Welcome to the first in a series of periodic Evaluate Vantage updates on developments in the PD-(L)1 inhibitor space.
Perhaps the most significant move in July and August was last week’s withdrawal by Roche of Tecentriq’s first-line triple-negative breast cancer indication, a use backed by the Impassion-131 trial, but whose accelerated approval failed to be backed by Impassion-130.
The move means that four of six accelerated approvals of anti-PD-(L)1 drugs with failed confirmatory trials scrutinised at an April 27-29 US advisory panel meeting have now been pulled. The remaining two are Merck & Co’s Keytruda in second-line liver cancer and in urothelial bladder cancer, an indication that had already been narrowed by the FDA.
The Roche development was surprising because the adcom appeared to have given Tecentriq a relatively strong endorsement, with panellists voting seven to two in favour of retaining the TNBC indication. Moreover, the failed Impassion-130 trial did not demonstrate an overall survival benefit largely owing to a statistical quirk.
Either way, an adcom seen at the time as endorsing most so-called “dangling” PD-(L)1 approvals – those with failed confirmatory studies – has actually resulted in numerous market withdrawals. Perhaps that had always been part of the FDA’s thinking when the panel was convened.
Just four days later Keytruda had its front-line urothelial carcinoma label restricted further, specifying that it can only be used in this setting in patients ineligible for platinum chemo; previously it could have been used in those eligible for non-cisplatin chemo if their tumours expressed PD-L1 at ≥10%. On the plus side, this newly restricted use was granted full approval.
In other regulatory developments Bristol Myers Squibb’s Opdivo got its third US endorsement as adjuvant treatment – a setting that is vital if Opdivo is to regain lost ground on Keytruda.
On August 20 the FDA approved Opdivo for adjuvant high-risk urothelial carcinoma on the basis of the Checkmate-274 study, which at this year’s Asco-GU meeting was reported as showing the drug improving disease-free survival to 21.0 months, versus 10.9 months for placebo recipients, amounting to a 30% reduction in disease recurrence at any point.
Interestingly, Opdivo’s updated label makes no mention of muscle-invasive disease, the specific setting for the Checkmate-274 data. The approval is especially important since Roche’s rival Tecentriq failed Imvigor-010, a separate trial as adjuvant therapy in high-risk, muscle-invasive urothelial carcinoma.
Two months earlier the US regulator had greenlit Opdivo for adjuvant treatment of oesophageal/gastroesophageal junction cancer on the basis of Checkmate-577. The Bristol drug’s other approved perioperative use is for adjuvant melanoma, dating back to 2017.
Keytruda is of course also in the perioperative game, its own 2019 adjuvant melanoma label being supplemented in July with US approval for neoadjuvant and adjuvant triple-negative breast cancer.
This is backed by the controversially designed Keynote-522 trial, which is very similar to Tecentriq’s Impassion-031 trial, which like Keynote-522 has yielded positive pCR data but – unlike the Merck study – has yet to show an effect on its much more important event-free survival endpoint.
Other recent US approvals were rounded out by Keytruda’s combo with Lenvima in front-line renal cell carcinoma, cementing Merck’s lead in this fast-changing space, and a nod for Tecentriq plus Cotellic and Zelboraf in first-line Braf-positive melanoma.
Glaxosmithkline/Anaptysbio’s Jemperli, meanwhile, had its initial second-line MMR-deficient endometrial cancer label expanded to comprise all second-line dMMR solid tumours, still on an accelerated basis and backed by the same Garnet trial. This drug’s big threat is Keytruda, which has a March 28 2022 Pdufa date for a US regulatory decision in second-line MSI-high/dMMR endometrial carcinoma, backed by Keynote-258’s cohorts D and K, to be presented in full at Esmo.
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