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

By Adrian Barfield

For patients with advanced NSCLC lacking a targetable mutation, platinum-based doublets have been the standard of care for 30 years. The anti-PD1 antibodies nivolumab (Opdivo; Bristol-Myers Squibb), pembrolizumab (Keytruda; Merck) and atezolizumab (Tecentriq; Genentech) each demonstrated improved survival over docetaxel in patients progressing on platinum-based doublets.

Having already revolutionized the treatment of advanced NSCLC, these compounds are being tested in previously untreated patients. This where the compounds may be parting ways.

Phase 3 studies in NSCLC were the highlights of the European Society for Medical Oncology (ESMO) 2016 Congress. Most importantly, in the front-line setting, the KEYNOTE 024 trial of single-agent pembrolizumab met its primary endpoint, achieving not only a progression-free survival (PFS) but an overall survival (OS) benefit versus chemotherapy.1

Nivolumab, on the other hand, essentially tanked as a first-line agent in CheckMate 026.2

A preliminary analysis of the phase 3 OAK study of second-line atezolizumab also stoked the checkpoint inhibitor fire.3

OBR was there to capture the data and obtain insights from lung cancer experts.

Invited discussant of KEYNOTE 024, Jean-Charles Soria, MD, of the Institute Gustave Roussy and Paris University XI, noted that since PFS was improved with pembrolizumab by 50% and OS by 40%, platinum doublets are “no longer dominant.” “There’s a new player, and probably a new standard of care,” he said.

Assuming its likely FDA approval in the front line, pembrolizumab has become “the ultimate game changer in our therapeutic landscape,” agreed Corey Langer, MD, Director of the Thoracic Oncology Program, Abramson Cancer Center, University of Pennsylvania Health System, who said the results of the study usher in a “complicated but also very exciting” change in the treatment paradigm for advanced NSCLC.

Pembrolizumab Trial Meets Primary Endpoint

KEYNOTE 024 was an open-label, randomized phase 3 trial of pembrolizumab versus platinum-doublet chemotherapy as first-line treatment in 305 advanced NSCLC patients with PD-L1 expression ≥50% and no targetable mutation (which would warrant targeted treatment).

After a median follow-up of 11.2 months, median PFS was 10.3 months with pembrolizumab versus 6.0 months with chemotherapy (HR=0.50; P<0.001), reported Martin Reck, MD, PhD, of the German Center of Lung Research in Grosshansdorf.

One-year survival was 70% versus 54%, respectively (HR=0.60; P=0.005). Pembrolizumab was also associated with higher objective response rates (ORR) (45% vs 28%), longer response duration (median not reached, vs 6.3 months), and a lower incidence of adverse events.

“In untreated patients without targetable mutations and with high expression of PD-L1, pembrolizumab has been shown to be a very attractive first-line treatment option,” commented Dr. Reck.

Also at ESMO, Dr. Langer reported positive results of a phase 2 study of pembrolizumab plus chemotherapy (carboplatin/pemetrexed) versus chemotherapy alone as first-line treatment in patients with non-squamous histology.4

The study enrolled 123 patients from KEYNOTE 021 (cohort G) with any PD-L1 status. The primary endpoint, ORR, was 55% with pembrolizumab/chemotherapy versus 29% for chemotherapy alone (P=0.0016).

PFS was significantly improved, from 8.9 months with chemotherapy to 13.0 months with the combination (HR=0.53; P=0.0102).

“This makes KEYNOTE-021 one of the first randomized, controlled trials of first-line therapy for advanced NSCLC in which median PFS exceeded 1 year,” noted Dr. Langer.

Response rates appeared to be similar in patients with PD-L1 expression <1% and those with higher levels of PD-L1 expression. With early follow-up, and with nearly three quarters of control subjects crossing over to immunotherapy upon progression, there was no difference in overall survival.

_________________________________________________________________________________

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

     

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

Nivolumab Studies

The first-line study of nivolumab, however, failed to live up to expectations set by its earlier trials, when CheckMate 026 failed to show an improvement in PFS for single-agent nivolumab versus a platinum-based doublet.

The trial randomized 541 PD-L1-positive patients (≥1% PD-L1) to nivolumab (3 mg/kg) or chemotherapy by physician’s choice.

“Nivolumab did not meet the primary endpoint of superior PFS compared with chemotherapy in patients with PD-L1 expression ≥5%,” reported Mark Socinski, MD, Executive Medical Director of Florida Hospital Cancer Institute.

Median PFS was 4.2 months with nivolumab and 5.9 months with chemotherapy (HR=1.15; P=.2511). Median overall survival was also similar: 14.4 months versus 13.2 months (HR=1.02; 95% CI, 0.80, 1.30; no P value was shown).

Crossover was allowed, and 57% of the chemotherapy arm ultimately received nivolumab on study. Responses were observed in 26.1% and 33.5%, respectively, with median duration of response being 12.1 months and 5.7 months. Treatment-related events, however, were much less with nivolumab.

Atezolizumab Trials

Also reported at ESMO were first results from the phase 3 OAK study of atezolizumab versus docetaxel as second- and third-line treatment in 1,225 patients.

Atezolizumab received Breakthrough Therapy designation earlier this year and is currently under priority review with the FDA for late-line treatment of PD-L1-positive patients.

Median OS was superior with atezolizumab: 13.8 months versus 9.6 months with docetaxel (HR=0.73; P=0.0003); in patients with PD-L1 expression ≥1%, OS was 15.7 months versus 10.3 months, respectively (HR=0.74; P=0.0102, and was improved regardless of PD-L1 expression levels. Even PD-L1-negative patients derived benefit (HR=0.75; P=0.0215).

Implications of Phase 3 Trials

Until now, nivolumab has often been the favored anti-PD1 agent in the second-line setting, since testing for PD-L1 expression is not required for its use. “Now, we will test all patients, and the results will determine what we do next,” said David Spigel, MD, Director of the Lung Cancer Research Program at Sarah Cannon Research Institute, Nashville.

“I will ask for the Merck PD-L1 assay in essentially 100% of my patients and they will get pembrolizumab if they are eligible…Pembrolizumab will become a new standard of care in the first-line setting for about one third of our patients—those with at least 50% expression of PD-L1.”

Roy Herbst, MD, PhD, Ensign Professor of Medicine (Medical Oncology), Professor of Pharmacology and Chief of Medical Oncology at Yale Cancer Center, agreed.

“Patients with targetable mutations should still get targeted treatment, but those who do not—whether squamous or non-squamous histology—should get pembrolizumab,” he said. “We predicted the biomarker would be important in the front-line setting, and we are seeing that today.”

This means that for all newly diagnosed advanced NSCLC patients, testing for PD-L1 expression will be required.

“Once pembrolizumab is approved,” Dr. Langer added, “PD-L1 assessment must be part of our diagnostic work-up, on a reflex and not reactive basis. Patients cannot wait for these results.”

The experts agreed, however, that pembrolizumab’s run as the preferred first-line treatment for non-mutated patients could be short-lived.

“I think that pembrolizumab will be the [favored] first-line drug for a while,” Dr. Spigel said, “but I think there will be better strategies than single-agent checkpoint inhibitors. I think ipilimumab plus nivolumab will yield higher response rates than either single agent alone…I think a year from now, when the combination data read out, there could be a new first-line treatment overtaking pembrolizumab and PD-L1 expression may not matter anymore. Combinations may show us we don’t need it.”

_________________________________________________________________________________

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

     

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.”

______________________________________________________________________________

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

     

______________________________________________________________________________

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.

© Caribou Publishing. All rights reserved. Reproduction in whole or in part is prohibited.