With Merck & Co and Bristol-Myers Squibb recently revealing timelines for the readouts of Keytruda and Opdivo studies in first-line lung cancer the battle lines have been drawn in the most lucrative immuno-oncology indication so far.
Over the past year Opdivo has pulled away from Keytruda in terms of approved uses and settings, and first-line NSCLC gives Merck a chance to regain lost ground (see table below). But subtleties of trial design mean that Bristol could actually have the bigger market. Roche and AstraZeneca, meanwhile, can only hope to play catch-up.
Reality hit home for Astra last week, when it abandoned its pursuit of durvalumab’s monotherapy use in third-line NSCLC. This is a perfectly logical analysis of a situation on which Bristol and Merck have a stranglehold, and Astra’s previously stated immuno-oncology strategy is to pursue monotherapy only in new indications, while for established uses it will look at combos.
Meanwhile, Roche last year submitted rolling NDAs for atezolizumab in bladder and lung cancers, but only the former has been completed. At its fourth-quarter call the Swiss group said it was waiting for studies to read out, and its second/third-line NSCLC filing is to be completed by the end of March; it expects approval for both indications this year.
The importance of NSCLC is a matter of the available patient population, and can easily be gleaned by looking at sellside consensus in EvaluatePharma’s sales by indication tab.
By 2020 NSCLC is expected to account for 71% and 63% of the respective $4.5bn and $7.8bn revenues generated by Keytruda and Opdivo, easily eclipsing the agents’ first approved uses in melanoma, where both are now used first line irrespective of patients’ Braf status.
Both are also approved in second-line NSCLC, but clearly frontline use – replacing chemotherapy – is the biggest prize.
|Anti-PD-1 MAb approvals in major Western markets|
|Opdivo (Bristol-Myers Squibb/Ono)*|
|23 Jan 2016||US||Yervoy combo||1st-line Braf-positive melanoma||Checkmate-067 study|
|23 Jan 2016||US||Monotherapy||1st-line Braf-positive melanoma||Complete response letter on 27 Nov 2015|
|24 Nov 2015||US||Monotherapy||2nd-line renal cell carcinoma||First anti-PD1 to show OS benefit in renal cancer|
|24 Nov 2015||US||Monotherapy||1st-line Braf-W/T melanoma||Checkmate-066 study|
|9 Oct 2015||US||Monotherapy||2nd-line non-squamous NSCLC||Checkmate-057 study|
|1 Oct 2015||US||Yervoy combo||1st-line Braf-W/T melanoma||1st I-O combo in cancer; Checkmate-069|
|20 Jul 2015||EU||Monotherapy||2nd-line squamous NSCLC||–|
|19 Jun 2015||EU||Monotherapy||1st & 2nd-line melanoma regardless of Braf status||Checkmate-066 & 037 studies|
|4 Mar 2015||US||Monotherapy||2nd-line squamous NSCLC||Checkmate-017 study|
|22 Dec 2014||US||Monotherapy||2nd-line melanoma||First US approval; Checkmate-037 study|
|Keytruda (Merck & Co)|
|18 Dec 2015||US||Monotherapy||1st-line melanoma regardless of Braf status||Keynote-006 study|
|2 Oct 2015||US||Monotherapy||2nd-line PD-L1-positive NSCLC||Keynote-001 study|
|22 Jul 2015||EU||Monotherapy||1st & 2nd-line melanoma regardless of Braf status||Keynote-001, 002 & 006 studies|
|4 Sep 2014||US||Monotherapy||2nd-line melanoma||First anti-PD-1 agent to get US approval; Keynote-001 study|
|Note: *Additionally, Opdivo's pivotal squamous head & neck study (Checkmate-141) was stopped early for efficacy on 28 Jan 2016.|
Merck will be first out of the gate with its Keynote-024 trial, which it says is on track to yield data by mid-year. Bristol’s Checkmate-026 study, meanwhile, will not report until near the end of 2016, and there is no early interim analysis of the data.
Both studies measure progression-free survival as the primary endpoint. There has been some criticism of late for basing immuno-oncology studies around PFS owing to the risk of so-called “pseudo-progression”, though the groups reckon they can get around this via a smart trial design.
But, even if Keytruda reads out six months before Opdivo, trial design is how Bristol could regain the upper hand: while Merck is recruiting only PD-L1-high patients into Keynote-024 – in line with its previous NSCLC efforts – Bristol is enrolling a broad population of PD-L1 expressers.
And here lies the key point: if Checkmate-026 yields sufficiently good data in PD-L1-high patients in the initial analysis, its statistical design enables Bristol to analyse the data across all comers – which, if positive, opens up a broader market for Opdivo.
|1st-line NSCLC studies|
|Keynote-024||Keytruda vs chemo in 300 high-PD-L1 expressers||NCT02142738||Mid-2016|
|Checkmate-026||Opdivo vs chemo in 535 pts with known PD-L1 status||NCT02041533||End 2016|
A separate distinction, NSCLC histology, is no longer relevant since Checkmate-026 and Keynote-024 recruit patients with squamous and non-squamous disease (Opdivo steals Keytruda’s thunder – again, October 12, 2015). Bristol seems to have overcome its initial disadvantage, reporting 60% and 70% respective shares of new US prescriptions for non-squamous and squamous second-line NSCLC.
If Bristol and Merck have now edged out both Astra and Roche in this race to the most lucrative indication, where does immuno-oncology’s dark horse, Pfizer/Merck KGaA’s avelumab, stand?
At JP Morgan last month Pfizer said it would become a leading player in the second wave of combinations. Given that the group missed the first two waves of monotherapies, lost the first combo wave to Bristol and looks likely to lose the second wave to Astra, even this modest goal looks like wishful thinking.