Early Keytruda approval and Bristol’s other nasty surprises

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The checkpoint inhibitor showdown continues to astonish, and the fact that yesterday’s first-line lung cancer approval for Merck & Co’s Keytruda came exactly two months before the US FDA’s action date was not the only surprise.

A separate battle in the background, concerning access to an influential listing that opens the door to reimbursement, is throwing up its own surprises, especially as listings frequently precede FDA action. And a less-appreciated aspect of yesterday’s decision will see Bristol-Myers Squibb’s rival, Opdivo, come under even more pressure.

This involves the FDA separately expanding Keytruda’s second-line NSCLC approval to include patients whose tumours express PD-L1 at just 1% or more, versus the >50% threshold included in the drug’s label since October 2015.

Opdivo still holds the upper hand in second-line disease, as for over a year now it has boasted a label in all-comers, irrespective of histology or PD-L1 status. This dominance came under threat after last week’s approval of Roche’s Tecentriq – also in all-comers – and Keytruda’s expansion will challenge it further (Bristol waits for the other PD-1 shoe to drop, October 14, 2016).

Compendia listing

Inclusion – or not – in US National Comprehensive Cancer Network (NCCN) compendia is a separate issue where Keytruda has seized an advantage.

Compendia listing represents an important endorsement that serves as a prelude to reimbursement by Medicare and most private US insurers. Keytruda’s first-line NSCLC use got this accolade even before its earlier-than-expected US approval.

This in itself might not be too surprising, as compendia listing frequently precedes regulatory action; this was the case with both Opdivo and Keytruda, which got listed in first-line melanoma at a time when they were approved only second line, and when Keytruda had not yet even generated data in the first-line setting.

Companies often submit early findings to the NCCN in the hope of a quick thumbs-up, which is what Merck did with its highly positive Keynote-024 trial.

No such luck for Bristol, which had tried to make amends for its monumental Checkmate-026 failure by applying to have Opdivo listed for use in a Yervoy combo, based on the Checkmate-012 trial. Bristol was denied this listing, as was Merck’s application for a Keytruda combo in NSCLC based on Keynote-021 and, interestingly, Roche’s Tecentriq as monotherapy in second-line NSCLC.

However, the Tecentriq denial related to Poplar, a much smaller study than the Oak trial that was the basis for Tecentriq’s approval. Eventual compendia listing for Tecentriq on the strength of Oak looks to be a slam-dunk that will put the squeeze on Opdivo again.

US anti-PD-1/PD-L1 MAb approvals
Approval date Therapy Indication Notes
Tecentriq (Roche)
18 Oct 2016 Monotherapy 2nd-line NSCLC Oak study; denied compendia listing based on Poplar study
18 May 2016 Monotherapy 2nd-line urothelial carcinoma Imvigor-210 study
Opdivo (Bristol-Myers Squibb/Ono)
17 May 2016 Monotherapy 3rd-line classical Hodgkin lymphoma  Checkmate-205 & 039 studies
23 Jan 2016 Yervoy combo 1st-line Braf-positive melanoma  Checkmate-067 study
23 Jan 2016 Monotherapy 1st-line Braf-positive melanoma  Complete response letter on 27 Nov 2015
24 Nov 2015 Monotherapy 2nd-line renal cell carcinoma First anti-PD1 to show OS benefit in renal cancer
24 Nov 2015 Monotherapy 1st-line Braf-W/T melanoma Checkmate-066 study
9 Oct 2015 Monotherapy 2nd-line non-squamous NSCLC Checkmate-057 study
1 Oct 2015 Yervoy combo 1st-line Braf-W/T melanoma 1st I-O combo in cancer; Checkmate-069
4 Mar 2015 Monotherapy 2nd-line squamous NSCLC Checkmate-017 study
22 Dec 2014 Monotherapy 2nd-line melanoma First US approval; Checkmate-037 study
Keytruda (Merck & Co)
24 Oct 2016 Monotherapy 1st-line PD-L1-positive (>50%) NSCLC Keynote-024 study; compendia listed pre-approval
24 Oct 2016 Monotherapy 2nd-line PD-L1-positive (>1%) NSCLC Keynote-010 study
5 Aug 2016 Monotherapy 2nd-line head & neck cancer regardless of PD-L1 status Keynote-012 study
18 Dec 2015 Monotherapy 1st-line melanoma regardless of Braf status Keynote-006 study
2 Oct 2015 Monotherapy 2nd-line PD-L1-positive (>50%) NSCLC Keynote-001 study
4 Sep 2014 Monotherapy 2nd-line melanoma First anti-PD-1 to get US approval; Keynote-001 study

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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