Frontline Opdivo-Yervoy Combo Shows Promise in Advanced Non-Small Cell Lung Cancer

Brielle Urciuoli

Immunotherapy continues to impress throughout many different cancer types.

Most recently, the dynamic duo of Yervoy (ipilimumab) plus Opdivo (nivolumab) – both checkpoint inhibitors – extended average progression-free survival (PFS) rates more than three times than standard-of-care chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) with high tumor mutational burden (TMB).

“Lung cancer is the greatest cause of cancer death worldwide and for most patients with newly diagnosed advanced NSCLC, chemotherapy has long been the standard,” Matthew Hellmann, M.D., assistant attending at Memorial Sloan Kettering Cancer Center, said in a press release. “While PD-1 immunotherapies have recently emerged as a critical new treatment option for this patient population, only a minority of all patients with NSCLC respond.”

These initial findings were seen in the large, open-label, randomized phase 3 CheckMate-227 trial, presented at the American Association for Cancer Research (AACR) Annual Meeting and simultaneously published in the New England Journal of Medicine. In the trial, researchers randomized patients with stage 4 or recurrent NSCLC who had not received prior treatment to receive either Opdivo monotherapy, Opdivo plus Yervoy or Opdivo plus platinum-doublet chemotherapy compared with chemotherapy alone.

“Based on rapidly emerging data suggesting the importance of TMB as a predictive biomarker for benefit with immunotherapy, CheckMate-227 was amended to include – in addition to the initial study design examining nivolumab plus ipilimumab in PD-L1 selected patients – a co-primary endpoint of nivolumab plus ipilimumab versus chemotherapy in patients with high TMB, pre-defined as 10 mutations per megabase,” said Hellmann.

These data represented part one of a three-part trial, designed to compare the immunotherapy combination regimen and chemotherapy. In total, 299 previously untreated patients with stage 4 NSCLC whose cancer had high TMB were randomized to either the immunotherapy combination (139 patients) or platinum-doublet chemotherapy (160 patients).

After a minimum follow-up of 11.5 months, patients who received the combination were 42 percent less likely to experience disease progression compared to the chemotherapy group. Overall, patients treated with the combination regimen demonstrated superior PFS (43 percent vs. 13 percent), duration of response at one year (68 percent vs. 25 percent), and objective response rate (45.3 percent vs. 26.9 percent) compared with those who received chemotherapy.

Yervoy plus Opdivo appeared well-tolerated, with no unexpected side effects. Thirty-one percent of patients on the combination regimen experienced a grade 3 or 4 treatment-related toxicity compared to 36 percent of those on chemotherapy.

Rash, diarrhea and anemia were the most common grade 3 or 4 side effects on the combination arm, each affecting less than 2 percent of patients. It should be noted, however, that 12 percent of patients on the combination arm decided to stop treatment due to severe side effects, compared to 4.9 percent in the chemotherapy arm.

These findings are still exciting, as they point toward another group of patients with lung cancer who can benefit from checkpoint inhibitors. Typically, PD-1 or PD-L1 status was used to determine if a patient should be given an immunotherapy regimen. Even then, not all patients would respond, Hellmann said. Patients with high TMB benefitted from the combination regardless of PD-L1 status.

“The results show that in TMB-high NSCLC patients, nivolumab plus ipilimumab provides improved benefit compared to chemotherapy, increases benefit compared to anti-PD-1 monotherapy, yields durable responses, spares the use of chemotherapy in the first-line setting, and could preserve an effective option in the second line of therapy, if needed,” Hellmann said.
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