Dual Checkpoint Blockade With Some Chemo Boosts OS in NSCLC

Dual Checkpoint Blockade With Some Chemo Boosts OS in NSCLC

A first-line immune checkpoint inhibitor combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) improved survival in patients with advanced non-small cell lung cancer (NSCLC) when added to a limited course of chemotherapy, results of the phase III CheckMate-9LA trial showed.

With 8.1 months minimum follow-up, overall survival (OS) reached a median 14.1 months when nivolumab plus ipilimumab was added to two cycles of platinum-based chemotherapy, as compared to 10.7 months with four cycles of chemotherapy plus optional pemetrexed (Alimta) maintenance (HR 0.69, 96.71% CI 0.55-0.87, P=0.0006), reported David Carbone, MD, PhD, of the Ohio State University Comprehensive Cancer Center in Columbus.

And with longer follow-up (12.7 months), median OS reached 15.6 months in the immunotherapy-chemotherapy arm versus 10.9 months in the chemotherapy-alone arm (HR 0.66, 95% CI 0.55-0.80), he said during a presentation at the virtual North America Conference on Lung Cancer.

Landmark analyses showed that 81% of patients treated with the PD-1/CTLA-4 inhibitors plus chemotherapy combination were alive at 6 months compared to 73% with chemotherapy alone. At 12 months, 63% versus 47% remained alive, respectively.

“Importantly, there was early separation of the overall survival curves and lower progressive disease rates as best overall response,” said Carbone. “Thus, the basic hypothesis for adding two cycles of chemo was validated.”

Asked where nivolumab-ipilimumab plus limited chemotherapy could fit into the current treatment landscape, Carbone pointed out that none of the available first-line immunotherapy options in NSCLC have been compared head to head, but that the findings revealed two things.

“One is that two cycles of chemotherapy may be enough when used with this combination, and that’s certainly an advantage, and the other advantage is the lack of maintenance chemotherapy. The maintenance pemetrexed has always been a little problematic, especially with the steroids required with every cycle,” he said.

“I also am intrigued in the activity in the PD-L1 negatives, which seems to be at least as good as the positives,” Carbone added.

OS improvement with nivolumab-ipilimumab was independent of PD-L1 expression, as defined by tumor proportion score (TPS):

  • TPS <1%: HR 0.62 (95% CI 0.45-0.85)
  • TPS ≥1%: HR 0.64 (95% CI 0.50-0.82)
  • TPS 1-49%: HR 0.61 (95% CI 0.44-0.84)
  • TPS ≥50%: HR 0.66 (95% CI 0.44-0.99)

Results of the trial led to FDA approval earlier this year as a first-line treatment for patients with metastatic or recurrent NSCLC, regardless of PD-L1 status or tumor histology.

“This really represents an option for either histology,” said discussant Deborah Doroshow, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York City.

Patients with non-squamous tumors had a median OS of 17 months with the combination treatment versus 11.9 months with chemotherapy alone. In patients with squamous disease, OS was 14.5 versus 9.1 months.

“For patients with squamous tumors, this really is a second option for them, as previously only one regimen was FDA approved,” added Doroshow.

All secondary efficacy endpoints were improved with the immunotherapy plus chemotherapy combination. Progression-free survival reached 6.7 months in the nivolumab-ipilimumab arm versus 5 months in the chemotherapy-alone arm (HR 0.68, 95% CI 0.57-0.82).

Overall response rates were 38% with the combination compared to 25% with chemotherapy alone, including complete responses in 2% and 1%, respectively. Fewer patients had progressive disease as best response with the combination as well (9% vs 13%).

Median duration of response doubled with immunotherapy plus chemotherapy (11.3 vs 5.6 months). At 1 year, 49% of patients treated with the combination were still in response against 24% in the chemotherapy-alone group.

CheckMate-9LA was an international phase III study that randomized 719 patients with recurrent or metastatic NSCLC who had received no prior systemic therapy to either nivolumab (360 mg every 3 weeks) plus ipilimumab (1 mg/kg every 6 weeks) plus two cycles of chemotherapy, or four cycles of chemotherapy alone plus optional pemetrexed maintenance. Eligible patients included those without EGFR mutations or ALK alterations, and those with an Eastern Cooperative Oncology Group performance status of 0 or 1. Stratification factors included PD-L1 status (<1% or ≥1%), sex, and histology (squamous or non-squamous).

Median age of patients was 65, most were former smokers (86%-87%), a little over two-thirds had non-squamous tumors, and about 40% had low PD-L1 expression (<1%).

Nearly all subgroups benefited from nivolumab-ipilimumab, with the possible exception of patients ages 75 and older and never smokers, though both subgroups were small, Carbone said.

Grade 3/4 adverse events were more common in the combination arm (47% vs 38%), which led to increased discontinuation for any treatment component (16% vs 5%). Common toxicities with the immunotherapy combination were skin, endocrine, and gastrointestinal in nature. Serious events occurred in 25.5% of patients on the combination arm versus 15% in the chemotherapy-alone alone. Two treatment-related deaths occurred in each arm.

Carbone and Doroshow both commented that biomarkers are needed to spare patients the additional potential toxicity of ipilimumab.

Last Updated October 17, 2020

  • Ian Ingram joined MedPage Today in 2018 as Deputy Managing Editor, and covers oncology for the site.

Disclosures

The study was funded by Bristol Myers Squibb (BMS).

Carbone disclosed relevant relationships with AbbVie, Adaptimmune, Amgen, Agenus, Ariad, AstraZeneca, Biocept, Boehringer Ingelheim, BMS, Celgene, Flame Biosciences, Foundation Medicine, Gen-Plus, Genentech/Roche, Gritstone, Guardant Health, Inovio, Merck, MSD, Novartis, Palobiofarma, Pfizer, Prime Oncology, Stemcentrx, and Takeda.

Doroshow disclosed no relevant relationships with industry.

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