Esmo 2017 – Renal cancer battlefront moves to the front line

Bristol-Myers Squibb upped the ante in the treatment of first-line metastatic renal cell carcinoma with its dramatic eve-of-Esmo revelation of an early efficacy stop for the Checkmate-214 study. But the detailed data highlighted several unexpected trends for the Opdivo plus Yervoy combo that could hand an advantage to Exelixis, the company that the markets had last week decided was the main loser.

The initial disclosure of the study showed that Opdivo plus Yervoy conferred a 37% improvement in risk of death and 18% improvement in risk of progression, relative to Sutent, in intermediate/poor-risk patients – 75% of the overall group. However, close inspection of the data presented later at Esmo suggests that not all patients benefited from the checkpoint inhibitor doublet, and remarkably that the performance of good-risk patients was statistically inferior to Sutent. This means the benefit in the overall group was entirely driven by the majority intermediate/poor-risk patients.

Furthermore, an analysis of PFS by PD-L1 status suggests no PFS benefit in PD-L1 negatives, although there might be some activity in good-risk PD-L1 positives. OS data were not reported for either good-risk or by PD-L1 status.

Bristol’s OS result in intermediate/high-risk patients was significant, but PFS did not meet the statistical requirement, despite having a p value of 0.0331, because of the higher threshold applied at an interim analysis. There was no significant difference in PFS for the intent-to-treat (ITT) group, although an OS advantage was shown.

Checkmate-214 results reported at Esmo
Intermediate/poor-risk (~75% of pts) Good risk (~25% of pts) All patients (ITT)
PFS 11.6 vs 8.4 mos. HR=0.82; p=0.0331. 15.9 vs 25.1 mos. HR=2.18, p<0.0001 in favour of Sutent. 12.4 vs 12.3 mos, HR=0.98, p=0.8499.
PD-L1 negative PFS=11.0 vs 10.4 mos. HR=1.00, p=0.9670. PFS not disclosed, but HR likely to be >1.0. (ORR  estimated to ~33% vs 56%.)* PFS not disclosed. (ORR 36% vs 35%, p=0.8799.)
PD-L1 positive  22.0 vs 5.9 mos. HR=0.48, p= 0.0003. PFS not disclosed. PFS not disclosed. (ORR=53% vs 22%, p<0.0001.)
OS NR vs 26.0 mos. HR 0.63, p<0.0001. Not disclosed. Likely to favour Sutent. NR vs 32.9 mos. HR=0.68 p=0.0003.
All comparisons Opdivo/Yervoy vs Sutent. NR: not reached.*by EPVantage.

Patients in Checkmate-214 received Opdivo and Yervoy for four doses followed by Opdivo maintenance in the experimental arm or Sutent as control. Roughly 10% of patients on the control arm received Opdivo, which is an approved second-line agent for RCC, on progression, so there could have been some confounding effect of subsequent therapy on the OS result.

Presenting the data at a press conference, principal investigator Professor Bernard Escudier said that he thought the study would drive a practice change, and that Opdivo/Yervoy would quickly become first-line standard of care. However, much of the detailed data were reserved for a presentation later in the day, leaving Exelixis struggling to react at its own analyst/media meeting that took place less than 30 minutes after the Checkmate-214 presentation.

Exelixis fights back

Exelixis – whose stock fell 9% on Friday as a result of the Checkmate-214 news – and its partner Ipsen disclosed updated data at Esmo from the Phase II Cabosun trial, which supports their recent regulatory applications for Cabometyx in the first-line RCC setting. Cabsun now shows a significant 52% improvement in relative risk of progression, with a non-significant 20% trend towards improvement in risk of death. Cabosun recruited only intermediate and poor-risk patients.

Cabosun: updated results presented at Esmo*
PFS 8.6 vs 5.3 mos. HR=0.48, p=0.0008.
OS 26.6 vs 21.2 mos. HR=0.80, p=0.27, non-significant trend.
ORR 20% vs 9%
*Data now IRC reviewed (previously published figures were investigator assessed) and new FDA censoring rules have been applied.

The across-trial comparison surprisingly gives a number of advantages to Cabometyx, albeit from a smaller study without a statistically significant OS result. Notably, the TKI’s PFS matched that of Opdivo/Yervoy (HR=0.48) in its best subgroup, the PD-L1 positive intermediate/high-risk patients, despite Cabosun having recruited much sicker patients as evidenced by the performance of the control arms.

Cabometyx does have a first mover advantage. By coincidence, on Friday it received an NCCN guideline recommendation for first-line use in RCC ahead of formal approval and Professor Escudier conceded that he expected the drug to be approved on the basis of Cabosun.

Commercially, a likely outcome if both agents are approved must be that Cabometyx becomes the preferred choice in PD-L1 negative intermediate/poor-risk patients, as no advantage was shown here for Opdivo/Yervoy relative to Sutent. What is perhaps not appreciated yet is that this might represent 75% of all RCC patients.

Of course, physicians will want to see the OS results for the Bristol doublet by PDL-1 status and would probably want to see some data on Cabometyx activity in PD-L1 negatives. Although the TKI is mechanistically independent of PD-L1, there might be some correlation that affects its activity in this group. But, essentially, it looks like the new data will mean similar arguments end up being made for Opdivo/Yervoy vs Cabometyx in the first-line choices as are currently being made for Opdivo and Cabometyx as single agents in second line.

What physicians would like to see next is a triple therapy of Opdivo/Yervoy/Cabometyx, and the companies have a clinical collaboration to provide this in the form of the recently started Checkmate-9ER study. However, this might need to be changed as a result of Checkmate-214. Notably, this study includes favourable-risk patients and has no selection by PD-L1 status.

The fact that benefit in Checkmate-214 correlated so closely with PD-L1 status will undoubtedly spell problems for companies not selecting patients in this indication. Roche is the only one of several anti-PD-(L)1 competitors to do so, in its phase III Immotion-151 study (Asco-GU – Roche’s renal success spells danger for all-comer studies, February 22, 2017).

Checkmate-214 has, nevertheless, raised the bar in RCC, and Sutent will lose its long-held monopoly as first-line standard of care. However, it is too soon for the market to write off Cabometyx’s chances as a first-line choice.

To contact the writer of this story email Robin Davison at Esmo in Madrid at [email protected] or follow @RobinDavison2 on Twitter

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