Tecentriq’s ovarian failure highlights a changing market

An Avastin combination draws a blank in the Imagyn-050 study. Will a combo with a Parp inhibitor fare any better?

Immunotherapy has made inroads into virtually every aspect of oncology, but ovarian cancer looks like it might remain intractable. Roche’s Tecentriq today became the second anti-PD-(L)1 drug, after Bavencio, to fail a first-line pivotal trial in this cancer type.

Several similarly acting drugs continue to be studied in big phase III trials in various front-line settings, however, including Keytruda, Imfinzi and Opdivo. But the Roche failure raises important questions about a market that is being reshaped by Parp inhibitors, and about the role of Avastin in ovarian cancer.

Roche’s Imagyn-050 trial, which today failed to meet its primary endpoint of progression-free survival, tested Tecentriq plus Avastin and chemo, versus Avastin and chemo alone. With Roche attempting in many cases to make Avastin the backbone of immunotherapy combos, the ovarian failure will spell bad news for part of the Avastin lifecycle management plan.

However, use of Avastin in ovarian cancer is controversial, being backed by a PFS benefit over chemo; the drug’s US label shows no statistically significant overall survival advantage for Avastin. At last year’s Asco the academic-sponsored GOG-0218 study showed no overall survival benefit for Avastin versus chemo alone.

The Parp factor

A second point is that two Parp inhibitors, Astrazeneca’s Lynparza and Glaxosmithkline’s Zejula, have shaken up the ovarian cancer market, and look like becoming standard of care in some genetically defined patient subgroups (Lynparza nod confirms a leg up for Glaxo, May 11, 2020).

For immunotherapy companies it might be more relevant, therefore, to focus on PD-(L)1 blockade as part of Parp inhibition, rather than as an Avastin combo.

Indeed, Merck & Co’s Keytruda and Astrazeneca’s Imfinzi are both in phase III first-line ovarian cancer trials that include Lynparza, either as part of the front-line combo or in subsequent maintenance. Bristol-Myers Squibb’s Opdivo is in Athena, a maintenance trial with or without Clovis’s rival Parp inhibitor, Rubraca.

Unfortunately for Roche, the Swiss group’s own efforts here are very early. A small phase II study, measuring safety as its primary endpoint, tests Tecentriq plus Rubraca in relapsed patients and reads out this year. A pivotal study has yet to be initiated.

Selected studies of immunotherapy in ovarian cancer
Trial Ovarian cancer setting Active treatment Comparator Note
Imagyn-050 1L Tecentriq + Avastin + chemo Avastin + chemo Failed PFS co-primary
WO39409* ≥2L (part 2 also has TNBC) Tecentriq + Rubraca Uncontrolled Safety, ends mid-2020
Merck KGaA/Pfizer
Javelin Ovarian 100 1L & maintenance Bavencio + chemo Chemo Failed interim PFS primary
Javelin Ovarian Parp 100 1L & Talzenna maintenance Bavencio + chemo + Talzenna Avastin + chemo Discontinued after failure of above
Merck & Co and/or Astrazeneca
Keynote-100* ≥2L Keytruda None "Modest efficacy"
Keylynk-001 1L & Lynparza maintenance Keytruda + chemo + Lynparza Chemo PFS & OS co-primaries; ends 2025
Duo-O 1L & Imfinzi/Avastin/Lynparza maintenance Imfinzi + Avastin + chemo (+ Lynparza) Avastin + chemo PFS primary, ends 2023
Bristol Myers Squibb/Clovis
Athena 1L maintenance Opdivo +/- Rubraca Placebo PFS primary, ends 2024
Source: company statements & clinicaltrials.gov; *not phase 3.

Still, Tecentriq is not the first PD-(L)1 inhibitor to have failed in ovarian cancer. Late last year Pfizer/Merck KGaA’s Bavencio flunked the first-line Javelin Ovarian 100 trial, where a chemo combo failed to beat chemo alone in terms of PFS at its interim analysis.

Shortly afterwards the companies scrapped the Javelin Ovarian Parp 100 study, which added Pfizer’s own Parp inhibitor, Talzenna, into the mix and had an Avastin/chemo combo as control. The reasons given for the early discontinuation of this trial, in a genetically unselected population, were Bavencio’s failure in Javelin Ovarian 100, a changing treatment landscape and the recent approval of Zejula in the maintenance setting.

Earlier, a small, uncontrolled trial called Keynote-100 showed only a modest ORR benefit for Keytruda, according to Asco 2020, in second to sixth-line ovarian cancer. Merck & Co’s hope now rests in a Lynparza combo, but its Keylynk-100 study will not yield data for several years.

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