Merck & Co hedges its checkpoint bet with Lenvima

Eisai deal to help Merck expand checkpoint inhibitor franchise.

Merck & Co buying into Eisai’s marketed small-molecule drug Lenvima likely marks another big pharma effort to broaden the scope of checkpoint inhibition beyond obvious patient groups, such as those whose cancers express high levels of PD-L1.

Similar considerations marked Merck’s tie-up last year with Astrazeneca on Lynparza, as well as Bristol-Myers Squibb’s recent $1.85bn deal for rights to Nektar’s NKTR-214. Merck will also surely want to avoid the controversy generated by Bristol’s rival Opdivo in the Checkmate-214 trial in renal cancer – a setting where Lenvima was approved two years ago.

The obvious focus of the deal on Lenvima, a VEGFR tyrosine kinase inhibitor, is combinations. Indeed, a combo of Lenvima plus Merck’s Keytruda was granted US breakthrough designation in renal cancer in January – something that surely focused Merck’s mind – and a pivotal first-line study, Clear, should read out in 2019/20.

PD-L1-negative problem

The problem Merck will want to solve – especially, it seems, with renal cancer – is that first-line patients who are not PD-L1-positive do not benefit from checkpoint blockade alone.

Despite the lead investigator’s claims that Bristol’s Opdivo plus Yervoy showed broad utility in Checkmate-214, the trial suggested that PD-L1-negative subject might actually be better off on Pfizer’s Sutent, the current standard of care (Spotlight – Medical disclosure farrago hits Esmo 2017, September 15, 2017). 

Opdivo is the only anti-PD-(L)1 drug to have renal cancer on its label, in second-line use, and it might soon be joined by Roche’s Tecentriq.

Broad first-line use likely needs a combo approach, and this is where Lenvima comes in. The Keynote-146 trial showed Keytruda and Lenvima to have an additive effect, yielding overall remission of 63% in renal cancer; this was irrespective of PD-L1 status, and was above that seen previously with Lenvima and Novartis’s Afinitor (37%), or with Opdivo monotherapy (25%).

Of course, renal cancer is not Merck’s only focus in the Lenvima deal; the company says it wants to evaluate the combo in six other cancers, including endometrial, liver and non-small cell lung tumours.

Evercore ISI’s Umer Raffat points out that across the cancers studied in Keynote-146 Lenvima plus Keytruda yielded a 52.2% overall response rate, including in patients whose tumours had low levels of microsatellite instability. Keytruda is approved broadly in microsatellite instability-high cancers – a particularly strong marker of efficacy for checkpoint blockade.

And liver cancer is an obvious target, since this is a setting where Lenvima has been filed for first-line treatment. Again, Opdivo is the only anti-PD-(L)1 drug approved here, again for second-line use.

Trials of Keytruda plus Lenvima combinations
Study Conditions Enrolment Trial ID Primary completion Note
Keynote-523 Solid tumors 6 NCT03006887 Jun 2018
Keynote-524 Hepatocellular carcinoma 30 NCT03006926 Aug 2018 Lenvima filed for 1st-line liver cancer
ACCRU-ITOG-1504 Thyroid cancer 60 NCT02973997 Sep 2018 Investigator-initiated trial
17-00626 Gastro-oesophageal cancer 24 NCT03321630 Oct 2018 Investigator-initiated trial
Keynote-146/Study 111 Solid tumors 191 NCT02501096 Aug 2019 Basis of US BTD for renal cancer, where Lenvima is approved 2nd-line
Clear 1st-line renal cell carcinoma 735 NCT02811861 Oct 2019 Phase III study (all others are I or II)
S17-00626 Gastric or gastro-oesophageal cancer 29 NCT03413397 Nov 2020 Investigator-initiated trial
Source: Clinicaltrials.gov.

As such it looks likely that Merck just chose Lenvima as a hedge against the future threat of its checkpoint inhibitor franchise being marginalised. The financials back this up: Eisai got $300m up front and a $450m R&D expenditure reimbursement, and could get $650m for certain future option rights, in addition to milestone fees.

Other tie-ups aiming to broaden the potential of anti-PD-(L)1 drugs include Merck’s deal with Astrazeneca to combine Lynparza or selumetinib with Keytruda or Imfinzi. Bristol is combining Opdivo with various in-house biologicals, and last month’s licencing of NKTR-214 gave it an asset that hits the IL-2 pathway and has specifically shown combinatorial efficacy in PD-L1-negative cancers.

This is likely to remain a key focus as immuno-oncology players seek to grab market share – a good reason why combo studies continue to generate such interest at scientific meetings.

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobPlieth on Twitter

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