Esmo – Merck carries off first-line NSCLC prize

Rarely have scientific data presentations been so keenly awaited than the disclosures of two phase III trials of checkpoint inhibitors in first-line non-small cell lung cancer that were delivered at Esmo yesterday. Those presentations were of course for the Keynote-024 study of Merck’s Keytruda and Checkmate 026 trial of Bristol-Myers Squibb’s Opdivo.

The first was known to be positive, the second negative, as topline results were reported in June and August (EP Vantage – Bristol swings for the fences and strikes out, August 5, 2016). At the time, the unexpected divergence in outcome for what were then considered two similar agents led to stock market movements for those companies that were measured in tens of billions of dollars. Today's movement was of a similar magnitude for Bristol, which fell 10% after its disappointing Esmo presentation.

The two studies were largely similar in design except to the extent to which patients were selected by their degree of expression of PD-L1. Merck, wisely as it turned out, focused only on high expressers, or PD-L1 >50%, representing around 30% of all patients, and has achieved a stunning result.

Median progression-free survival (PFS), the primary endpoint, was extended by 4.3 months, with a hazard ratio of 0.5 – almost unprecedented for NSCLC – and equivalent to a 50% improvement in the relative risk of progression or death. Data for Keynote-024 were published simultaneously in the NEJM, and show an extraordinary separation of curves for Keytruda, known generically as pembrolizumab, on the Kaplan-Meier plot after about five months.

By contrast, Bristol-Myers, which recruited patients into its study based on a lower >1% PD-L1 cut-off, but conducted its primary analysis based on a >5% figure, obtained results that were clearly worse than feared. Its PFS at the 5% level trended in the wrong direction and the hazard ratio suggests that patients were probably better off on chemotherapy. The Kaplan-Meier plot also confirms that a significant proportion of patients in the study perform better on chemo than on Opdivo, known generically as nivolumab. 

Worse still, Bristol-Myers disclosed >50% PD-L1 cut-off figures in an investor presentation last night, and these were as bad as those in the broader population. The like-for-like hazard ratio for PFS for Opdivo was 1.07. Indeed the analysis suggests only one subgroup of 11 where there was a hazard ratio below 1.0, with one, never-smokers, achieving an unusual ratio of 2.5 favouring chemotherapy.

Analysts who had speculated since August that exploratory data from CheckMate 026 at higher PD-L1 cut-offs would show effective equivalence for Opdivo and Keytruda will now have to revisit those assumptions. That hope is now looking very doubtful, and it seems unlikely that Opdivo, at least as a monotherapy, will be used outside its indicated second-line setting in NSCLC.

A tale of two studies in first-line NSCLC
Keynote-024 PD-L1 cutoff Keytruda Chemotherapy Statistics
mPFS (mos) >50% 10.3  (6.7 –NR)  6.0 (4.2 to 6.2) HR=0.50 (0.37- 0.68); P<0.001
OS rate at 6 mos >50% 80.2%  72.4% HR = 0.60 (0.41-0.89),  P=0.005
ORR >50% 44.8% (36.8 to 53.0)  27.8% (20.8 to 35.7)  N/A
CheckMate 026 PD-L1 cut Opdivo Chemotherapy Statistics
mPFS (mos) >5% 4.2 (3.0-5.6) 5.9 (5.4-6.9) HR=1.15 (0.91-1.45), p=0.2511
mPFS (mos) >50% N/A N/A HR=1.07
OS >5% 14.4 13.2 HR=1.02 (0.8-1.30)

Combination with chemotherapy

Bristol-Myers will have to place its hopes on combinations, in particular with Yervoy, to have any chance of traction in first-line NSCLC. However, combinations of chemotherapy with checkpoint inhibitors are also looking promising, an approach being notably pioneered by Roche with Tecentriq.

This approach also received a significant boost at Esmo yesterday with data from a combination phase II trial of Keytruda in first-line NSCLC. Researchers reported data that the addition of Keytruda to a doublet of carboplatin and pemetrexed boosted overall response rate from 29% to 55% (HR=0.53, p=0.0016). While patients were not selected by PD-L1 expression levels, a higher response rate (~80%) was observed in the combination arm in patients with the highest PD-L1 expression (>50%).

Some 11 phase III studies are under way of checkpoint inhibitors in first-line NSCLC, the first of which could start to read out next year. Unfortunately for Bristol-Myers, these are all for its competitors.

Ongoing phase III studies in first-line NSCLC with PD-1/PD-L1 MAbs 
Study  Intervention  Population  Primary endpoint  Data  Trial ID 
Mystic  Durvalumab +/-tremelimumab  –  PFS, OS  Jan 2017 (OS 2018)  NCT02453282 
IMpower150  Tecentriq + CP + Avastin  Non-squamous   PFS  Jan 2017  NCT02366143 
JavelinLung100  Avelumab  PDL1 +ve  PFS  Aug 2017  NCT02576574 
Keynote-189  Keytruda + chemo    Non-squamous  PFS  Sep 2017  NCT02578680 
CheckMate-227  PDL1 +ve: Opdivo +/-Yervoy.  
PDL1 -ve: Opdivo +Yervoy 
–  OS, PFS  Jan 2018  NCT02477826 
Keynote-042  Keytruda  PDL1 +ve  OS  Feb 2018  NCT02220894 
Neptune   Durvalumab +tremelimumab  –  OS  Oct 2018  NCT02542293 
IMpower130  Tecentriq + chemo  Non-squamous   PFS  Jan 2019  NCT02367781 
IMpower110 Tecentriq  PDL1 +ve   PFS  Mar 2019  NCT02409342 
IMpower132  Tecentriq + Pt +pemetrexed  Non-squamous  PFS May 2019  NCT02657434 
IMpower131  Tecentriq + Abraxane/carbo or Tecentriq + CP  Squamous  PFS  Feb 2023  NCT02367794 
N/A  Durvalumab +/- tremelimumab + chemo  Non-squamous  N/A  N/A  N/A 
Notes: CP= carboplatin + paclitaxel.

To contact the writer of this story email Robin Davison in Copenhagen at robind@epvantage.com or follow @RobinDavison2 on Twitter

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