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

Lung cancer is the most common cancer worldwide, with an estimated 1.8 million new cases in 2012, comprising nearly 13% of the total new cancer cases (excluding non-melanoma skin cancers) diagnosed that year [1]. In the majority of patients with non-small cell lung cancer (NSCLC), and especially those with advanced disease, cytotoxic chemotherapy remains the mainstay of treatment [2, 3, 4]. Cisplatin, a highly emetogenic chemotherapeutic, is the gold standard in the adjuvant setting [5, 6], although a less emetogenic carboplatin regimen is the recommended treatment option for patients with comorbidities or who are unable to tolerate cisplatin [7].

One of the most feared side effects of chemotherapy is chemotherapy-induced nausea and vomiting (CINV) [8], which, if poorly controlled, may lead to impaired functioning and quality of life [9], anorexia [6], and potentially postponement or dose reduction of chemotherapy [10]. Recent advances in the development of antiemetic agents and the publication of several evidence-based antiemetic guidelines [6, 11, 12] have led to vast improvements in the control of CINV, which can now be prevented in 70–80% of patients [13].

To achieve optimal control of CINV, the choice of appropriate antiemetic prophylaxis is paramount. International antiemetic guidelines published by the Multinational Association of Supportive Care in Cancer (MASCC) and the European Society for Medical Oncology (ESMO) [11], the American Society of Clinical Oncology [12], and the National Comprehensive Cancer Network (NCCN) [6] categorize chemotherapy agents according to their emetogenic potential (high, moderate, low, and minimal), and base their recommendations on the level of risk that a chemotherapeutic agent poses. For patients receiving highly emetogenic chemotherapy (HEC), such as cisplatin, the guidelines recommend the triplet combination of a 5-hydroxytryptamine-3 (5-HT₃) receptor antagonist (RA), a neurokinin-1 (NK₁) RA, and a corticosteroid, such as dexamethasone [6, 11] or a four-drug combination with the addition of olanzapine to the triplet [12]. For patients receiving moderately emetogenic chemotherapy (MEC), the general recommendation for antiemetic prophylaxis is treatment with a 5-HT₃ RA in combination with dexamethasone. Although until recently considered MEC, guidelines currently advise that patients receiving carboplatin should be treated with a combination of an NK₁ RA, a 5-HT₃ RA, and dexamethasone [6, 11, 12], and the NCCN guidelines propose the addition of an NK₁ RA if high-risk factors are present, or if previous 5-HT₃ RA-dexamethasone treatment has failed [6]. Despite evidence demonstrating that CINV control can be achieved if these recommendations are followed [14], the guidelines are often inadequately adhered to in clinical practice. This may be, in part, due to the perceived complexity of some antiemetic regimens and subsequent poor patient compliance.

NEPA is an oral fixed combination of the highly selective NK₁ RA netupitant (NETU; 300 mg) and the clinically [15] and pharmacologically [16] distinct 5-HT₃ RA palonosetron (PALO; 0.5 mg) administered as a single dose prior to chemotherapy. The simultaneous targeting of two critical emetic pathways, in concert with the single-dose administration per chemotherapy cycle, results in convenient and long-lasting protection from CINV. Clinical studies have demonstrated the superiority of NEPA plus dexamethasone, compared with PALO plus dexamethasone, in preventing CINV during both the acute and delayed phases in the HEC [17] and anthracycline-cyclophosphamide (AC) settings [18]. In addition, NEPA has been shown to be efficacious over multiple cycles of AC [18] HEC or MEC [19]. Each of these pivotal studies demonstrated the safety and efficacy of NEPA in a population of patients with mixed solid tumors, but did not address any particular patient subgroup.

Herein, we report the results of a post-hoc subgroup analysis from two of the pivotal trials [17, 19]. The objective was to evaluate the efficacy of NEPA in the subsets of patients with lung cancer who were receiving platinum-based chemotherapy.

Pivotal trials in patients with a wide range of solid tumors have shown that NEPA, the first combination antiemetic, is superior to PALO in preventing CINV [17, 18], and maintained high CR rates across multiple cycles of chemotherapy, with a small but consistent numeric advantage over aprepitant plus PALO [19]. Herein, we report the safety and efficacy results of a post-hoc analysis of the subgroups of patients with lung cancer from two pivotal trials [17, 19]. In study 1 [17], patients received a cisplatin-based regimen, while in study 2 [19], patients received a regimen containing either cisplatin or carboplatin, two agents that are commonly used to treat lung cancer [7]. While cisplatin is well-established as the most highly emetogenic chemotherapeutic, carboplatin is at the high end of the MEC category, with recent antiemetic guidelines now recommending that patients receiving carboplatin be given a prophylactic triplet antiemetic combination of an NK₁ RA, a 5-HT₃ RA, and dexamethasone [6, 11, 12].

In this report, NEPA appears to be effective in preventing nausea and vomiting in the subgroup of patients with lung cancer. High CR rates were observed across the acute, delayed, and overall phases regardless of whether cisplatin- or carboplatin-based chemotherapy was administered. As expected, the highest CR rates were seen in the acute phases in both studies, although NEPA was also efficacious in the delayed and overall phases, with sustained efficacy demonstrated across multiple cycles. In study 1, numerically higher CR rates were observed in NEPA-treated patients with lung cancer, compared with those who received PALO, mirroring the results in the original study [17], although no formal statistical comparisons were undertaken in this subgroup analysis. Of note, in study 2 [19] the CR rates observed in cycle 1 were higher in the delayed and overall phases for lung cancer patients receiving cisplatin than those patients receiving carboplatin. These findings are somewhat surprising given the respective emetogenic potential of cisplatin and carboplatin. However, as there were no appreciable differences between the baseline characteristics or potential CINV risk factors of patients receiving cisplatin or carboplatin, it is most likely that this observation was an artefact of the small sample size.

Consistent with the CR results, high NSN rates were observed in NEPA-treated lung cancer patients receiving either carboplatin or cisplatin. In study 1, NSN rates were surprisingly similar for NEPA and PALO treatment groups across all phases. However, the lack of a difference during the delayed/overall phases (89.0 vs 88.1% for NEPA and PALO, respectively, in the delayed phase, and 87.2 and 88.1% for NEPA and PALO, respectively, in the overall phase) appeared to be due to the higher-than-expected efficacy seen with PALO rather than with NEPA, as the NSN rates for NEPA in lung cancer patients mimicked those seen in the overall study population [17], while the rates for PALO were approximately 8% higher in the lung cancer subset than in the overall study population [17]. This may simply be a function of the small sample size (N = 42) in the PALO subset.

PALO, a second-generation 5-HT₃ RA, has been shown to be more effective than older 5-HT₃ RAs for the control of CINV in the delayed and overall phases [20]. Included both as a component of the fixed combination NEPA, and in the aprepitant-PALO-dexamethasone reference regimen, PALO may have contributed to the high antiemetic efficacy observed in both studies.

Considering the subsets of patients with non-lung cancers, the data suggest that NEPA is at least as effective in lung cancer patients as those with other cancers. In NEPA-treated non-lung cancer patients, high rates of CR and NSN were observed, with slightly better control achieved in patients receiving carboplatin than may be anticipated.

NEPA was also well tolerated in both studies in the lung and non-lung cancer populations, with AEs typical of a population of cancer patients undergoing emetogenic chemotherapy.

Limitations to the present study include its exploratory nature, given it is a post-hoc analysis, as well as the lack of formal statistical comparisons. Recent developments in the field of CINV have led to the approval of new drugs that have been rapidly incorporated in guidelines recommendations. Due to its post-hoc nature, the comparator arms included in this subgroup analysis do not correspond with current guidelines recommendations [6, 11, 12]. Factors that preclude the ability to perform formal statistical analyses between study arms (NEPA vs PALO) and patient subgroups (lung cancer vs non-lung cancer) include (1) the limited sample size of the lung cancer population in both studies, (2) non-balanced patient demographics between the different subgroups due to the loss of patient stratification by gender for the analysis, and (3) further division of the subgroups according to the anticancer treatment received (cisplatin or carboplatin) resulting in a further reduction of the sample size.

The data reported herein are not dissimilar to results from a number of studies examining the efficacy of the aprepitant-PALO-dexamethasone triplet regimen in preventing CINV in patients with lung cancer. One study reported overall CR rates in cisplatin- (71%) and carboplatin-treated patients (86%) that are similar to those reported in the current study [21]. Two other studies evaluating the efficacy of the aprepitant-PALO-dexamethasone combination in patients with NSCLC receiving a carboplatin-based regimen [22, 23] also reported CR rates in the overall phase (83.8% [22] and 80.5% [23]) similar to those reported herein (77.2%). Finally, there is at least one report that has assessed the aprepitant-PALO-dexamethasone antiemetic triplet in lung cancer patients receiving multiple cycles of cisplatin-based chemotherapy [24]. In that study, the reported CR rates in the overall phase increased from 74.4% (cycle 1) to 78.6% (cycle 6), which are slightly lower than those reported herein, where the overall CR rate was 88.4% in cycle 1 and increased to 93.5% by cycle 4 for cisplatin-treated patients in study 2. The above-mentioned limitations of the present study may help explain the differences in the results.

In conclusion, the data from this post-hoc analysis of the subgroup of patients with lung cancer from two pivotal trials are in alignment with the results reported in the parent studies [17, 19]. NEPA, the first oral combination antiemetic, has been shown to be safe and effective in patients with lung cancer receiving platinum-based chemotherapy across the acute, delayed, and overall phases and throughout multiple cycles. As an oral treatment targeting two antiemetic pathways with a single dose administered only once per cycle, NEPA offers a convenient and simplified prophylactic option. Consequently, this drug may facilitate adherence to antiemetic guidelines and improve treatment compliance, which in turn could lead to improved CINV prevention.