EMA Recommends Approval of Nivolumab/Ipilimumab Plus Chemo in Frontline Metastatic NSCLC

Abderrahim Oukessou, MD

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of the dual-immunotherapy combination nivolumab (Opdivo) plus ipilimumab (Yervoy) with 2 cycles of platinum-based chemotherapy for the frontline treatment of patients with metastatic non–small cell lung cancer (NSCLC) whose tumors do not harbor a sensitizing EGFR mutation or ALK translocation.¹

The positive opinion was based on data from the phase 3 CheckMate-9LA trial, which met its primary end point of superior overall survival (OS) versus chemotherapy alone at the time of the pre-planned interim analysis (hazard ratio [HR], 0.69; 96.71% CI, 0.55-0.87; P =.0006).² The toxicity profile of this combination proved consistent with the known profiles of immunotherapy and chemotherapy agents in this disease.

“The positive CHMP opinion reflects the potential for [nivolumab plus ipilimumab] with 2 cycles of chemotherapy to offer the chance for a longer life to patients across subgroups of metastatic NSCLC, a devastating cancer where unmet needs still exist,” Abderrahim Oukessou, MD, vice president an thoracic cancers development lead at Bristol Myers Squibb, stated in a press release. “We look forward to the European Commission’s decision and hope to soon introduce this innovative, dual immunotherapy approach to patients across the EU who may benefit.”

In the randomized, open-label, multicenter phase 3 trial, investigators examined nivolumab plus ipilimumab with 2 cycles of platinum-doublet chemotherapy versus platinum-doublet chemotherapy as frontline treatment in patients with metastatic or recurrent NSCLC, irrespective of PD-L1 and histology.

Overall, 361 patients received the immunotherapy combination and platinum-doublet chemotherapy until progressive disease, intolerable toxicity, or for up to 2 years. Participants were randomized in a 1:1 fashion to receive either nivolumab at 360 mg plus ipilimumab at 1 mg/kg with 2 cycles of platinum-doublet chemotherapy (n = 361) or 4 cycles of chemotherapy alone, based on histology (n = 358).

A total of 358 patients received treatment with platinum-doublet chemotherapy for 4 cycles and optional maintenance pemetrexed if they had nonsquamous disease until progressive disease or unacceptable toxicity. Patients who had not received any prior treatment were permitted for inclusion if they had histologically confirmed stage IV/recurrent NSCLC, an ECOG performance status of 0 or 1, and no sensitizing EGFR/ALK aberrations. Participants were stratified by PD-L1 expression, sex, and histology.

The primary end point of the trial was OS, while key secondary end points included progression-free survival (PFS), ORR, and efficacy by PD-L1 subgroups. Additional end points included safety and tolerability.

Results from the phase 3 trial presented during the 2020 ASCO Virtual Scientific Program showed that the combination plus 2 cycles of platinum-doublet chemotherapy showed improved OS compared with chemotherapy, with a median OS of 14.1 months (95% CI, 0.55-0.80) versus 10.7 months (95% CI, 9.5-12.5), respectively.

At a follow-up of 12.7 months, the HR increased numerically to 0.66 (95% CI, 0.55-0.80). The median OS was 15.6 months in the experimental arm (95% CI, 13.9-20.0) versus 10.9 months in the control arm (95% CI, 9.5-12.5).

At 1 year, more than half of patients, or 63%, who received nivolumab/ipilimumab plus chemotherapy were alive, as well as 47% of those who just received chemotherapy.

Additionally, the overall response rate (ORR) per blinded independent central review (BICR) with the nivolumab plus ipilimumab and limited chemotherapy was 38% (95% CI, 33-43) versus 25% (95% CI, 21-30) with chemotherapy alone.

With regard to safety, serious toxicities were experienced by 57% of participants. Twenty-four percent of patients in the investigational arm discontinued treatment because of adverse effects (AEs) and more than half, or 56%, had at least 1 treatment withheld due to toxicity.

The most frequently experienced serious AEs included pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Additionally, fatal toxicities were reported in 7 patients; these AEs included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.

The most common toxicities reported included fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%).

In May 2020, the FDA approved nivolumab/ipilimumab with 2 cycles of platinum-doublet chemotherapy for use in the first-line treatment of patients with metastatic or recurrent NSCLC without EGFR or ALK aberrations based on data from CheckMate-9LA.

References

1. Bristol Myers Squibb receives positive CHMP opinion recommending approval of Opdivo (nivolumab) plus Yervoy (ipilimumab) combined with two cycles of chemotherapy as first-line treatment of metastatic non–small cell lung cancer. News release. Bristol Myers Squibb. September 18, 2020. Accessed September 18, 2020. https://bit.ly/2EdQXcW.
2. Reck M, Ciuleanu TE, Cobo Dols M, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. J Clin Oncol. 2020;38(suppl 15):9501. doi:10.1200/JCO.2020.38.15_suppl.9501