Clinical Advances in Hematology & Oncology
August 2016, Volume 14, Issue 8, Supplement 10

Highlights in CINV From the 2016 MASCC/ISOO Annual Meeting

A Review of Selected Presentations From the 2016 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology Annual Meeting • June 23-25, 2016 • Adelaide, Australia

With Expert Commentary by:
Lee S. Schwartzberg, MD
Professor of Medicine
Chief, Division of Hematology & Oncology
The University of Tennessee Health Science Center
Memphis, Tennessee

Rolapitant for Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV) in Patients With Breast Cancer

Chemotherapy-induced nausea and vomiting (CINV) is commonly associated with antineoplastic treatment. It is categorized into 3 main phases. The acute phase occurs within 24 hours of chemotherapy administration, the delayed phase occurs from 24 to 120 hours after chemotherapy administration, and the overall phase encompasses 0 through 120 hours after administration. Acute-phase CINV is mediated primarily by peripherally released serotonin that binds to 5-hydroxytryptamine (5-HT₃) receptors in the vagal afferent neurons. Delayed-phase CINV is caused primarily by binding of substance P to the central neurokinin-1 (NK₁) receptors. CINV causes many patients extreme stress while decreasing quality of life and functional status.^1,2 Female sex and young age are 2 risk factors for CINV.

Rolapitant is a selective, long-acting NK₁ receptor antagonist. In September 2015, the US Food and Drug Administration (FDA) approved rolapitant, in an oral formulation, for use in combination with a 5-HT₃ receptor antagonist plus dexamethasone for the prevention of delayed CINV in adults receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC).³ The approval was based on three global, double-blind, randomized, placebo-controlled phase 3 trials showing that oral rolapitant (180 mg) improved control of CINV when added to standard treatment among patients receiving HEC or MEC.^4,5 An intravenous (IV) formulation is currently under review by the FDA.

Breast cancer is the most common malignancy diagnosed in women around the world.⁶ Many of these patients receive chemotherapy regimens that include anthracyclines and are therefore highly emetogenic. Approximately half of breast cancer patients are diagnosed before age 60 years, imparting a high risk of CINV. Dr Lee Schwartzberg presented results from a post hoc subgroup analysis of the rolapitant MEC trial, focusing on patients with breast cancer. The MEC trial included patients treated with an anthracycline plus cyclophosphamide (AC), which was considered a moderate emetic risk at the time of the trial design.⁷ In this international, double-blind, placebo-controlled, phase 3 trial, the addition of rolapitant (180 mg) demonstrated efficacy and safety in the prevention of delayed CINV in patients receiving MEC regimens.⁵ The trial enrolled 1332 patients at 170 cancer centers in 23 countries. MEC regimens included carboplatin, cyclophosphamide, doxorubicin, and/or fluorouracil. Patients were stratified by sex and then randomly assigned to receive rolapitant (180 mg) or placebo in combination with dexamethasone (20 mg) on day 1 and granisetron (2 mg) on days 1 to 3. The trial’s primary endpoint was the rate of complete response (CR) for delayed emesis. Secondary endpoints included the CR rate during the acute and overall phases. In the overall study population, rolapitant (n=666) showed a 10% improvement over placebo (n=666; 71.3% vs 61.6%; P=.002) in the delayed-phase CR rate, thus achieving the primary endpoint (Figure 1). This improvement carried through to the overall phase (68.6% vs 58.1%; P<.001), but was not evident during the acute phase (83.5% with rolapitant vs 80.3% with placebo; P=.1425).

Breast cancer patients represented approximately two-thirds of the overall study population. Among the entire subpopulation of breast cancer patients, 417 received rolapitant and 428 received placebo. These patients had a median age of 53 to 54 years (range, 22-86 years). Among the subset of breast cancer patients treated with AC chemotherapy, 333 received rolapitant and 347 received placebo. For the entire subgroup of breast cancer patients, rolapitant demonstrated superior control of CINV during the delayed phase (66.7% vs 59.8%; P=.039) and the overall phase (62.8% vs 55.1%; P=.023), but was similar to placebo during the acute phase (77.9% with rolapitant vs 77.8% with placebo; P=.963; Figure 2). The subset of breast cancer patients who received AC chemotherapy yielded similar results, with a significant improvement provided by rolapitant (66.7%) vs placebo (58.8%; P=.034). Again, rolapitant showed superior CINV control during the overall phase (62.5% vs 53.9%; P=.024), but did not demonstrate an advantage during the acute phase (76.0% with rolapitant vs 76.7% with placebo; P=.835).

Rolapitant increased the proportion of patients without emesis during the delayed phase (77.2% vs 68.7%; P=.005) and in the overall phase (74.3% vs 62.6%; P<.001). No significant improvement was observed during the acute phase (84.4% with rolapitant vs 82.5% with placebo; P=.351). Similar improvements were obtained in the breast cancer patients who received AC treatment for the delayed phase (P=.007) and the overall phase (P<.001), with no significant improvement in the acute phase (P=.359). Throughout all phases, the rates of nausea, significant nausea, and complete protection did not differ significantly between the rolapitant and placebo arms. For the entire breast cancer population in the overall phase, no nausea was observed in 35.5% who received rolapitant vs 37.4% who received placebo (P=.520). Thus, control of nausea remains an unmet need in breast cancer patients receiving MEC or AC-based chemotherapy.

Consistent with the results observed in the entire study population, similar safety profiles were observed for breast cancer patients treated with rolapitant or placebo. Approximately 69% of patients had at least 1 treatment-emergent adverse event (AE). The proportion of patients with a treatment-related AE was 11.2% in the rolapitant group vs 8.8% in the control group. Among patients treated with AC, treatment-related AEs occurred in 9.0% vs 8.8%, respectively. Treatment-emergent AEs causing discontinuation of the study drug occurred in 0.7% of the rolapitant group vs 1.2% of the placebo group. The most common treatment-related AEs were constipation, headache, and fatigue, occurring in 2.3% to 3.3% of patients. No unexpected AEs emerged.

References

1. Rhodes VA, McDaniel RW. Nausea, vomiting, and retching: complex problems in palliative care. CA Cancer J Clin. 2001;51(4):232-248.

2. Lee J, Dibble SL, Pickett M, Luce J. Chemotherapy-induced nausea/vomiting and functional status in women treated for breast cancer. Cancer Nurs. 2005;28(4):249-255.

3. Varubi [package insert]. Waltham, MA: Tesaro, Inc; 2015.

4. Rapoport BL, Chasen MR, Gridelli C, et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials. Lancet Oncol. 2015;16(9):1079-1089.

5. Schwartzberg LS, Modiano MR, Rapoport BL, et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial. Lancet Oncol. 2015;16(9):1071-1078.

6. Cancer facts and figures: worldwide data. World Cancer Research Fund International. http://www.wcrf.org/int/cancer-facts-figures/worldwide-data. Accessed July 20, 2016.

7. Schwartzberg LS, Navari RM, Arora S, Powers D, Jordan K, Rapoport BL. Rolapitant for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with breast cancer. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0316.

Rolapitant for Control of Chemotherapy-Induced Nausea and Vomiting (CINV) in Patients With Lung Cancer

Three pivotal phase 3 trials demonstrated that the addition of a single dose of oral rolapitant to standard therapy reduced the incidence of delayed CINV in patients receiving MEC or HEC.^1,2 The Highly Emetogenic Chemotherapy trials 1 and 2 (HEC-1 and HEC-2) evaluated cisplatin-based chemotherapy.¹ Patients were randomly assigned to receive rolapitant (180 mg on day 1) or matching placebo, plus granisetron (10 µg/kg on day 1), and dexamethasone (20 mg on day 1 followed by 8 mg twice daily, on days 2-4). In the overall study population of 1070 patients who were receiving cisplatin-based treatment, the addition of rolapitant resulted in a significant improvement in delayed-phase CINV control over placebo (71% vs 60%; P=.0001), thus meeting the primary endpoint. The study met its secondary endpoints as well, demonstrating improved CINV control during the acute phase (82% vs 77%; P=.0045) and the overall phase (69% vs 59%; P=.0005). A companion trial by Schwartzberg and colleagues investigated the addition of rolapitant to dexamethasone plus granisetron in patients with various cancer types who were receiving MEC or AC.² In this study, oral rolapitant demonstrated a 10% improvement over placebo for the delayed-phase CR rate (71.3% vs 61.6%; P=.002), thus achieving the primary endpoint.

Dr Rudolph Navari presented results from a post hoc analysis of the subgroup of lung cancer patients included in these 3 trials, with 337 patients in the rolapitant subgroup and 350 in the control group.³ The rolapitant vs placebo groups were well-balanced with respect to age, sex, alcohol consumption, region, and chemotherapies. Patients had a median age of 61 to 62 years (range, 24-88 years). In both arms, approximately 70% of patients were male. In the rolapitant group, the chemotherapy regimens included cisplatin in 70.0% and carboplatin in 29.4% (vs 65.7% and 32.6% in the placebo group).

For lung cancer patients treated with either cisplatin or carboplatin, the addition of oral rolapitant provided significantly more protection against CINV than placebo. The trial met its primary endpoint, demonstrating increased control of CINV when rolapitant was added to a 5-HT₃ receptor antagonist plus dexamethasone (77.4% vs 65.1%; P<.001; Table 1). Rolapitant also demonstrated an increased CR rate vs placebo in the acute phase (88.4% vs 82.7%; P=.014) and the overall phase (75.4% vs 63.1%; P<.001). Emesis control was superior with rolapitant vs placebo in the delayed phase (81.0% vs 69.7%; P<.001), the acute phase (91.1% vs 84.6%; P=.009), and the overall phase (79.8% vs 67.7%; P<.001). In contrast to the breast cancer subgroup,⁴ in the lung cancer population, the addition of rolapitant reduced the proportion of patients experiencing nausea in the delayed and overall phases. The proportions of patients with no nausea were 63.5% with rolapitant vs 51.1% with placebo in the delayed phase (P=.001), 75.7% vs 70.9% in the acute phase (P=.155), and 60.5% vs 48.6% in the overall phase (P=.002). The demonstration of nausea control stands in contrast to results observed with other NK₁ receptor antagonists. Significantly improved rates of complete protection were also observed in lung cancer patients who received rolapitant vs placebo, at 73.0% vs 60.3% for the delayed phase (P<.001), 86.1% vs 80.3% for the acute phase (P=.044), and 70.9% vs 58.6% for the overall phase (P<.001).

No new safety signals emerged in patients who received rolapitant. The rolapitant and control groups demonstrated similar safety profiles. Treatment-emergent AEs were reported in 58.0% of the rolapitant group vs 58.1% of the placebo group.

References

1. Rapoport BL, Chasen MR, Gridelli C, et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials. Lancet Oncol. 2015;16(9):1079-1089.

2. Schwartzberg LS, Modiano MR, Rapoport BL, et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial. Lancet Oncol. 2015;16(9):1071-1078.

3. Navari RM, Rapoport BL, Arora S, Powers D, Jordan K, Schwartzberg LS. Rolapitant for control of chemotherapy-induced nausea and vomiting (CINV) in patients with lung cancer. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0321.

4. Schwartzberg LS, Navari RM, Arora S, Powers D, Jordan K, Rapoport BL. Rolapitant for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with breast cancer. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0316.

Quality of Life, Efficacy and Patient-Reported Outcome With NEPA as CINV Prophylaxis in Highly or Moderately Emetogenic Chemotherapy

The fixed-dose oral combination tablet NEPA was approved by the FDA in October 2014 for the management of acute and delayed CINV during initial and subsequent cycles of HEC or MEC.¹ NEPA contains netupitant (300 mg) and palonosetron (0.5 mg). Netupitant is an NK₁receptor antagonist, and palonosetron is a 5-HT₃ receptor antagonist. Netupitant has an 8-fold longer half-life than its predecessor, aprepitant, and has high binding affinity to NK₁ receptors. Palonosetron is a second-generation serotonin receptor antagonist with antiemetic activity at central and gastrointestinal sites.^2,3 Compared with first-generation 5-HT₃ receptor antagonists, palonosetron has a 30-fold higher receptor binding affinity and a longer half-life that confer higher potency. Palonosetron has also demonstrated superior tolerability compared with other serotonin receptor antagonists.

Dr Petra Feyer presented preliminary results of a study evaluating quality of life, efficacy, and patient-reported outcomes with NEPA in patients receiving MEC or HEC on 1 or 2 days per cycle.⁴ The multicenter, prospective, noninterventional study has a planned enrollment of 2500 patients at 200 centers in Germany and an observation period of 2 years. The study’s primary endpoint is quality of life based on the Functional Living Index—Emesis (FLIE) questionnaire. The secondary endpoints include efficacy, safety, and use of rescue medication. Patients receive documented antiemetic prophylaxis with NEPA during 3 consecutive chemotherapy cycles. After the completion of each chemotherapy cycle, NEPA efficacy is evaluated and electronically documented by physicians using a 4-point scale representing very good, good, satisfactory, or poor. Patients are required to keep a diary reporting use of rescue medication as well as levels of emesis and vomiting using a 4-point scale indicating no, rare, moderate, or strong symptoms, with separate reporting for anticipatory nausea and vomiting.

The study population consisted of adults who were receiving treatment with MEC or HEC in regimens of 1 or 2 days. NEPA was administered based on the physician’s choice. Between September 2015 and June 2016, the study recruited 704 patients. Among the 583 patients available for preliminary analysis, the median age was 56 years (range, 28-88 years), and 89% were female. The majority of patients had breast cancer (71.0%), followed by cancer of the ovary (7.7%), colon or rectum (4.8%), lung (4.5%), stomach (2.1%), pancreas (1.9%), head and neck (1.2%), and cervix (1.0%). The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 57.6%, 1 in 35.0%, and 2 in 7.4%. Chemotherapy was administered in the adjuvant setting in 50.9%, the neoadjuvant setting in 26.7%, and as palliative care in 22.4%. Treatment regimens included AC-based chemotherapy in 55.9%, carboplatin in 17.7%, cisplatin in 7.5%, oxaliplatin in 6.5%, other MECs in 6.3%, and low emetogenic chemotherapy in 6.1%.

The analysis included 486, 409, and 350 patients with data from chemotherapy cycles 1, 2, and 3, respectively. Based on physician evaluation, NEPA efficacy was very good or good in 90.7% of patients in cycle 1, 93.4% in cycle 2, and 92.9% in cycle 3 (Figure 3). During cycle 1, self-assessments from 87 patients demonstrated a high CR rate. There was no emesis or use of rescue medication during the acute phase in 88.8% of patients, during the delayed phase in 85.1%, and during the overall phase in 79.2%. No emesis was reported by 94% of patients in the acute phase, 99% in the delayed phase, and 93% in the overall phase.

References

1. Akynzeo [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2015.

2. Navari RM. Profile of netupitant/palonosetron (NEPA) fixed dose combination and its potential in the treatment of chemotherapy-induced nausea and vomiting (CINV). Drug Des Devel Ther. 2014;9:155-161.

3. Janicki PK. Management of acute and delayed chemotherapy-induced nausea and vomiting: role of netupitant-palonosetron combination. Ther Clin Risk Manag. 2016;12:693-699.

4. Feyer P, Schilling J, Karthaus M, et al. Quality of life, efficacy and patient-reported outcome with NEPA as CINV prophylaxis in highly or moderately emetogenic chemotherapy. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0289.

Olanzapine for the Prophylaxis and Rescue of Chemotherapy-Induced Nausea and Vomiting (CINV): A Retrospective Study

Olanzapine is an established anti-psychotic agent of the thieno-ben-zodiazepine class that targets many different receptors, including the dopaminergic, serotonergic, adrenergic, histaminergic, and muscarinic recep-tors.^1-5 It has demonstrated efficacy in the setting of CINV prophylaxis among patients receiving treatment with MEC or HEC, but little information is available regarding its use as rescue medication for breakthrough CINV.

Olanzapine was compared with metoclopramide for the ability to control breakthrough CINV in a double-blind, randomized phase 3 trial.⁶ The study included chemotherapy-naive patients receiving HEC containing cisplatin or doxorubicin plus cyclophosphamide. All patients received prophylactic palonosetron, fosaprepitant, and dexamethasone. Patients were randomized to receive oral olanzapine (10 mg daily for 3 days) or oral metoclopramide (10 mg 3 times daily for 3 days). Of the 276 randomized patients, 112 developed breakthrough CINV, and 108 were evaluable. During the 72-hour observation period after administration of therapy for breakthrough CINV, no emesis occurred in 70% of patients treated with olanzapine vs 31% of patients treated with metoclopramide (P<.01). Olanzapine was also associated with a higher proportion of patients who did not report nausea (68% vs 23%; P<.01).

Dr Leonard Chiu presented results of a study that retrospectively evaluated the safety and efficacy of olanzapine for the treatment of breakthrough CINV, with additional data on the efficacy and safety of the drug’s use in the prophylactic setting in a smaller cohort of patients.⁷ A retrospective review was conducted of electronic medical records of adult patients who received a prescription for olanzapine from a single hospital-associated pharmacy between January 2013 and June 2015. Included patients had received 1 or more doses of olanzapine for the rescue or prophylaxis of CINV with documentation of the outcome. The analysis included 154 patients and 193 treatment cycles in the rescue setting, as well as 16 patients representing 20 treatment cycles in the prophylactic setting.

In the rescue setting, nausea improved in 88.1% of patients, and vomiting improved in 21.8% (Table 2). In the prophylactic setting, olanzapine reduced nausea in 100% of patients and vomiting in 35%.

The adverse events included sedation and constipation. Sedation was reported by 42.5% of patients in the breakthrough setting and by 65.0% of patients who received olanzapine as prophylaxis. Constipation occurred in 31.6% of patients in the rescue setting and 35.0% of patients in the prophylactic setting.

References

1. Navari RM. Treatment of breakthrough and refractory chemotherapy-induced nausea and vomiting. Biomed Res Int. 2015;2015:595894.

2. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al; Aprepitant Protocol 054 Study Group. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer. 2003;97(12):3090-3098.

3. Schmoll HJ, Aapro MS, Poli-Bigelli S, et al. Comparison of an aprepitant regimen with a multiple-day ondansetron regimen, both with dexamethasone, for antiemetic efficacy in high-dose cisplatin treatment. Ann Oncol. 2006;17(6):1000-1006.

4. Hesketh PJ, Grunberg SM, Gralla RJ, et al; Aprepitant Protocol 052 Study Group. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—the Aprepitant Protocol 052 Study Group. J Clin Oncol. 2003;21(22):4112-4119.

5. Hashimoto H, Yamanaka T, Shimada Y, et al. Palonosetron (PALO) versus granisetron (GRA) in the triplet regimen with dexamethasone (DEX) and aprepitant (APR) for preventing chemotherapy-induced nausea and vomiting (CINV) in patients (pts) receiving highly emetogenic chemotherapy (HEC) with cisplatin (CDDP): a randomized, double-blind, phase III trial [ASCO abstract 9621]. J Clin Oncol. 2013;31(15S).

6. Navari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Support Care Cancer. 2013;21(6):1655-1663.

7. Chiu L, Chiu N, Chow R, et al. Olanzapine for the prophylaxis and rescue of chemotherapy-induced nausea and vomiting (CINV): a retrospective study. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0153.

Rolapitant for Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV) in Patients Aged <65 Versus ≥65 Years

Patients younger than 65 years are at increased risk for CINV.^1,2 Patients ages 65 years and older are at greater risk for CINV-related complications, including dehydration, impaired renal function, and abnormal blood pressure. The efficacy of rolapitant (180 mg) administered as a single dose in combination with a 5-HT₃ receptor antagonist plus dexamethasone has been demonstrated in placebo-controlled, randomized phase 3 trials in patients receiving HEC or MEC.^3,4 In these pivotal, phase 3 trials, patients recorded emetic episodes and use of rescue medication in diaries for approximately 120 hours following administration of chemotherapy. Each trial had a primary endpoint of CR, defined as no emesis and no use of rescue medication during the delayed phase.

Dr Matti Aapro presented results of an exploratory analysis of pooled data from these phase 3 trials based on patient age (<65 years vs ≥65 years).⁵ The 3 trials included 2402 patients in the modified intent-to-treat population, of whom 73.1% were younger than 65 years and 26.9% were ages 65 years and older. Data from the trials of HEC showed that CR rates were similar for the younger and older patients in the acute phase (76.8% vs 76.1%), delayed phase (59.8% vs 61.3%), and overall phase (58.5% for both). Data from the placebo arm of the MEC or AC chemotherapy trial showed a trend toward a lower CR rate in younger patients vs older patients in all phases (acute, 56.6% vs 60.7%; delayed, 60.9% vs 63.3; and overall, 56.6% vs 60.7%), consistent with the known increased risk of CINV in younger patients as well as the greater proportion of female patients in the younger cohort.

As was observed in the overall populations of the 3 pivotal studies, the addition of rolapitant improved the CR rate compared with placebo for the cohorts of younger and older patients in the acute, delayed, and overall phases of the HEC-1 and HEC-2 trials and in the delayed and overall phases of the MEC or AC chemotherapy trial. The analysis showed that patients younger than 65 years as well as those ages 65 years or older benefited from the addition of rolapitant to a 5-HT₃ receptor antagonist plus dexamethasone.

Based on Kaplan-Meier analysis of time to first emesis or use of rescue medication, rolapitant protected against CINV during the entire 120-hour study duration in younger patients and older patients in the pooled cohorts from the HEC-1 and HEC-2 trials (P=.004 and P=.008, respectively; Figure 4) and in patients from the MEC or AC chemotherapy trial (P=.001 and P=.016, respectively). In the MEC or AC chemotherapy trial, the older patients showed a delayed time to first emesis and delayed use of rescue medication compared with the younger cohort. However, this study had a greater proportion of female patients, who are more likely to develop CINV. Rolapitant was generally well-tolerated in both of the age-based patient cohorts from the 3 pivotal trials.

References

1. Benrubi GI, Norvell M, Nuss RC, Robinson H. The use of methylprednisolone and metoclopramide in control of emesis in patients receiving cis-platinum. Gynecol Oncol. 1985;21(3):306-313.

2. Pollera CF, Giannarelli D. Prognostic factors influencing cisplatin-induced emesis. Definition and validation of a predictive logistic model. Cancer. 1989;64(5):1117-1122.

3. Schwartzberg LS, Modiano MR, Rapoport BL, et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial. Lancet Oncol. 2015;16(9):1071-1078.

5. Aapro M, Arora S, Powers D. Rolapitant for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients aged <65 versus ≥65 years. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0432.

A Single-Dose Bioequivalence Study of Rolapitant Following Oral and Intravenous Administration in Healthy Volunteers

The FDA approved rolapitant in an oral formulation for the prevention of CINV in the delayed phase based on results of three phase 3 trials.^1,2 The FDA is currently reviewing an IV formulation of rolapitant. Dr Xiaodong Wang presented results from an open-label, single-center, parallel-group, randomized study that assessed the bioequivalence, safety, and efficacy of a single oral dose of rolapitant (180 mg) administered in four 45-mg capsules vs a single IV dose of rolapitant (166.5 mg) administered via a 30-minute infusion.³ Blood samples were obtained for pharmacokinetic analysis before rolapitant administration and at specified time points up to 912 hours after drug administration. Mean plasma concentration time profiles for rolapitant were generated and evaluated for the maximum concentration (C_max) and area under the curve (AUC). Ninety percent confidence intervals (CIs) between 0.80 and 1.25 were specified as equivalence bounds.

Oral rolapitant was administered to 67 patients, and the IV formulation was administered to 71. The study demonstrated bioequivalence of the 2 formulations. The mean plasma concentrations as measured from 0 to 912 hours were similar (Figure 5). The 90% CIs of the geometric least-squares mean ratio (GMR) fell within the prespecified bounds of 0.80 to 1.25 for all pharmacokinetic parameters, for AUC through the last measured concentration (GMR, 1.01; 90% CI, 0.94-1.09), and for AUC extrapolated to infinity (GMR, 1.01; 90% CI, 0.93-1.10). As anticipated, the C_max values were higher following IV administration of rolapitant (GMR=1.90). M19 is a major metabolite of rolapitant, and analysis of M19 pharmacokinetic parameters also demonstrated bioequivalence (Figure 6), with GMR values of 0.98 (90% CI, 0.93-1.04) for C_max, 0.97 (90% CI, 0.91-1.03) for AUC through the last measured concentration, and 0.95 (90% CI, 0.88-1.03) for AUC extrapolated to infinity.

There were no severe or serious treatment-emergent AEs. No new rolapitant-associated AEs were identified.

References

1. Schwartzberg LS, Modiano MR, Rapoport BL, et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial. Lancet Oncol. 2015;16(9):1071-1078.

2. Rapoport BL, Chasen MR, Gridelli C, et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials. Lancet Oncol. 2015;16(9):1079-1089.

3. Wang X, Zhang ZY, Arora S, et al. A single-dose bioequivalence study of rolapitant following oral and IV administration in healthy volunteers. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0485.

No Signals of Increased Toxicity After Concomitant Administration of NEPA With Etoposide or Docetaxel: Pooled Safety Data From 4 Pivotal Studies

NEPA is an oral, fixed-dose combination of the NK₁receptor antagonist netupitant and the 5-HT₃ receptor palonosetron. Netupitant also moderately inhibits the cytochrome P450 isoenzyme 3A. Etoposide and docetaxel are metabolized primarily by CYP3A4 and CYP3A5, leading to concerns of potential drug-drug interactions between netupitant and these therapies. Dr Matti Aapro presented results of a post hoc safety analysis that evaluated toxicities in patients treated with etoposide and/or docetaxel plus either NEPA or palonosetron (oral or IV).¹ The analysis included data from 3280 patients enrolled in a single phase 2 trial or three phase 3 studies.^2-5

The median ages ranged from 53 to 59 years. Most patients who received etoposide were male and had cancer of the lung or respiratory tract. Patients treated with docetaxel had cancer of the breast, head and neck, lung or respiratory tract, and others. Most patients had an ECOG performance status of 0 or 1.

There were no clinically relevant differences in the frequency of serious AEs or treatment-emergent AEs. In the etoposide cohort, the proportion of patients who experienced at least 1 serious AE was 9.0% with NEPA, 9.4% with oral palonosetron, and 13.3% with IV palonosetron (Table 3). The proportions of patients with any treatment-emergent AE were 7.9% with NEPA, 4.7% with oral palonosetron, and 13.3% with IV palonosetron. In the docetaxel cohort, the proportion of patients who experienced at least 1 serious AE was 20.4% with NEPA, 13.5% with oral palonosetron, and 30.8% with IV palonosetron. The proportions of patients with any treatment-emergent AE were 20.4%, 8.1%, and 15.4% in the 3 subcohorts, respectively.

References

1. Aapro M, Arora S, Powers D. No signals of increased toxicity after concomitant administration of NEPA with etoposide or docetaxel: pooled safety data from 4 pivotal studies. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0565.

2. Hesketh PJ, Rossi G, Rizzi G, et al. Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study. Ann Oncol. 2014;25(7):1340-1346.

3. Aapro M, Rugo H, Rossi G, et al. A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol. 2014;25(7):1328-1333.

4. Gralla RJ, Bosnjak SM, Hontsa A, et al. A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy. Ann Oncol. 2014;25(7):1333-1339.

5. Karthaus M, Tibor C, Lorusso V, et al. Efficacy and safety of oral palonosetron compared with IV palonosetron administered with dexamethasone for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with solid tumors receiving cisplatin-based highly emetogenic chemotherapy (HEC). Support Care Cancer. 2015;23(10):2917-2923.

Phase II Study of Palonosetron, Aprepitant, Dexamethasone and Olanzapine for the Prevention of Cisplatin-Based Chemotherapy-Induced Nausea and Vomiting in Patients With Thoracic Malignancy

The 3-drug combination of a 5-HT₃ receptor antagonist, aprepitant, and dexamethasone is recommended for patients receiving HEC. Phase 3 studies investigating this 3-drug combination have reported CINV CR rates of approximately 60% to 70% in the overall phase. Olan-zapine inhibits several neurotransmitter pathways that are involved in nausea and vomiting, including those mediated by the serotonergic, dopaminergic, α-1 adrenergic, histaminic, and muscarinic receptors.^1-4 The combination of olan-
zapine plus standard antiemetic therapy demonstrated efficacy in preventing CINV in several clinical trials of patients receiving HEC.^5-7

Dr Kouichi Yokoyama presented results of an open-label, single-center, single-arm phase 2 study that evaluated the combination of olanzapine, palonosetron, aprepitant, and dexamethasone for the prevention of CINV in patients with thoracic malignancy receiving cisplatin-based chemotherapy.⁸ Patients were ages 20 years or older and had histologically or cytologically confirmed thoracic malignant disease and an ECOG performance status of 0 or 1. All patients received combination chemotherapy that included a minimum cisplatin dose of 60 mg/m². Patients also received oral olanzapine (5 mg) once daily at night on days 1 to 5 in combination with standard antiemetic therapy consisting of IV palonosetron (0.75 mg, day 1), oral aprepitant (125 mg, day 1; 80 mg days, 2 and 3), and IV dexamethasone (9.9 mg, day 1) followed by oral dexamethasone (8 mg, days 2-4). The trial’s primary endpoint was the CR rate in the overall phase. Secondary endpoints included CR rates in the acute and delayed phases; complete control rates, defined as no vomiting, no rescue, and no significant nausea and a numeric rating scale value of 0 to 2; total control rates, defined as no vomiting, no rescue, and no significant nausea and a numeric rating scale value of 0; and AEs.

Thirty patients were enrolled from May 2015 through October 2015. Patients had a median age of 64 years (range, 36-75 years), and 77% were male. Tumor types included non–small cell lung cancer (63.3%), small cell lung cancer (26.7%), malignant pleural mesothelioma (6.7%), and thymoma (3.3%). The majority of patients received cisplatin-based treatment as part of systemic chemotherapy (63.3%) or chemoradiation (30.0%), with 6.7% of patients receiving it as postoperative adjuvant therapy. Most patients received cisplatin at 75 mg/m² (46.7%) or 80 mg/m² (40.0%), with 13.3% receiving a dose of 60 mg/m². Cisplatin was most commonly administered in combination with pemetrexed (46.7%), etoposide (23.3%), or vinorelbine (13.3%).

The olanzapine combination yielded a CR rate of 83% in the overall phase, meeting its primary endpoint. In the acute and delayed phases, the CR rates were 100% and 83%, respectively. The complete control rates in the acute, delayed, and overall phases were 93%, 73%, and 70%, respectively (Table 4). The total control rates in the acute, delayed, and overall phases were 77%, 70%, and 63%. No grade 3 or 4 AEs occurred during treatment, and no patients discontinued olanzapine treatment. Four patients (13%) experienced grade 1 somnolence, an AE commonly observed in patients treated with olanzapine.

References

1. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al; Aprepitant Protocol 054 Study Group. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer. 2003;97(12):3090-3098.

2. Schmoll HJ, Aapro MS, Poli-Bigelli S, et al. Comparison of an aprepitant regimen with a multiple-day ondansetron regimen, both with dexamethasone, for antiemetic efficacy in high-dose cisplatin treatment. Ann Oncol. 2006;17(6):1000-1006.

3. Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin–the Aprepitant Protocol 052 Study Group. J Clin Oncol. 2003;21(22):4112-4119.

4. Hashimoto H, Yamanaka T, Shimada Y, et al. Palonosetron (PALO) versus granisetron (GRA) in the triplet regimen with dexamethasone (DEX) and aprepitant (APR) for preventing chemotherapy-induced nausea and vomiting (CINV) in patients (pts) receiving highly emetogenic chemotherapy (HEC) with cisplatin (CDDP): a randomized, double-blind, phase III trial [ASCO abstract 9621]. J Clin Oncol. 2013;31(15S).

5. Navari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Support Care Cancer. 2013;21(6):1655-1663.

6. Abe M, Kasamatsu Y, Kado N, et al. Efficacy of olanzapine combined therapy for patients receiving highly emetogenic chemotherapy resistant to standard antiemetic therapy. Biomed Res Int. 2015;2015:956785.

7. Navari RM, Qin R, Ruddy KJ, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med. 2016;375(2):134-142.

8. Yokoyama K, Murakami H, Nakashima K, et al. Phase II study of palonosetron, aprepitant, dexamethasone and olanzapine for the prevention of cisplatin-based chemotherapy-induced nausea and vomiting in patients with thoracic malignancy. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0198.

Nausea as a Symptom Cluster

Therapies introduced during the last decade have alleviated the majority of chemotherapy-associated vomiting.^1,2 To combat CINV associated with HEC, guidelines recommend triple-therapy combinations that include a 5-HT₃ receptor antagonist, dexamethasone, and an NK₁ receptor antagonist. Although these combinations are effective in reducing emesis, nausea continues to be a concern for a large proportion of patients.

In a symposium focused on nausea, Dr Ian Olver presented an overview of studies revealing that patients use the term “nausea” to describe a wide range of symptoms, and that treatments addressing these broader symptoms may be needed to increase efficacy.³ Nausea has been described as “an unpleasant feeling that is usually accompanied by changes in autonomic nervous system activity, particularly (but not exclusively) the parasympathetic division.”⁴ Up to 75% of patients undergoing chemotherapy will report nausea at some point, and many patients continue to experience anticipatory or conditioned nausea years after the cessation of chemotherapy treatment.⁵

In a qualitative study of 17 patients who experienced nausea during chemotherapy, patients described their experience as distressing and complex.⁶ Patients attempted to understand their symptoms by analyzing their own experience of nausea and related symptoms, attributing causation to nausea, and comparing their own experiences with those of others and with their own expectations. Concurrent symptoms included sleep disturbance, fatigue, bloating, sore throat, sweating, weakness, dizziness, headache, flu-like symptoms, and feeling hot and cold. Combinations of these symptoms were present when nausea arose.

CINV negatively impacts quality of life, as described in a longitudinal secondary analysis of data derived from a prospective, observational study of 200 newly diagnosed cancer patients who underwent combined modality treatment.⁷ Quality of life, psychological adjustment, and patient and clinical characteristics were examined before treatment, during 8 weeks of treatment, and after treatment. Nausea was more than twice as common as vomiting, with 62% and 27% of patients reporting the symptoms, respectively. Quality-of-life scores yielded a recurrent gastrointestinal symptom cluster consisting of nausea, vomiting, and loss of appetite, with approximately two-thirds of patients reporting these symptoms concomitantly. This symptom cluster was accompanied by reductions in physical and social functioning; increased fatigue, nausea and vomiting; loss of appetite; increased psychological distress; and decreases in overall physical health and quality of life. The symptom cluster resulted in reduced quality of life for affected patients compared with unaffected patients. In a study of 16 breast cancer patients who had completed chemotherapy, patients tended to describe nausea as an ache or unsettled feeling in the stomach or throat or as feeling the need to vomit.⁸

A study was conducted to further elucidate whether patients’ experience of nausea in fact represents a cluster of symptoms.⁹ Patients with current or past experience of chemotherapy-induced nausea were interviewed. Each group of patients consisted of 12 women and 9 men. Study participants had a median age of 50 years, and were a median 3.5 years past treatment. Current patients had a median age of 54 years, and were treated in an outpatient clinic. Across both patient groups, the nature, number, location, duration, and intensity of experiences described as nausea varied, and no single symptom was common to all descriptions. Physical and psychological symptoms included dry retching, vomiting, loss of appetite, indigestion, change of taste, dizziness, bloating, reflux, inability to concentrate, fatigue, and physical restlessness. Onset ranged from immediate to the fifth day after chemotherapy. The duration of nausea ranged from 1.5 hours to 6 months; however, conditioned stimuli could trigger nausea for years after cessation of treatment. For most patients, chemotherapy-induced nausea was distinguished from other experiences of nausea by several factors, including its constant presence over time, emotional associations with the cancer diagnosis, and the concomitant presence of fatigue. Nausea often had a negative impact on social and work interactions. Antiemetic agents reduced the intensity of nausea but did not fully alleviate it. Preferred management techniques included relaxation and distractions, such as working and watching television.

Most physical sensations involved the stomach, with descriptions of pressure or feeling full, feelings of queasiness or churning, or feeling that the stomach was rejecting food. Nausea affected patients’ eating patterns and appetite. Many patients experienced swallowing difficulties tied to sensations of the throat constricting, and others experienced taste alterations that made food undesirable, whereas 2 patients reported increased appetite. Other physical sensations included whole body fatigue, restlessness, dizziness, and fever. The psychological symptoms led to added distress because they provided a constant reminder of the cancer. The findings suggest that more effective treatment of nausea may require treatment of the component symptoms by more judicious use of drugs, including olanzapine, cannabinoids, and antacids, but also through nonpharmacologic approaches, such as changes to the diet and determining which distractions are most effective.

A meta-analysis of olanzapine was conducted to assess the efficacy of olanzapine for the prevention of CINV after MEC or HEC.¹⁰ The analysis included 6 studies involving a total of 726 patients, of whom 441 were Chinese. The authors concluded that for the overall and Chinese populations, regimens containing olanzapine are more effective at reducing CINV than regimens that do not contain olanzapine, particularly in the delayed phase.

In addition to underscoring the need to develop more effective drugs, Dr Olver described development of a patient-reported outcomes tool, ePRO, to identify and assess components of the larger nausea symptom cluster during chemotherapy. Use of the tool could enable treatment of patients on a personalized basis by targeting specific symptoms. Other potential uses for the ePRO tool include assessment of pretreatment risk factors to guide prophylactic treatment and to reduce anticipatory nausea in cancer survivors.

References

1. Janicki PK. Management of acute and delayed chemotherapy-induced nausea and vomiting: role of netupitant-palonosetron combination. Ther Clin Risk Manag. 2016;12:693-699.

2. Warr D. Management of highly emetogenic chemotherapy. Curr Opin Oncol. 2012;24(4):371-375.

3. Olver I. Nausea as a symptom cluster. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia.

4. Morrow GR, Roscoe JA, Hickok JT, Andrews PR, Matteson S. Nausea and emesis: evidence for a biobehavioral perspective. Support Care Cancer. 2002;10(2):96-105.

5. Colagiuri B, Zachariae R. Patient expectancy and post-chemotherapy nausea: a meta-analysis. Ann Behav Med. 2010;40(1):3-14.

6. Molassiotis A, Stricker CT, Eaby B, Velders L, Coventry PA. Understanding the concept of chemotherapy-related nausea: the patient experience. Eur J Cancer Care (Engl). 2008;17(5):444-453.

7. Pirri C, Bayliss E, Trotter J, et al. Nausea still the poor relation in antiemetic therapy? The impact on cancer patients’ quality of life and psychological adjustment of nausea, vomiting and appetite loss, individually and concurrently as part of a symptom cluster. Support Care Cancer. 2013;21(3):735-748.

8. Salihah N, Mazlan N, Lua PL. Chemotherapy-induced nausea and vomiting: exploring patients’ subjective experience. J Multidiscip Healthc. 2016;9:145-151.

9. Olver IN, Eliott JA, Koczwara B. A qualitative study investigating chemotherapy-induced nausea as a symptom cluster. Support Care Cancer. 2014;22(10):2749-2756.

10. Wang XF, Feng Y, Chen Y, Gao BL, Han BH. A meta-analysis of olanzapine for the prevention of chemotherapy-induced nausea and vomiting. Sci Rep. 2014;4:4813.

Highlights in CINV From the 2016 MASCC/ISOO Annual Meeting: Commentary

Lee S. Schwartzberg, MD
Professor of Medicine
Chief, Division of Hematology & Oncology
The University of Tennessee Health Science Center
Memphis, Tennessee

The 2016 annual meeting of the Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology was held on June 23 to 25 in Adelaide, Australia. Several studies were presented in the field of chemotherapy-induced nausea and vomiting (CINV), with a focus on the newer antiemetic agents. Data were presented from new trials, subanalyses of pivotal trials, and retrospective studies.

In the last 2 years, the US Food and Drug Administration approved 2 new agents for CINV. Before these approvals, CINV management generally consisted of a 5-hydroxytryptamine 3 (5-HT₃) receptor antagonist and dexamethasone. Both of the new agents are neurokinin 1 (NK₁) receptor antagonists. NEPA is a fixed-dose oral combination of netupitant, a new NK₁ receptor antagonist, and palonosetron, a second-generation 5-HT₃ receptor antagonist. NEPA was approved in 2014. Rolapitant, a new NK₁ antagonist, was approved in 2015. Rolapitant is long-acting and has no known interactions with cytochrome P450 (CYP450), in contrast to previous NK₁ antagonists. In practice, CYP450 interactions require dose adjustment of other medications, such as dexamethasone. Many of the CINV studies at MASCC presented trial data for rolapitant and NEPA.

Studies of Rolapitant

The largest group of studies evaluated rolapitant. Several of the abstracts presented post hoc subgroup analyses derived from the pivotal phase 3 trials that proved the benefit of rolapitant, as defined by complete response rates and other secondary endpoints. In these trials, patients were randomly assigned to receive the 5-HT₃ receptor granisetron plus dexamethasone, with either rolapitant (180 mg orally) or placebo. Two of these trials were conducted in patients receiving highly emetogenic chemotherapy (HEC) regimens that included cisplatin.¹ The third trial enrolled patients receiving moderately emetogenic chemotherapy (MEC) that included anthracycline and cyclophosphamide (AC).² At the time this trial was designed, AC was considered MEC. Subsequently, it was recognized that the specific AC combination has emesis potential in the high range (90%+), and the combination was reclassified as HEC. Approximately half of the patients received AC and the other half received other MECs, including carboplatin.

Dr Lee Schwartzberg presented results from a post hoc subgroup analysis of the rolapitant phase 3 trial of patients receiving MEC,² focusing on the breast cancer population.³ The phase 3 trial included 1332 patients, of whom 845 had breast cancer. As in the overall population, approximately half of the breast cancer patients received AC and the other half received other MECs, including carboplatin. The subgroup analysis showed superior control of CINV with rolapitant during the delayed phase and the overall phase, which is the 5-day period after administration of chemotherapy. In terms of secondary endpoints, there was also an improvement in emesis.

We learned from this study that CINV occurred in approximately half of the patients who received a 2-drug combination of a 5-HT₃ receptor antagonist and dexamethasone. Rolapitant improved control of CINV by 8% to 10%. The incidence of adverse events was low and similar in the rolapitant and active-control arms. There is still an unmet need in breast cancer patients for control of nausea after MEC or AC-based chemotherapy.

Dr Rudolph Navari presented an analysis of the lung cancer patients from the HEC and MEC phase 3 trials.^1,2,4 This analysis included 687 patients, who received treatment with carboplatin or cisplatin. (Eight patients received treatment with other MECs, AC, or no chemotherapy, and were excluded from this analysis.) In the HEC trials, most of the patients who received cisplatin had lung cancer. Again, rolapitant improved the complete response rate very substantially, by more than 12% in the overall and delayed phases. In addition, rolapitant was associated with clinical and statistical improvements in other secondary endpoints, such as no emesis, no nausea, and complete protection.

A third subanalysis, on gynecologic oncology patients, was presented by Dr Bernardo Rapoport.⁵ Among the 201 patients in this subgroup, approximately half had received cisplatin and the other half carboplatin. The addition of rolapitant improved complete response rates in the delayed and overall phases by approximately 15% compared with granisetron and dexamethasone alone. There was also an improvement in no emesis, no nausea, and complete protection against CINV.

Another post hoc analysis by Dr Rudolph Navari focused on how well rolapitant controls nausea.⁶ Treatment of nausea remains an unmet need, even with the introduction of excellent therapies, such as the NK₁agents. In the 3 pivotal trials, the addition of rolapitant improved the aggregated rates of patients without nausea.^1,2 Rolapitant also improved the ability of patients to function while they had nausea, as assessed by the Functional Living Index-Emesis (FLIE) questionnaire, a validated tool that patients completed daily for 5 days after receiving chemotherapy.

Dr Matti Aapro analyzed data from the phase 3 rolapitant trials according to age.⁷ It has been known for many years that younger patients tend to develop more CINV. In this analysis, age 65 years was the cutoff. The analysis also considered the use of AC vs other agents. Rolapitant had a good benefit in both the younger and older patients. Older patients treated with AC were less susceptible to developing CINV than the younger patients. Interestingly, among patients in the control arm who received the highly emetogenic agent cisplatin, rates of CINV did not differ substantially between the patients who were younger vs older. Rolapitant improved the complete response rate in younger and older patients in similar increments.

There were several pharmacokinetic studies of rolapitant. Dr Xiaodong Wang, a pharmacologist, presented results from a study that compared oral vs intravenous (IV) administration of rolapitant in healthy volunteers.⁸ The oral dose was 180 mg, and the IV dose was given as a 30-minute infusion of 166.5 mg. The study found that the pharmacokinetics of the doses were very similar, and the systemic exposure was equivalent. A follow-up study evaluated supratherapeutic doses of rolapitant that reached 270 mg, which is up to 1.5 times the standard dose.⁹ The pharmacokinetics were dose proportional; that is, there was an expected increase in exposure that was relative to the actual dose. Importantly, there was no additional or significant toxicity with the higher dose.

The potential for rolapitant to act on P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) substrates prompted a drug-drug interaction study presented by Dr Jing Wang.¹⁰ Some chemotherapeutic agents are potential substrates for P-gp and BCRP, and might interact with them. This analysis evaluated IV rolapitant. A previous study of oral rolapitant had shown no interaction. The study by Dr Jing Wang found no major effect of IV rolapitant on the pharmacokinetics of the P-gp substrate digoxin or the BCRP substrate sulfasalazine. No dose adjustments were deemed necessary.

Studies of NEPA and Palonosetron

Several studies evaluated NEPA. Dr Petra Feyer presented preliminary results from a large survey study conducted in Germany of patients who received NEPA in the setting of HEC or MEC.¹¹ Data concerning CINV are being gathered through patient self-assessment on the FLIE questionnaire and physician surveys. The study is expected to accrue more than 2000 patients. This preliminary analysis provided results for 583 of the 700 patients recruited so far. The vast majority of patients were female, and 70% had breast cancer. The treatment regimens included AC in 56% and carboplatin in 18%.

The clinicians judged the efficacy of NEPA as good or very good in more than 90% of patients. The complete response rates were remarkable, at 85.1% for the delayed phase and 79.3% for the overall phase. The emesis rates were remarkably low, with control rates consistently over 90%. This study provides real-world data showing extremely good control with NEPA and dexamethasone in MEC and HEC.

Dr Matti Aapro presented a drug-drug interaction study evaluating whether there was increased toxicity when NEPA was given with docetaxel or etoposide.¹² Netupitant is known to have an inhibitory effect on cytochrome P450 isoenzyme 3A4 (CYP3A4).¹³ This pooled safety analysis included data from 4 studies. There was some increase in exposure to chemotherapy owing to the effect of NEPA on CYP3A4, but no change in toxicity. It was therefore safe to administer NEPA in patients receiving docetaxel or etoposide without any dose adjustments.

Dr Michiko Tsuneizumi pre-sented the results of a phase 3 trial that compared palonosetron vs grani-setron, both in combination with the NK₁ receptor antagonist aprepitant and dexamethasone.¹⁴ Palonosetron, a component of NEPA, has shown superiority over a first-generation 5-HT₃ receptor antagonist when given in a 2-drug combination with dexamethasone.¹⁵ This study enrolled nearly 500 patients. It found that palonosetron was associated with numeric improvements as compared with granisetron in the treatment of CINV in the delayed and overall phases, but the differences did not reach statistical significance.

Studies in Olanzapine

Olanzapine is a multi-neuroreceptor tar-geted drug that inhibits several dopamine receptors, as well as other types. There has been great interest in olanzapine as an adjunctive drug in CINV. It is being evaluated as an addition to the current triplet regimen for patients who require maximal prophylaxis against CINV, as a substitute for an NK₁, and as a rescue medication for patients who develop breakthrough CINV. Phase 3 studies have shown similar results when olanzapine replaces an NK₁ receptor antagonist.

Kouichi Yokoyama presented results from a small, phase 2 study of a 4-drug combination in patients with thoracic malignancies.¹⁶ Olanzapine, given at 5 mg/day for 5 days after the administration of platinum-based chemotherapy, was added to treatment with palonosetron, aprepitant, and dexamethasone. The study evaluated rates of total control, an endpoint indicating no vomiting, emesis, or nausea. The overall total control rate was 63%, which was good.

A retrospective study evaluated the use of olanzapine at a hospital system based on pharmacy records.¹⁷ There were 2 groups of patients. The larger group used olanzapine for breakthrough CINV, and a smaller group used olanzapine in the prophylactic setting. The study found that the addition of olanzapine improved breakthrough CINV in 87% of patients. The patients who received olanzapine as prophylactic treatment also had improved control of CINV. As expected, sedation was the major side effect of olanzapine.

Nausea

The MASCC meeting included a symposium on nausea.¹⁸ There is increasing recognition in the CINV community that nausea represents the major remaining unmet need in CINV management, and it is a substantial one. This need is particularly acute for certain chemotherapies, such as AC. Although nausea is related to vomiting, it is a purely subjective finding, making it more difficult to measure. Triggers of nausea may utilize alternative neurologic and gastrointestinal pathways compared with vomiting.

The speakers at the symposium suggested that future attention will be placed on control of nausea and eval-uating nausea as a primary end-point. The traditional endpoint in clinical trials, complete response rate, is defined as no emesis. To some extent, this endpoint is a clinical trial construct and used because it can be easily measured objectively. Another common endpoint, no use of rescue medication, is subjective and variable depending on the study design. Going forward, the aim is for trials to incorporate more stringent endpoints, such as no significant nausea or no nausea, because the goal is to prevent any CINV symptoms whatsoever.

Disclosure

Dr Schwartzberg is a consultant for Tesaro, Merck, Helsinn, and Eisai. He has received research support from Helsinn.

References

3. Schwartzberg LS, Navari RM, Arora S, Powers D, Jordan K, Rapoport BL. Rolapitant for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with breast cancer. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0316.

4. Navari RM, Rapoport BL, Arora S, Powers D, Jordan K, Schwartzberg LS. Rolapitant for control of chemotherapy-induced nausea and vomiting (CINV) in patients with lung cancer. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0321.

5. Rapoport B, Schwartzberg L, Arora S, Powers D, Jordan K, Navari R. Rolapitant for control of chemotherapy-induced nausea and vomiting (CINV) in patients with gynecologic cancer. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0318.

6. Navari R, Nagy C, Arora S, Powers D, Clark-Snow R. Rolapitant for the prevention of nausea in patients receiving moderately or highly emetogenic chemotherapy. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0322.

7. Aapro M, Arora S, Powers D. Rolapitant for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients aged <65 versus ≥65 years. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0432.

8. Wang X, Zhang ZY, Arora S, et al. A single-dose bioequivalence study of rolapitant following oral and IV administration in healthy volunteers. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0485.

9. Wang X, Zhang ZY, Wang J, et al. Single ascending dose pharmacokinetics of rolapitant administered intravenously at supratherapeutic doses in healthy volunteers. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0489.

10. Wang J, Wang I, Zhang ZY, et al. Effects of rolapitant administered intravenously on the pharmacokinetics of digoxin (P-gp) and sulfasalazine (BCRP) in healthy volunteers. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0494.

11. Feyer P, Schilling J, Karthaus M, et al. Quality of life, efficacy and patient-reported outcome with NEPA as CINV prophylaxis in highly or moderately emetogenic chemotherapy. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0289.

12. Aapro M, Arora S, Powers D. No signals of increased toxicity after concomitant administration of NEPA with etoposide or docetaxel: pooled safety data from 4 pivotal studies. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0565.

13. Lanzarotti C, Rossi G. Effect of netupitant, a highly selective NK₁ receptor antagonist, on the pharmacokinetics of midazolam, erythromycin, and dexamethasone. Support Care Cancer. 2013;21(10):2783-2791.

14. Tsuneizumi M, Saito M, Ogata H, et al. Trial of antiemetic triplet therapy comparing palonosetron and granisetron in breast cancer patients receiving AC chemotherapy: double blind randomised comparative phase III study. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0245.

15. Kitamura H, Takahashi A, Hotta H, et al. Palonosetron with aprepitant plus dexamethasone to prevent chemotherapy-induced nausea and vomiting during gemcitabine/cisplatin in urothelial cancer patients. Int J Urol. 2015;22(10):911-914.

16. Yokoyama K, Murakami H, Nakashima K, et al. Phase II study of palonosetron, aprepitant, dexamethasone and olanzapine for the prevention of cisplatin-based chemotherapy-induced nausea and vomiting in patients with thoracic malignancy. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0198.

17. Chiu L, Chiu N, Chow R, et al. Olanzapine for the prophylaxis and rescue of chemotherapy-induced nausea and vomiting (CINV): a retrospective study. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract MASCC-0153.

18. Olver I. Nausea as a symptom cluster. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia.

ABSTRACT SUMMARY Single Ascending Dose Pharmacokinetics of Rolapitant Administered Intravenously at Supratherapeutic Doses in Healthy Volunteers

A 2-part, open-label, single-ascending dose study was performed to evaluate the safety and tolerability of IV rolapitant at supratherapeutic doses in healthy volunteers (Abstract 0489). In part 1, 36 healthy subjects received a 30-minute infusion of rolapitant (202.5 mg to 270 mg). In part 2, 64 subjects received a single 30-minute infusion of rolapitant (270 mg) for further safety evaluation. Based on AUC analysis, the plasma concentration of rolapitant increased proportionately across the dose range. C_max appeared to increase proportionately with the dose, with some variation seen at dose 247.5 mg. In subjects who received the 270 mg dose, the mean C_max was approximately 3500 ng/mL to 3700 ng/mL, demonstrating a C_max similar to that observed in prior studies of subjects who received oral rolapitant (720 mg). The mean half-life of IV rolapitant ranged from 135 hours to 155 hours, which was consistent with results from oral rolapitant. The pharmacokinetics of the rolapitant metabolite, M19, were also similar to those observed with the oral formulation of the drug. There were no serious AEs or severe treatment-emergent AEs related to the study drug.

ABSTRACT SUMMARY Trial of Antiemetic Triplet Therapy Comparing Palonosetron and Granisetron in Breast Cancer Patients Receiving AC Chemotherapy: Double Blind Randomised Comparative Phase III Study

The antiemetic efficacy of palonosetron was compared with that of granisetron as part of triplet therapy for breast cancer patients receiving AC chemotherapy in a double-blind, randomized phase 3 trial (Abstract 0245). The study included 491 women with breast cancer from 11 institutions. Most patients were outpatients with access to metoclopramide as rescue medicine. Patients were stratified according to age, institution, and habitual alcohol intake. They were randomly assigned to receive a single dose of either palonosetron (0.75 mg) or granisetron (40 mg/kg) 30 minutes before AC chemotherapy on day 1. In addition, patients received IV dexamethasone (9.9 mg) and oral aprepitant (125 mg) on day 1, plus oral aprepitant (80 mg) on days 2 and 3. Patients who received palonosetron achieved a numerically superior CR rate compared with those who received granisetron (58.5% vs 53.8%), but the difference was not significant. The incidence of vomiting is being examined as a secondary endpoint of the same study.

ABSTRACT SUMMARY Rolapitant for the Prevention of Nausea in Patients Receiving Moderately or Highly Emetogenic Chemotherapy

Data from the pivotal phase 3 trials of rolapitant were analyzed for control of chemotherapy-induced nausea (Abstract 0322). Nausea was self-assessed by patients for 5 days following chemotherapy using a visual analog scale to indicate severity. Patients self-assessed the impact of CINV on daily life using the validated FLIE questionnaire on day 5 after chemotherapy. All patients included in the analysis received at least 1 dose of study drug. During the overall and delayed phases, 42% to 54% of patients receiving control therapy reported no nausea. Rolapitant consistently provided an 11% improvement in rates of no nausea relative to the control arm. Rolapitant significantly improved rates of no nausea or no significant nausea in patients treated with cisplatin-based chemotherapy (P=.020) and in the combined cohort of patients treated with carboplatin-based chemotherapy or other types (P=.010). Among patients receiving AC-based chemotherapy, however, nausea domain scores were similar, at 51.2% with rolapitant and 50.2% with placebo (P=.440).

ABSTRACT SUMMARY Rolapitant for the Prevention of Nausea in Patients Receiving Moderately or Highly Emetogenic Chemotherapy

ABSTRACT SUMMARY Effects of Rolapitant Administered Intravenously on the Pharmacokinetics of Digoxin (P-gp) and Sulfasalazine (BCRP) in Healthy Volunteers

An integrated safety analysis from the rolapitant pivotal phase 3 trials showed no evidence of drug interactions when rolapitant was coadministered with P-glycoprotein or therapies that target breast cancer resistance protein substrates (Abstract 0494). An open-label drug-drug interaction study was conducted to evaluate the effects of IV rolapitant on the pharmacokinetics of a P-glycoprotein substrate and a breast cancer resistance protein substrate and to evaluate the safety and tolerability of these drug combinations in healthy volunteers. Patients initially received a single dose of oral digoxin (0.5 mg; n=36) or oral sulfasalazine (500 mg; n=36). After approximately 24 hours, patients then received a second dose of the same substrate plus a single dose of IV rolapitant (166.5 mg). Sulfasalazine (500 mg) was administered a third time on day 13. The introduction of rolapitant did not affect the digoxin AUC and increased the digoxin C_max by 21% (GMR, 1.21; 90% CI, 1.07-1.37). Rolapitant decreased the sulfasalazine C_max by 18% on day 13 (GMR, 0.82; 90% CI, 0.69-0.97). The drug combinations were well-tolerated, and no clinically significant safety signals emerged.

ABSTRACT SUMMARY Development of a Prediction Tool for Identifying Patients at High Risk for Chemotherapy-Induced Nausea and Vomiting (CINV)

Pooled data from 4 noninterventional prospective studies were analyzed to identify factors associated with increased risk of CINV in patients receiving outpatient anticancer therapy (Abstract 0602). The study included 1198 patients who received a total of 4197 cycles of chemotherapy. Patients had a median age of 58 years, and 75% were female. Chemotherapeutic regimens included anthracycline in 52.8%, platinums in 27.4%, other types in 12.4%, and taxane monotherapy in 7.4%. More than 60% of patients experienced nausea and/or vomiting during the 5 days after chemotherapy, with 42.2% of patients reporting CINV of at least grade 2. Numerous factors were associated with increased risk of CINV, including platinum- or anthracycline-based chemotherapy (odds ratio [OR], 2.37), use of nonprescribed antiemetics at home (OR, 2.26), CINV during a prior treatment cycle (OR, 1.73), and age younger than 60 years (OR, 1.47). Disease sites with an increased risk of CINV vs breast cancer included genitourinary (OR, 2.43), gastrointestinal (OR, 1.80), gynecologic (OR, 1.43), and other nonlung and nonbreast disease (OR, 1.92). Other factors included early-stage disease (OR, 1.30), patient expecting to develop CINV (OR, 1.38), less than 7 hours of sleep (OR, 1.25), and a history of morning sickness (OR, 1.41). The likelihood of CINV was greatest during the first chemotherapy cycle. The authors presented a CINV prediction tool to aid physicians in evaluating patients at risk of developing CINV. Receiver operator characteristic analysis indicated that the tool provided good predictive accuracy, with an AUC of 0.71 (95% CI, 0.69-0.73) and a close association between score and risk of CINV (OR, 1.18; P<.001).

ABSTRACT SUMMARY Rolapitant for Control of Chemotherapy-Induced Nausea and Vomiting (CINV) in Patients With Gynecologic Cancer

A post hoc analysis of data from the phase 3 trials of IV rolapitant was conducted to evaluate control of CINV in patients with gynecologic cancer (Abstract 0318). The analysis included 106 women who received IV rolapitant (180 mg) and 95 who received placebo. Patients had a median age of 57 years (range, 21-81 years). Tumor sites included the ovary in 59%, the uterus in 29%, and the cervix in 12%. Chemotherapy regimens included cisplatin in 55.2% and carboplatin in 43.8%. CR rates were 9% to 16% higher with rolapitant in the acute (P=.048), delayed (P=.011), and overall (P=.012) phases of CINV. During the overall phase, rolapitant yielded higher rates of no emesis (P=.016), no nausea (P=.004), and complete protection (P=.005), conferring an advantage of approximately 13% to 20% improvement over placebo. Significant improvements with rolapitant were also observed during the delayed phase for rates of no emesis (P=.023), no nausea (P=.007), and complete protection (P=.005). Differences in outcomes during the acute phase were not significant. Some patients continued to experience CINV, particularly nausea, despite treatment with the study drug combination. The overall safety profiles were similar for patients in the rolapitant and placebo arms, with no treatment-related serious AEs and no treatment-related deaths.

ABSTRACT SUMMARY Quantitative Market Research to Identify Factors That Influence Chemotherapy-Induced Nausea and Vomiting (CINV) Treatment Compliance

Adherence to CINV management guidelines is often suboptimal (Aapro M et al. Ann Oncol. 2012;23[8]:1986-1992). Oncologists were queried via an online questionnaire regarding perceived patient antiemetic use to determine the rate of antiemetic treatment failure and factors that contribute to patient nonadherence (Abstract 0444). The questionnaire was sent to 300 oncologists in 5 European countries, all of whom prescribed antiemetics and typically saw at least 50 cancer patients per month. Despite antiemetic prophylaxis, emesis rates were higher for patients receiving HEC compared with MEC in the acute phase (21% vs 15%) and the delayed phase (26% vs 18%). In the acute and delayed phases, the most common reason for antiemetic treatment failure was underestimating the emetogenic potential of chemotherapy (43% vs 39%), followed by choosing weaker antiemetic regimens than required (31% vs 33%) and mistakes with administration of antiemetic treatments (21% vs 17%). Oncologists estimated that 35% of patients had adherence issues with administration of antiemetic agents at home. Patient nonadherence with antiemetic treatments was a significant concern for 42% of oncologists.

ABSTRACT SUMMARY Quantitative Market Research to Identify Factors That Influence Chemotherapy-Induced Nausea and Vomiting (CINV) Treatment Compliance

ABSTRACT SUMMARY Results of a Survey of Oncology Nurses Assessing Practice Patterns for Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV) and Adherence to Antiemetic Guidelines

An online survey of oncology nurses was conducted to evaluate awareness of antiemetic guidelines and to assess current practice patterns in the administration of antiemetic therapies (Abstract 0452). Approximately 8000 practicing oncology nurses in the United States were invited to participate in the survey. Among the 531 nurses who completed the survey, most were full-time, oncology-certified staff nurses working in the outpatient setting. Of the surveyed nurses, 73% were familiar with National Comprehensive Cancer Network guidelines, and 48% were familiar with those of the American Society of Clinical Oncology. Only 6% cited familiarity with MASCC guidelines. In the HEC setting, NK₁ receptor antagonists were used on day 1 by 81% of respondents, and 5-HT₃ receptor antagonists were used by 78% of respondents on day 2 and beyond. In the MEC setting, dexamethasone was underutilized, with 89% of respondents reporting use on day 1 and 61% reporting use on day 2 and beyond. Use of phenothiazines and benzodiazepines on day 2 and beyond, which contradicts guidelines, was reported by 47% and 30% of respondents, respectively. Physician preference was cited as the greatest barrier interfering with administration of guideline-recommended prophylactic treatment by oncology nurses in both the HEC and MEC settings (71% and 70%, respectively). The greatest challenges cited by respondents were controlling CINV in the delayed phase and the effect of CINV on patient quality of life.

ABSTRACT SUMMARY Managing Chemotherapy-Induced Nausea and Vomiting (CINV) in Head and Neck Cancer Patients Receiving Cisplatin Chemotherapy With Concurrent Radiation

A retrospective study of patients with head and neck cancer receiving cisplatin-based chemotherapy and concurrent radiation was conducted to determine patterns of CINV and to assess changes made to antiemetic therapy in subsequent treatment cycles (Abstract 0122). The analysis included a consecutive cohort of patients receiving high-dose cisplatin every 3 weeks (n=161) or low-dose cisplatin every week (n=38) with concurrent radiation between January 2013 and June 2015. In the high- and low-dose cisplatin cohorts, nausea and/or vomiting occurred in 85% and 60% of patients, respectively, during cycle 1 and in 14% and 20% of patients during cycle 2. Among patients who experienced CINV, changes to antiemetic therapies were made in only half of the high-dose arm and two-thirds in the low-dose arm. In most patients, modification of the antiemetic regimen consisted of changes to the 5-HT₃ receptor antagonist—either a dose extension or a switch to a different agent. Other changes to antiemetic therapy included changes to breakthrough antiemetics and changes to dexamethasone dosing.