good performance status metastatic pancreatic adenocarcinoma (mPC): SWOG S1313 (NCT #01959139) [ASCO GI abstract 208]. J Clin Oncol. 2018;36
(suppl 4S).
5. Sato N, Kohi S, Hirata K, Goggins M. Role of hyaluronan in pancreatic cancer biology and therapy: once again in the spotlight. Cancer Sci. 2016;107(5):569-575.
6. Hingorani SR, Zheng L, Bullock AJ, et al. HALO 202: randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma. J Clin Oncol. 2018;36(4):359-366.
7. Gu D, Schlotman KE, Xie J. Deciphering the role of hedgehog signaling in pancreatic cancer. J Biomed Res. 2016;30(5):353-360.
8. ClinicalTrials.gov. A study of PEGylated recombinant human hyaluronidase in combination with nab-paclitaxel plus gemcitabine compared with placebo plus nab-paclitaxel and gemcitabine in participants with hyaluronan-high stage IV previously untreated pancreatic ductal adenocarcinoma. https://clinicaltrials.gov/ct2/show/NCT02715804. Identifier: NCT02715804. Accessed March 6, 2018.
9. O’Reilly EM, Oh D-Y, Dhani N, et al. A randomized phase 2 study of durvalumab monotherapy and in combination with tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): ALPS study [ASCO GI abstract 217]. J Clin Oncol. 2018;36(suppl 4S).
10. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929.
11. Maio M, Scherpereel A, Calabrò L, et al. Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Lancet Oncol. 2017;18(9):1261-1273.
12. Golan T, Varadhachary GR, Sela T, et al. Phase II study of olaparib for BRCAness phenotype in pancreatic cancer [ASCO GI abstract 297]. J Clin Oncol. 2018;36(suppl 4S).
13. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244-250.
14. Dockery LE, Gunderson CC, Moore KN, et al. Rucaparib: the past, present, and future of a newly approved PARP inhibitor for ovarian cancer. Onco Targets Ther. 2017;10:3029-3037.
15. Zhang M, Liu G, Xue F, et al. Copy number deletion of RAD50 as predictive marker of BRCAness and PARP inhibitor response in BRCA wild type ovarian cancer. Gynecol Oncol. 2016;141(1):57-64.
16. Aung KL, Fischer S, Denroche R, et al. Genomics-driven precision medicine for advanced pancreatic ductal carcinoma (PDAC): early results from the COMPASS trial (NCT02750657) [ASCO GI abstract 211]. J Clin Oncol. 2018;36(suppl 4S).