Preventing chemotherapy-induced nausea and vomiting in patients with lung cancer: efficacy of NEPA (netupitant-palonosetron), the first combination antiemetic

The current report is a post-hoc analysis of the subgroup of patients with lung cancer from two published pivotal trials, hereafter referred to as study 1 [17] and study 2 [19]. In both trials, the protocols were approved by the relevant institutional bodies, and each study was followed in accordance with the Declaration of Helsinki principles (2008), International Conference on Harmonization E6 Good Clinical Practice guidelines, as well as national/local laws and regulations.

This was a phase II, multinational, randomized, double-blind, single-cycle, dose-ranging study of oral NEPA versus oral PALO in solid tumors [17]. Patients were scheduled to receive a first dose of cisplatin-based chemotherapy and were stratified by gender and randomized to one of five treatment arms: PALO 0.50 mg; NEPA₁₀₀ (NETU 100 mg plus PALO 0.50 mg); NEPA₂₀₀ (NETU 200 mg plus PALO 0.50 mg); NEPA₃₀₀ (NETU 300 mg plus PALO 0.50 mg); intravenous ondansetron 32 mg plus oral aprepitant, at a dose of 125 mg on day 1 and 80 mg daily on days 2 and 3 (exploratory arm) [17]. All patients also received oral dexamethasone; the PALO arm at a dose of 20 mg on day 1 and 8 mg twice daily on days 2–4; and the NEPA and aprepitant treatment arms at a dose of 12 mg on day 1 and 8 mg daily on days 2–4.

This phase III, multinational, randomized, double-blind, parallel-group study [19] evaluated NEPA over multiple cycles of chemotherapy. Patients, stratified by HEC/MEC and gender, were randomized in a 3:1 ratio to receive either oral NEPA (NETU 300 mg plus PALO 0.50 mg) or oral aprepitant 125 mg plus PALO 0.50 mg on day 1, followed by oral aprepitant 80 mg daily on days 2–3 [19]; the aprepitant arm was included as a reference arm for safety. Patients receiving HEC received oral dexamethasone at a dose of 12 mg on day 1 and 8 mg on days 2–4, while patients receiving MEC only received oral dexamethasone 12 mg on day 1.

Eligible patients were aged ≥ 18 years, diagnosed with any type of lung cancer, chemotherapy naive, and had a Karnofsky Performance Status (PS) score ≥ 70% (study 1) or Eastern Cooperative Oncology Group (ECOG) PS 0–2 (study 2).

In each study, the efficacy endpoints of complete response (CR; defined as no emetic episodes and no rescue medication) and no significant nausea (NSN; defined as a visual analog scale score of < 25 mm on a scale of 0–100 mm) during the acute (0–24 h), delayed (25–120 h), and overall (0–120 h) phases post-chemotherapy in cycle 1 (study 1) and cycles 1–4 (study 2) were assessed. Safety was evaluated primarily by treatment-emergent adverse events (TEAEs, occurring after the first dose of study drug) and treatment-related AEs (TRAEs).

The primary aim of this post-hoc analysis was to determine the efficacy of NEPA in preventing CINV in subsets of patients with lung cancer from two pivotal trials [17, 19], who received either cisplatin or carboplatin. The efficacy data were not pooled due to the different comparators and chemotherapy regimens administered in the two trials (study 1: PALO- and cisplatin-based regimen; study 2: aprepitant/PALO and cisplatin- or carboplatin-based regimens). The aprepitant arms of both studies were not included in this analysis, as the arms served either an exploratory or reference purpose, and included small sample sizes. Descriptive statistics for the efficacy parameters were provided for the subpopulation of lung cancer patients receiving NEPA (study 1 and study 2) or PALO (study 1). There were no formal statistical comparisons made between the NEPA and PALO arms due to the limited sample size and also because the stratification by gender is lost when performing the subgroup analysis (see “Results” section). In study 1, data from the different NEPA dose groups (100/200/300 mg) were combined, as all showed similar efficacy in the subgroup of patients with lung cancer. The antiemetic outcomes following platinum-based chemotherapy of the non-lung cancer cohorts were also assessed in both studies to provide a context to interpret the results in the population of patients with lung cancer. Data were presented using descriptive statistics and no formal comparison between the lung cancer and non-lung cancer subsets was performed. All figures displaying demographics, baseline characteristics, and toxicity profile were based on the safety population. In study 1, two patients from the safety population were excluded from the efficacy population: one did not receive chemotherapy (NEPA, lung cancer) and one patient received carboplatin instead of cisplatin (NEPA, non-lung cancer).

Of the 694 patients randomized in study 1, 408 received NEPA and platinum-based chemotherapy, and 109 (26.7%) patients had lung cancer and were included in the safety population. Additionally, in study 1, 136 patients received PALO and chemotherapy, and 42 (30.9%) of them had lung cancer. In study 2, of the 413 patients randomized, 216 patients received NEPA and carboplatin or cisplatin, of which 122 (56.5%) had lung cancer and were included in the safety population.

Overall, this subgroup analysis presented data from 231 NEPA-treated patients with lung cancer and 393 NEPA-treated patients with non-lung cancers. In study 1, all patients in the efficacy population (N = 109) received a cisplatin-based regimen, while in study 2, the majority of lung cancer (79/122; 64.8%) and non-lung cancer (65/94; 69.1%) patients received a carboplatin-based regimen. Demographic and baseline characteristics of the NEPA-treated patients are shown in Table 1 for the safety population. The majority of NEPA-treated lung cancer patients were male (study 1: 89.0%; study 2: 68.9%) and had a Karnofsky PS of 80% (study 1) or ECOG PS of 1 (study 2); the mean age was 56.2 and 60.1 years for study 1 and study 2, respectively. For the non-lung cancer subset, in both studies, there was a greater proportion of females (study 1: 54.5%; study 2: 58.5%); the majority had a Karnofsky PS of 90% (in study 1) and ECOG PS of 1 (study 2); the mean age was 53.9. In both studies, the most common non-lung cancer types were gynecologic and head and neck.

In cycle 1, NEPA treatment resulted in high CR rates across the acute, delayed, and overall phases in the subset of lung cancer patients receiving cisplatin- (study 1 and study 2; Fig. 1a, b, respectively) or carboplatin-based (study 2; Fig. 1b) chemotherapy. In study 1, higher CR rates were observed for NEPA-treated patients compared with PALO-treated patients in the delayed and overall phases. However, comparable CR rates were seen in the acute phase (Fig. 1a). In study 2, overall phase, CR rates were sustained over repeated cycles in NEPA-treated lung cancer patients receiving either cisplatin or carboplatin (Fig. 2). When considering patients with cancers other than lung, high CR rates were observed regardless of whether patients received cisplatin- (Fig. 3a, b) or carboplatin-based (Fig. 3b) chemotherapy.

As was the case for CR, high rates of NSN were observed in the subset of NEPA-treated patients with lung cancer receiving cisplatin or carboplatin during cycle 1 (Table 2). Similar outcomes were seen for PALO-treated patients in study 1. NSN rates were maintained over repeated cycles in NEPA-treated lung cancer patients receiving either cisplatin or carboplatin (Fig. 4). High rates of NSN were also evident in patients with non-lung cancers (Table 2).

NEPA was well tolerated in patients with lung and non-lung cancers, regardless of whether cisplatin- or carboplatin-based regimens were administered. In study 1, asthenia (7.3%) and hiccups (5.5%) were the only TEAEs reported in ≥ 5% of patients with lung cancer; the most common TRAE was hiccups (5.5%). In lung cancer patients from study 2—cycle 1, the most frequently reported TEAEs in ≥ 5% of patients were neutropenia (21.3%), leukopenia (14.8%), anemia (10.7%), and alopecia (9.0%); headache (1.6%) was the most common TRAE. Overall, for the lung cancer subset, the only TRAEs occurring in ≥ 2% of the patients in either study were hiccups.

For the non-lung cancer subset, the most common TEAEs in study 1 were asthenia and leukocytosis (6.7% each), headache (6.4%), alanine aminotransferase increase (6.0%), and dyspepsia (5.4%); in study 2—cycle 1, the most common were leukopenia (17.0%), neutropenia (14.9%), alopecia (13.8%), anemia and pyrexia (8.5% each), cancer pain, constipation, dyspepsia, headache, and thrombocytopenia (5.3% each). Regarding TRAEs, the most frequently reported in study 1 were hiccups (3.7%) and, in study 2—cycle 1, constipation (2.1%).