AACR – Keytruda threatens avelumab, but feels more heat from Opdivo

Bristol-Myers Squibb’s Opdivo has impressed in numerous tumour types, and now looks set to add head and neck cancer to its conquests based on stunning survival data from the Checkmate-141 study presented at the AACR meeting on Tuesday.

This could help the Bristol drug extend its lead even further over Merck & Co’s Keytruda, though Keytruda had its own AACR success – in an academic study in Merkel cell carcinoma that could immediately hit Pfizer and Merck KGaA’s avelumab. Avelumab would be especially threatened if US doctors persuaded by Keytruda, an approved drug, immediately started using it off label in this rare cancer.

It is Merkel cell carcinoma, an orphan cancer with about 2,000 new US cases a year, that Merck KGaA and Pfizer are focusing on as a potential first use for avelumab (German Merck no longer the immuno-oncology underdog, November 17, 2014). The anti-PD-L1 MAb last year got US breakthrough therapy designation in this setting.

Stealing the thunder

However, if Keytruda threatens to steal avelumab’s thunder, at AACR its own efficacy in Merkel cell was overshadowed by Opdivo’s Checkmate-141 trial, which had been halted for efficacy in January.

A more than doubling of one-year overall survival against investigator’s choice in heavily pretreated squamous head and neck carcinoma was demonstrated, representing something “never before seen in this population,” said Checkmate-141’s primary investigator, Dr Maura Gillison, of Ohio State University.

Specifically, the 240 Opdivo patients had median overall survival of 7.5 months, versus 5.1 months for the 121 assigned to investigator’s choice, cutting risk of death by 30% (p=0.01). “This is the first time in my career that I’ve had an agent to reach for in these patients,” said Dr Gillison.

She had tested all patients for PD-L1 positivity as well as for HPV status, but in the event these parameters did not influence the survival benefit in Checkmate-141.

Anti-PD-1 MAb approvals in major Western markets
Approval date Region Therapy Indication Notes
Opdivo (Bristol-Myers Squibb/Ono)
1 Apr 2016* EU Yervoy combo 1st-line melanoma regardless of Braf status Checkmate-067 & 069 studies
6 Apr 2016 EU Monotherapy 2nd-line renal cell carcinoma Checkmate-025 study
6 Apr 2016 EU Monotherapy 2nd-line non-squamous NSCLC Checkmate-057 study
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: *CHMP recommendation for EU approval.

PD-L1 status was also measured in the NCI’s study of Keytruda for Merkel cell carcinoma, where it tends to be expressed at a frequency of 55% and predicts improved survival.

However, in this NCI trial pre-treatment levels of PD-L1 did not influence response to Keytruda, said the University of Washington School of Medicine’s Dr Paul Nghiem, the primary investigator.

This study was run on an open-label basis, recruiting 26 patients with first-line Merkel cell carcinoma, 25 of whom were evaluable. Progression-free survival was nine months, which compared with just three months for a historical control of patients given chemo, said Dr Nghiem.

He added that Keytruda was the first anti-PD-1 therapy to induce a high response rate in this cancer: across the 25 patients there were four complete and 11 partial responses.

Asco showdown

As a Merkel cell carcinoma expert who also acts as a consultant to Merck KGaA Dr Nghiem is uniquely placed to comment on avelumab in this tumour type.

He said no data were yet available to compare Keytruda versus avelumab, and the latter’s Javelin Merkel 200 study would be presented at Asco next month. He cautioned that, while with Keytruda he had decided to test it first line, the avelumab data were in “second line or beyond; [patients’] tumours were shrunk initially but they were selected for more aggressive ones, and that’s immunosuppressive.”

Dr Nghiem added that, as his was an academic study, it had no bearing on Keytruda’s approvability in Merkel cell carcinoma, and that the regulatory path was down to Merck & Co. It is also possible that the fact the trial was not randomised might deem it insufficient for approval.

Of course approval matters less when a drug is, like Keytruda, already available for other indications.

Merck KGaA and Pfizer’s strategy with avelumab was to develop it for tumour types that had no competition from early-mover anti-PD-1/PD-L1 agents. Yesterday’s data from the NCI could render their initial choice of Merkel cell carcinoma obsolete.

Study Detail Trial ID AACR abstract
Checkmate-141 Nivolumab in 360 refractory squamous H&N cancer pts; vs Erbitux or chemo NCT02105636 CT099
Pembrolizumab in 50 1st-line Merkel cell carcinoma pts NCT02267603 CT096
Javelin Merkel 200 Avelumab in 88 post-chemo Merkel cell carcinoma pts NCT02155647

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

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