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.
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|
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.