OS Benefit Observed With Frontline Nivolumab/Ipilimumab Plus Limited Chemotherapy in NSCLC

Martin Reck, MD, PhD

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) when administered in the frontline setting for patients with metastatic or recurrent non-small cell lung cancer (NSCLC) along with 2 cycles of platinum-doublet chemotherapy, should be considered as a new option for this patient population, said Martin Reck, MD, PhD, based on results from the CheckMate 9LA trial.

“CheckMate 9LA met its primary end point of overall survival at the pre-planned interim analysis…With early separation of overall survival curves and lower progressive disease rates as best overall response, the hypothesis for (this study) design was validated,” Reck, head of the department of thoracic oncology at Lung Clinic Grosshansdorf, said during a presentation of the results at the 2020 ASCO Virtual Scientific Program.

The trial found that nivolumab plus ipilimumab combined with 2 cycles of platinum-doublet chemotherapy demonstrated superior overall survival (OS) versus chemotherapy alone (HR, 0.69; 96.71% CI, 0.55-0.87; P = 0.0006), regardless of PD-L1 expression or tumor histology.

Moreover, median OS was 14.1 months (95% CI, 13.2-16.2) versus 10.7 months (95% CI, 9.5-12.5), respectively. In a follow-up analysis at 12.7 months, the hazard ratio improved numerically to 0.66 (95% CI, 0.55-0.80), with a median OS of 15.6 months (95% CI, 13.9-20.0) and 10.9 months (95% CI, 9.5-12.5).

At 1 year, 63% of patients treated with nivolumab plus ipilimumab with limited chemotherapy and 47% of those treated with only chemotherapy were still alive.

In the trial, the overall response rate (ORR) per Blinded Independent Central Review (BICR) was 38% (95% CI, 33-43) for patients treated with nivolumab plus ipilimumab with limited chemotherapy and 25% (95% CI, 21-30) for patients treated with chemotherapy.

Notably, serious adverse events (AEs) occurred in 57% of patients. Nivolumab plus ipilimumab in combination with platinum-doublet chemotherapy were discontinued for AEs in 24% of patients and 56% had at least 1 treatment withheld for an AE.

The most frequent serious AEs were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Further, fatal AEs occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia. The most common AEs were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%).

The randomized, open-label, multi-center, phase III CheckMate-9LA trial, evaluated nivolumab plus ipilimumab combined with 2 cycles of platinum-doublet chemotherapy versus platinum-

doublet chemotherapy (4 cycles followed by optional pemetrexed maintenance therapy if eligible) as a first-line treatment in patients with metastatic or recurrent NSCLC, regardless of PD-L1 and histology.

Overall, a total of 361 patients were treated with the combination and platinum-doublet chemotherapy until disease progression, unacceptable toxicity, or for up to 2 years. Patients were randomized 1:1 to receive either 360 mg of nivolumab plus 1 mg/kg (injections for intravenous use) of ipilimumab given with 2 cycles of platinum-doublet chemotherapy (n = 361) or 4 cycles of chemotherapy, based on histology, alone (n = 358). Patients with non-squamous NSCLC in the chemo-only arm could receive optional pemetrexed maintenance.

A total of 358 patients were treated with platinum-doublet chemotherapy for 4 cycles and optional pemetrexed maintenance for non-squamous patients (if eligible) until disease progression or toxicity. Treatment-naïve patients were eligible for the study if they had histologically confirmed stage IV/recurrent NSCLC, ECOG performance status 0–1, and no known sensitizing EGFR/ALK alterations.

Patients were stratified by PD-L1 (< 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous).

The primary end point was OS. Secondary end points included progression-free survival (PFS), ORR, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety and tolerability.

The FDA recently approved the use of nivolumab plus ipilimumab given with 2 cycles of platinum-doublet chemotherapy as a first-line treatment for adult patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations, based on results from the CheckMate-9LA trial.2

“The trial demonstrated that nivolumab plus ipilimumab with a limited course of chemotherapy should be considered as a new first-line treatment option for advanced non-small cell lung cancer,” Reck concluded.

_References:

_{1. 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; abstr 9501). doi:10.1200/JCO.2020.38.15_suppl.9501}

_{2. U.S. Food and Drug Administration Approves Opdivo® (nivolumab) + Yervoy® (ipilimumab) Combined with Limited Chemotherapy as First-Line Treatment of Metastatic or Recurrent Non-Small Cell Lung Cancer. News release. Bristol Myers Squibb. May 26, 2020. Accessed May 27, 2020. https://bit.ly/3caCxVW Accessed May 27, 2020.}