Perioperative use proves elusive for Tecentriq

Adjuvant and neoadjuvant settings are an important target for Roche’s Tecentriq, but how likely is the drug to become broadly applicable?

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While immuno-oncology is making inroads into ever more cancer types, settings where the drugs are given during or just after surgery remain an untapped opportunity. Judging by recent comments, however, this is a space on which Roche is making a sizeable bet, and analysts are naturally monitoring the opportunity closely.

Indeed, those at Nomura have already called results of Roche’s Impower-010 trial, testing adjuvant Tecentriq versus best supportive care in NSCLC, as immuno-oncology’s primary point of the coming year. But, while cautious forecasts exist, until Roche records a major win its chances of broad success will remain nebulous.

And, so far anyway, success has proved elusive. Just last month Roche revealed that Imvigor-010, testing adjuvant Tecentriq in high-risk muscle-invasive urothelial cancer, had failed to extend disease-free survival versus observation; the company had earlier called this a $1bn opportunity.

Continued confidence

At Roche’s fourth-quarter results presentation the group worked hard to stay positive, and expressed continued confidence in future Tecentriq (neo)adjuvant trials, of which at least 10, including Impower-010, should read out by 2025.

True, urothelial is one cancer where immunotherapies have struggled to generate unequivocally positive data, so each tumour type should be judged on its merits.

But an earlier failure, in neoadjuvant triple-negative breast cancer, could see Tecentriq diverging from Merck & Co’s Keytruda: the small NeoTRIPaPDL1 trial read out negatively in December. And earlier a separate neoadjuvant TNBC study with imminent readout, Impassion-031, had its enrolment increased, which is rarely a positive sign.

Meanwhile, Keytruda has scored a positive hit in Keynote-522, a TNBC trial that could open what Evercore ISI’s Umer Raffat reckons could be a $2bn neoadjuvant and adjuvant market. Merck has yet to disclose its TNBC filing strategy.

For now, only Keytruda and Bristol-Myers Squibb’s Opdivo boast adjuvant use on their labels – both in melanoma – and while the latter now seriously lags the I-O race Bristol is itself also making a sizeable bet on (neo)adjuvant settings.

For instance, the Checkmate-816 trial of neoadjuvant Opdivo plus Yervoy and chemo in NSCLC should yield pathological complete response data this year. And Checkmate-274, testing adjuvant Opdivo in muscle-invasive urothelial cancer, should read out later in 2020, and will be closely watched given Imvigor-010’s failure.

Of course, not only is each tumour type different, each competing study has a slightly different design, including different cuts of patients by PD-L1 status at baseline, for instance. And, while Imvigor-010 used observation only as control, Checkmate-274 gives subjects placebo, a subtle but important difference.

Roche’s Impower-010, which should read out by the end of 2020, has as its primary endpoint disease-free survival, but will look at subpopulations; subjects with stage II-IIIA NSCLC will be assessed by cuts of PD-L1 expression and across the board, and there will also be an all-comers, intent-to-treat analysis.

Finally, it is not clear whether the FDA will always insist on hard survival data for perioperative approvals, or whether a measure like pathological complete response could suffice, at least initially. Investors should know a lot more once Merck reveals what it will do with the Keynote-522 data, and once Impower-010 reads out.

Selected (neo)adjuvant studies of Tecentriq
Trial Enrolment Cancer setting Design Primary Status
NeoTRIPaPDL1 278 Neoadjuvant TNBC Chemo combo DFS vs chemo Failed Dec 2019
Imvigor-010 800 Adjuvant muscle-invasive urothelial Monotherapy DFS vs observation Failed Jan 2020
LCM3 180 Neo & adjuvant NSCLC Monotherapy pCR Ends Feb 2020
Imagyn-050 1,300 1st-line ovarian (nas neoadjuvant element) Avastin + chemo combo PFS & OS, in all-comers & in PD-L1+ve, vs Avastin + chemo Ends Apr 2020
Impassion-031 324 Neoadjuvant TNBC Abraxane combo pCR in all-comers & in PD-L1+ve vs Abraxane Ends Sep 2020*
Impower-010 1,127 Adjuvant NSCLC Monotherapy DFS vs best supportive care in PD-L1+ve & all-comers Ends Nov 2020 (fully enrolled)
Atomic 700 Adjuvant MSI-H colorectal Chemo combo DFS vs chemo Ends Dec 2020
Impassion-050 453 Neoadjuvant Her2+ breast Herceptin + Prejeta + chemo combo pCR in PD-L1+ve vs vs Herceptin + Prejeta + chemo Ends Apr 2021 (FPI Q4 2018)
Impassion-030 2,300 Adjuvant TNBC Chemo combo Invasive DFS vs chemo Ends Jan 2022 (FPI Q3 2018)
Immotion-010 664 Adjuvant renal cell Monotherapy DFS vs observation Ends May 2022 (fully enrolled)
Imbrave-050 662 Adjuvant hepatocellular Avastin combo DFS vs observation Ends Mar 2023 (FPI Q4 2019)
Imvoke-010 400 Adjuvant aquam H&N Monotherapy DFS & OS vs placebo Ends Aug 2023 (FPI Q1 2018)
GeparDouze 1,520 Neoadjuvant TNBC Monotherapy pCR & DFS vs chemo Ends Dec 2023
Impower-030 302 Neoadjuvant NSCLC Chemo combo pCR & DFS vs chemo Ends Mar 2025 (FPI Q2 2018)
Note: TNBC=triple-negative breast cancer; DFS=disease-free survival; pCR=pathological complete response; FPI=first patient in. *Completed enrolment of 120 additional subjects, per IDMC recommendation, in Q3 2019.

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