October 2016 Edition Vol.11, Issue 10

At ESMO: One Anti-PD1 Agent Moves to the Head of the Line in Advanced NSCLC

At ESMO: In Advanced NSCLC, One Anti-PD1 Agent Moves to the Front of the Line (cont.)

Why Negative for Nivolumab?

Principal investigators of other lung cancer trials were left scratching their heads over the negative findings of CheckMate 026. “Why was nivo negative, with almost no benefit? That’s somewhat perplexing,” Dr. Herbst offered.

“I’m puzzled,” Dr. Langer echoed. “I cannot really figure out why that trial was completely negative.”

Both lung cancer experts felt the CheckMate 026 broader population—patients with expression ≥1% (≥5% for the primary analysis)—could have “diluted” the effect of nivolumab.

As Dr. Herbst maintained, “They didn’t select the population well, and therefore the two studies had disproportionate numbers of patients with high expression.”

He also pointed to other imbalances in the study population, a point reiterated by the study’s discussant, and noted the good performance of the study’s comparator.

Dr. Langer, however, emphasized that all patients were PD-L1 expressors and were not PD-L1 negative. “You could argue they included patients that were probably less likely to benefit, but it was not a completely unselected population,” he said. “It was a large trial, and I don’t think imbalances would have made that big a difference.”

Could it simply be that one drug is better than the other?

“I don’t believe the drugs are that different,” Dr. Herbst said. “Certainly, nivo showed activity in other randomized trials. I would bet it’s the biomarker, so I think the nivolumab trial might be repeated in a population with higher biomarker expression.”

Dr. Langer, on the other hand, considers this a possibility. “Until today, I didn’t believe there were differences in the drugs, but one now begins to wonder,” he commented.  He said he is anxious to see subgroup analyses on patients with ≥50% expression, in never-smokers, and in patients with EGFR mutations.

“But regardless,” he added, “you cannot shine a laser pointer between those PFS curves. To be honest, I was expecting at least some separation…I think in light of what we saw at ESMO, the company’s current trials [nivolumab/ipilimumab combinations] are high-risk.”

In Second-Line Nivolumab Has Competition 

For patients with ≥50% expression apt to receive front-line pembrolizumab, what will patients receive in the second line?

“The interesting question is whether patients who score ‘low’ for PD-L1 expression will still be offered nivolumab second-line,” Dr. Spigel said. “The oncologist may say, ‘The patient is PD-L1-negative, so they don’t deserve nivo. I think that would be the wrong choice, but we could see some shift there in thinking they are not good candidates…I think this would be a mistake.”

He predicted that nivolumab should remain a frequent second-line choice, but atezolizumab will compete in this space and possibly surpass nivolumab because of its every-2-week dosing. “You save a visit every 6 weeks, and I think this will appeal to some physicians,” he offered.

Dr. Langer agreed that atezolizumab will be more “user friendly” and said its standard every-3-week dosing will “dovetail” nicely with future combinations of agents.

Furthermore, he added, the data are impressive. “In some ways, the OAK data are probably the most robust we have seen in the second-line setting,” he indicated. “For the first time, we are seeing a fairly clear-cut survival benefit in the PD-L1-negative group and in never-smokers.”

“Assuming that atezolizumab garners approval, one might conjecture that it will displace nivolumab,” he predicted.

Dr. Herbst suggested that in the second-line setting, the label for pembrolizumab could potentially be expanded to patients with PD-L1 ≥1%, opening up this space for more patients to receive pembrolizumab as well as nivolumab.

“From a business point of view, this could eat into some of the nivolumab market,” he said.

Oncologists will choose between the drugs based on comfort level and reimbursement issues, he predicted. “The main thing is that we want patients to get the best drug at the best time, and they are all active. It’s a great time for patients with lung cancer.”

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For related lung cancer videos, please check out our coverage of the ASCO 2016 annual meeting:

     

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References

1. Reck M, Rodriguez-Abreu, Robinson AG et al. KEYNOTE-024: Pembrolizumab vs platinum-based chemotherapy as first-line therapy for advanced NSCLC with a PD-L1 tumor proportion score ≥ 50%. 2016 ESMO Congress. Presented October 10, 2016.

2. Socinski M, Creelan B, Horn L et al. CheckMate 026: A phase 3 trial of nivolumab vs investigator’s choice of platinum-based doublet chemotherapy as first-line therapy for stage IV/recurrent programmed death ligand 1 (PD-L1)-positive NSCLC. 2016 ESMO Congress. Abstract LBA7_PR. Presented October 10, 2016.

3. Barlesi F, Park K, Ciardiello F et al. Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC. 2016 ESMO Congress. Abstract LBA44_PR. Presented October 10, 2016.

4. Langer C, Gadgeel S, Borghaei H, et al. Randomized phase 2study of carboplatin and pemetrexed with or without pembrolizumab as first-line therapy for advanced NSCLC: KEYNOTE-021 cohort G. 2016 ESMO Congress. LBA 46_PR. Presented September 10, 2016.

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