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).
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.
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|
|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.