Asco-GI – Roche challenges Keytruda’s colorectal cancer pole position

Though Merck & Co remains in the lead in developing checkpoint inhibitors for colorectal cancer, judging by discussions at the Asco-GI meeting on Saturday oncologists seem more excited by Roche’s strategy of combining therapies with Tecentriq.

This is because Roche could ultimately end up targeting the larger group of colorectal cancer patients who do not have a DNA mismatch repair (MMR)-deficient/microsatellite instability (MSI)-high phenotype. Merck will have to make the most of its opportunity to be first to market with Keytruda in a subgroup of patients thought to be highly sensitive to anti-PD-1/PD-L1 MAbs (see table below).

Head start

With a breakthrough therapy designation in hand, Merck has already filed in the US under accelerated review for Keytruda in advanced MSI-high cancers in solid tumours including colorectal cancer (CRC). Specialists expect the PD-1 antibody to become the new standard in this patient subgroup.

The application has a target review deadline of March 8, slightly ahead of the expected readout of Merck’s Keynote-164, a registrational single-arm phase II trial of Keytruda in third-line MMR-deficient or MSI-high CRC.

The registration is presumably therefore based on data from the earlier Keynote-016 study, which showed an objective response rate of 62% in patients with progressive MMR-deficient metastatic CRC. The study showed no responses in patients with the more common MMR-proficient CRC.

Patients with MSI have an exceptionally high mutation burden, but account for 15% of early-stage metastatic CRC and only 4% of later, stage IV disease. Merck also has a separate, larger study in the first-line setting, Keynote-177, where Keytruda is being compared against standard chemotherapy.

Roche in the frame

However, interest in the CRC field seems to focus on Roche’s strategy with Tecentriq. This is in part because it represents one of the first attempts at combining an immuno-oncology agent with a targeted therapy – in this case, the in-house Mek inhibitor Cotellic in the non-MSI-high group.

Tecentriq could also have a slightly better side-effect profile than other PD-1/PD-L1 agents, and thus might be the most suitable for such combinations.

Roche presented data at Asco last year from a phase Ib trial that showed a modest response rate of 17% with the two-drug combination, but there was no subsequent update at Asco-GI.

Roche’s Cotezo study evaluates Tecentriq alone and in combination with Cotellic against Bayer’s Stivarga, the standard of care, in third-line or later CRC. Tecentriq is also the subject of three large NCI or co-operative group-sponsored studies in combination with chemotherapy.

Opdivo's bid

Meanwhile, Bristol-Myers Squibb’s Checkmate-142 study is examining Opdivo alone and in various combinations in CRC, depending on MSI-high status.

Subjects with MSI-high tumours are enrolled into the cohorts testing Opdivo in combination with Yervoy or Bristol’s own Lag-3 antibody, BMS-986016. Non-MSI-high patients are randomised to cohorts testing Opdivo alone, in a triple combination with Yervoy and Cotellic, or combination with J&J’s Darzalex.

The readout from this study is due this year, and could further spur interest in combinations.

Key checkpoint inhibitor studies in CRC
Drug Name Patients Design Line NCT ID Data
Keytruda  Keynote-164* 120 Keytruda monotherapy (single arm) 3rd, MMR-d or MSI high  NCT02460198 May 2017
Keytruda  Keynote-177 270 Keyruda vs standard therapy 1st, MMR-d or MSI-high NCT02563002 Aug 2019
Opdivo in combination Checkmate-142 260 Opdivo +/- Yervoy (+/- Cotellic), Darzalex and BMS-986016 Allocated according to MSI-H status NCT02060188 Mar 2017
Tecentriq/Cotelliq Cotezo 360 Tecentriq +/- Cotelliq vs Stivarga >3rd NCT02788279 Apr 2019

CRC remains one of the three most commonly diagnosed solid tumours and should represent a substantial market opportunity for PD-1/PD-L1 inhibitors. Trial results over the next couple of years will determine whether this is one addressed by single agents or combinations. 

To contact the writer of this story email Robin Davison, reporting from Asco-GI in San Francisco, at [email protected] or follow @RobinDavison2 on Twitter

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