A surprise Keytruda approval, and what it means for biotech

A Her2-positive cancer is the setting for a Keytruda triplet that could influence the trial design of some immune-stimulating agents.

Yesterday’s surprising US approval of a Keytruda/Herceptin/chemo triple combo that few had even realised had been filed shines a light on data from its supporting Keynote-811 study. The trial’s results were to be presented for the first time at Asco next month, but thanks to Keytruda’s new label they can be seen today.

The data concern remission rates, and show a benefit versus Herceptin and chemo alone, an important fact that could affect development strategies from biotechs including Pieris and Silverback. And, of course, the unexpected approval allows Keytruda to compete against Bristol Myers Squibb’s Opdivo in an important setting.

The US green light, on an accelerated basis, concerns first-line Her2-positive gastric/gastroesophageal junction adenocarcinoma. In April Opdivo was approved in this cancer with no stipulation about Her2 status, but its label stresses that the supporting study, Checkmate-649, excluded Her2-positive patients.

Leerink analysts reckon some 10,000 gastric/GEJ adenocarcinoma patients are treated first line each year, and around a quarter are Her2-positive, which amounts to a $300m market.

The gastric/oesophageal cancer space is complicated by approvals in different settings based on histology and PD-L1 status. Specifically in gastric/GEJ adenocarcinoma Keytruda monotherapy is approved third line in ≥1% PD-L1 expressers, but the continued standing of this label got a negative US adcom vote last month.

A complex picture for immuno-oncology in gastric/oesophageal cancers
US approval Regimen Setting Supporting trial
Opdivo (Bristol-Myers Squibb/Ono)
16 Apr 2021 Chemo combo 1st-line gastric/GEJ/oesophageal adenocarcinoma Checkmate-649 (excluded Her2 +ves)
10 Jun 2020 Monotherapy 2nd-line oesophageal squamous cell cancer Attraction-3
Keytruda (Merck & Co)
5 May 2021 Herceptin+chemo combo 1st-line Her2 +ve gastric/GEJ adenocarcinoma Keynote-811 (AA)
22 Mar 2021 Chemo combo 1st-line oesophageal/GEJ carcinoma Keynote-590
30 Jul 2019 Monotherapy 2nd-line PD-L1 +ve (≥10%) oesophageal squamous cell carcinoma Keynote-180 & 181
22 Sep 2017 Monotherapy 3nd-line PD-L1 +ve (≥1%) gastric/GEJ adenocarcinoma Keynote-059 (AA)
Source: prescribing information. AA=accelerated approval.

So what about Keynote-811? This 732-patient phase 3 study compares the Keytruda/Herceptin/chemo triplet against Herceptin/chemo alone, and in the first 264 subjects randomised has demonstrated a 74% overall remission rate, including an 11% rate of complete responses, versus 52% (3% CRs) in the control group.

This advantage was strongly statistically significant, with a p value below 0.0001, Keytruda’s updated label reveals. This appears to be an unexpected positive, given that addition of PD-(L)1 blockade to Her2-targeting has not previously yielded much success.

Isac development

The result is relevant not only for Merck and Bristol, but also for several other companies testing the combination of Her2 inhibition with immune system stimulation. This includes CD3-targting T-cell engagers, as well as a more recent generation of so-called immune-stimulatory antibody conjugates, or Isacs.

The latter group includes Pieris’s troubled cinrebafusp, which adds 4-1BB co-stimulation to Her2 blockade, Innovent’s IBI315, a straight Her2 x PD-1 directed bispecific, and a trio of ADCs from Bolt Therapeutics, Silverback and Novartis that use TLR7 and/or TLR8 agonism for immune system stimulation.

What Keynote-811 shows is that Her2 antagonism and immune system activation has legs, but – crucially – perhaps only if also combined with chemotherapy in a triple approach.

Some Isac assets are in very early monotherapy development, while others are in studies in combination with anti-PD-(L)1 antibodies. However, the clinical trial of just one – Dragonfly’s DF1001 – also includes chemotherapy in the mix, in its case Abraxane.

Perhaps the next stage of testing the remainder of the Isac pipeline will be to add the chemotherapy secret sauce.

Selected clinical-stage Her2-directed immune-stimulatory antibodies
Project Design Company Relevant trials
Cinrebafusp alfa (PRS-343) Her2 x 4-1BB bispecific Pieris Pharmaceuticals Tecentriq combo in Her2 +ve cancers
IBI315/BH2950 Her2 x PD-1 bispecific Hanmi/Innovent Monotherapy in Her2 +ve cancers
RG6194 T-cell engager (via CD3) Roche Monotherapy in Her2 +ve cancers
ISB 1302 T-cell engager (via CD3) Ichnos Sciences Monotherapy in Her2 +ve breast cancer
DF1001 NK-cell engager (via ?) Dragonfly Opdivo + chemo (Abraxane) combo 
BDC-1001 Conjugate with TLR7/8 agonist Bolt Biotherapeutics Keytruda combo in Her2 +ve cancers
SBT6050 Conjugate with TLR8 agonist Silverback Keytruda combo in Her2 +ve cancers
NJH395 Conjugate with TLR7 agonist Novartis Monotherapy in Her2 +ve non-breast cancers
Source: Evaluate Pharma & clinicaltrials.gov.

This story has been corrected to reflect the fact that Dragonfly's DF1001 is not partnered with Merck & Co.

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