Keynote and compendium guidelines come to Keytruda’s aid


Close watchers of the battle between the first approved anti-PD-1 agents will have noted with interest Opdivo’s widening lead over Keytruda, as revealed today in third-quarter sales figures from Bristol-Myers Squibb and Merck & Co.

Bristol has made good use of its first-mover advantage in lung cancer, but Merck should not be ruled out just yet. Yesterday’s readout of the Keynote-010 trial suggests that Keytruda might not be restricted to patients with high levels of the PD-L1 biomarker – an important theme that has already been picked up by an influential US compendium group.

For now, however, quarter-on-quarter revenue comparisons show Opdivo beating consensus to grow 88% to $305m in the three months ended September 30, versus Keytruda’s slight consensus miss at $159m (+45%).

Of course, Opdivo’s sales increasingly reflect its March approval for lung cancer – a significantly bigger indication than melanoma, and one for which Keytruda only got the nod this month (Opdivo steals Keytruda’s thunder – again, October 12, 2015).

Another shift

Now the tectonic plates might be about to shift again, courtesy of the overall survival benefit Keytruda showed yesterday in Keynote-010, a trial in second-line NSCLC patients with both squamous and non-squamous histologies.

The key lies in the PD-L1 biomarker: in Keynote-010 Keytruda has shown an OS benefit in patients with over 50% PD-L1-positive tumours, but also in the much broader population of those within a 1% PD-L1 positivity cutoff. This should allay concerns that in NSCLC Keytruda would only be used in patients above a 50% cutoff, as per its current US label based on the earlier Keynote-001 trial.

The situation was pre-empted by the National Comprehensive Cancer Network (NCCN), an influential US compendium group on whose recommendations Medicare and most private insurers decide reimbursement. Updated NCCN guidelines recommend Keytruda treatment in NSCLC patients with any level of PD-L1 expression; though this comes short of use in all-comers it does not limit Keytruda to high-expressors only.

The recommendation and Keynote-010 readout are vital in light of Opdivo’s widening lead over the Merck antibody. Opdivo’s NSCLC approval does not limit it to PD-L1-positive patients, and has just been extended from squamous to include non-squamous histologies, based on Bristol’s Checkmate-057 study.

Selected 2nd-line NSCLC studies
Project   Study    PD-L1 status Histology Detail Trial ID   
Opdivo  Checkmate-017   All-comers Squamous OS benefit, approval 4 Mar 2015 NCT01642004 
Opdivo  Checkmate-057   All-comers Non-squamous OS benefit, approval 9 Oct 2015 NCT01673867
Keytruda  Keynote-001  >50% PD-L1 All-comers OS benefit, approval 2 Oct 2015 NCT01295827 
Keytruda  Keynote-010   >50% and >1% PD-L1 All-comers OS benefit shown NCT01905657 
Atezolizumab Poplar All-comers All-comers OS benefit correlates with PD-L1 status NCT01903993 
Atezolizumab Oak All-comers Non-squamous Data due in 2016 NCT02008227

If the Opdivo/Keytruda gap is about to narrow, where this leaves Roche and AstraZeneca’s competing anti-PD-L1 MAbs atezolizumab and durvalumab is less clear.

Roche recently said it would not submit atezolizumab for NSCLC, its first use, until next year. There had been hopes of a filing on the strength of phase II data alone, without waiting for readout of the larger Oak trial; the phase II Poplar study did hit a survival benefit versus docetaxel – in all-comers – though at lower statistical significance than Opdivo showed in Checkmate-057.

Roche will unlikely want to waste any more time than it has to, and will eagerly be watching whether Merck can catch up to Opdivo in NSCLC, courtesy of the NCCN guidelines. Already the influence of the NCCN compendium has been seen in melanoma, where a first-line recommendation – in spite of initial approval only in the second-line setting – drove very rapid adoption of both Opdivo and Keytruda.

A final consideration is whether the revolution in melanoma and NSCLC is leading to a situation where doctors view all approved anti-PD-1/PD-L1 agents as basically interchangeable, irrespective of their particular labels. That scenario would render moot all considerations about histology and PD-L1 expression.

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

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