For Roche Immuno-Oncology, It’s Steady As She Goes

Roche’s oncology R&D juggernaut gains momentum with surge of combination trials around cancer immunotherapy - as illustrated in the Pink Sheet's animated chart. But the company is keeping its focus on systematically building a base of randomized clinical data to back up efficacy signals for PD-L1 inhibitor Tecentriq.

Consistency was the dominant impression of Roche’s annual analyst presentation in conjunction with the American Society of Clinical Oncology annual meeting, as the company continued to progress its plans to build a broad network of new agents around the flagship cancer immunotherapy Tecentriq (atezolizumab) with an eye toward precision combination therapy.

“Our strategy shouldn’t change every time we see you, and it hasn’t,” Roche Pharmaceuticals CEO Daniel O’Day told the June 5 meeting in Chicago.

What has changed is the complexity of Roche’s clinical program. “Since we sat here last year, we more than doubled the number of combinations that we have,” O’Day said. “We have more than 50 trials going on. More than 30 of those are combination trials.”

Roche only recently received FDA approval for its first immunotherapy: the PD-L1 inhibitor Tecentriq was cleared May 18 as a monotherapy for metastatic urothelial carcinoma patients who progressed on or after chemotherapy (Also see "Atezolizumab At Last: Roche Makes Its Immuno-Oncology Debut" - Pink Sheet, 18 May, 2016.). Tecentriq is the third immune checkpoint inhibitor to reach the market, after Merck & Co. Inc.’s Keytruda (pembrolizumab) and the current market leader, Bristol-Myers Squibb Co.’s Opdivo (nivolumab).

Instead of racing to market, Roche is preparing to dominate the cancer immunotherapy space in the long run with a comprehensive strategy of combinations among immunotherapies, targeted therapies and conventional chemotherapy – all informed by the company’s substantial investment in diagnostics and analytics (Also see "Roche's Oncology Strategy: The Long Game Comes Into Focus" - Pink Sheet, 15 Jun, 2015.).

Roche has held to a consistent visual framework for presenting its oncology program to analysts at ASCO, which contributes to the sense of the steady growth of a well-mapped expansion plan. The difference between the portfolio image from last year’s meeting to this year’s emphasizes the rapid growth in density of combinations in development, with Tecentriq at the center of an expanding web.

Roche's Expanding Web Of Oncologics

Source: Roche presentations June 2016 and May 2015

Taking The Lead In Chemo/Immunotherapy Combinations

“We’ve taken the leadership position in terms of combination with chemotherapy,” Roche Global Head of Cancer Immunotherapy Dan Chen commented. While Tecentriq’s lead indications are for monotherapy – a second-line claim for PD-L1-positive non-small cell lung cancer is pending in addition to the bladder cancer approval – the company is running a number of pivotal trials of chemotherapy/immunotherapy combinations (see box).

Approaching Waves Of Tecentriq Data

Phase III Data Expected In 2016:

• Monotherapy in second-line+ NSCLC (the OAK trial)

Phase III Data Expected In 2017:

• With 3 different chemotherapy regimens for first-line NSCLC
• Monotherapy for first-line PD-L1-positive NSCLC
• Monotherapy for second-line+ urothelial bladder cancer
• With Avastin for first-line renal cell carcinoma

Phase III Data Expected In 2018:

• With chemotherapy for first-line NSCLC
• With chemotherapy for first-line, triple-negative breast cancer
• With targeted therapy (Cotellic) for third-line+ metastatic colorectal cancer

Phase III Data Expected After 2018:

• Monotherapy for adjuvant NSCLC
• With chemotherapy for first-line small cell lung cancer
• Monotherapy for adjuvant MIBC bladder cancer

Bristol, on the other hand, is focusing on moving Opdivo and the combination of Opdivo and Bristol’s CTLA4 inhibitor immunotherapy Yervoy (ipilimumab) into earlier disease stages and new tumor types (Also see "Bristol’s Full ASCO Roster Emphasizes Long-Term Survival Updates" - Pink Sheet, 18 May, 2016.). Late immunotherapy entrant Pfizer Inc. is going after triple immuno-oncology combinations (Also see "Pfizer Oncology Strategy: Keeping Pace In The Doublet/Triplet IO Race" - Pink Sheet, 9 May, 2016.).

Genentech VP-Cancer Immunology Ira Mellman explained Roche’s decision to go after the chemotherapy combination space during the ASCO analyst meeting. Roche was surprised by “very nice responses” to the combination of atezolizumab and chemotherapeutics in Phase Ib but “didn’t understand those,” he said. “So we went back into the laboratory and made another remarkable discovery, which was that chemotherapy is a type of immunomodulatory therapy.”

“Others in the field are starting to come up with this idea as well and extending the initial findings we made,” Mellman observed. “So we really do think we’re on the right track, at least from the point of view of understanding the relationship with chemo and how it affects the immune system.”

At ASCO, Roche presented early data on the combination of Tecentriq with chemotherapy in triple-negative breast cancer – data that convinced the company to move Tecentriq into the Phase III IMpassion 130 trial with Abraxis BioScience Inc.’s paclitaxel Abraxane. In Phase Ib, the 32 mTNBC patients who received Tecentriq plus Abraxane had an overall response rate (ORR) of 38% across all lines of therapy, and a safety profile “similar to that seen with Tecentriq or Abraxane chemotherapy alone,” the company reported.

The early combination data in TNBC shows that “not only can you generate a response … you can also see durable responses, something we generally don’t see with chemotherapy alone,” Chen said.

The company also presented early Phase Ib data from four heavily pretreated metastatic colorectal cancer patients treated with Tecentriq and Roche’s targeted therapy Cotellic (cobimetinib). The small sample had an ORR of 17% without synergistic toxicity.

The Cotellic/Tecentriq combo was chosen because Roche thought upregulating MHC class 1 could be beneficial in TNBC, Chen said. “When you look at the efficacy data of Cotellic plus Tecentriq, you’ll note that suddenly it appears that we have been able to unmask the activity of cancer immunotherapy in this disease,” he said.

“When you look at the biopsy samples from this Phase I study, you’ll note that not only do we inhibit the signaling pathway through the MEK kinase pathway, but we increased CD8 T-cell accumulation into the tumor and you increase the MHC class I expression on the tumor cells themselves.”

The Need For Phase III

While Tecentriq received accelerated approval on the basis of response rate shown in an open-label, non-randomized bladder cancer study, Chen emphasized the importance of randomized clinical trial data showing an effect on survival to establishing the best use of cancer immunotherapy.

“Early data clearly suggests that overall survival is likely to be the most sensitive and powerful endpoint for cancer immunotherapy,” Chen noted.

The fast approval and adoption of the checkpoint inhibitors has, however, complicated efforts to conduct gold standard trials. “Many patients will get cancer immunotherapy in the second-line, in the third-line, in the fourth-line setting,” Chen observed. “And we’ve seen that, unlike many of the therapies we’ve utilized, these therapies can still be very powerful even in late-line settings. It has the potential for a very powerful confounding effect on that survival.”

Ultimately, “we have to find the best way to deal with that,” he continued. “One of the strategies that we’ve taken in a number of our studies is to power our pivotal studies for survival, but take an early look at progression-free survival.”

“Progression-free survival won’t face the confounding effect of later-line use of immunotherapy, but may not be as sensitive an endpoint,” Chen observed. “We may be more likely to see that activity just in its diagnostic subset. So what we’ve tried to do is … design these studies in a way that gives us the maximum opportunities to understand the benefit by these different measures: Survival, likely in all-comers. Progression-free survival, maybe in all comers, maybe only in diagnostic subsets.”

Roche is also looking to randomized trials to settle questions about the role of biomarker testing. Tecentriq’s bladder cancer indication came with approval of a complementary PD-L1 diagnostic to guide therapy, but not as part of the indication, which would have been the case with a companion diagnostic (Also see "Keeping Track: Tecentriq, Opdivo Approvals Intensify Spotlight On Immuno-Oncology" - Pink Sheet, 23 May, 2016.). The pending NSCLC application is for PD-L1-positive patients.

“We don’t fully understand the relationship” of PD-L1 status to efficacy, Chen acknowledged. “These things ultimately will have to be answered by the ongoing randomized trials.”

“I don’t think any of us have a way to predict today, based on tiny Phase Ib populations, some of which … are segregated out into multiple different schedules [and] doses in small cohorts where you try to read out response rates,” Chen said “Statistically there’s going to be huge variability in those results.”

Small, early-phase, single-arm trials do, however, provide the type of data on biomarkers, response and dosing that is feeding back into Roche’s R&D operations to inform future development (Also see "Roche Oncology Trials Designed For “Learning On The Go”" - Pink Sheet, 9 Jun, 2014.).

Not Every Drug Needs To Be A Breakthrough

Roche’s commitment to cancer immunotherapy is extensive. In addition to Tecentriq, the company has nine immuno-oncologics in the clinic alone, along with a healthy pipeline of targeted therapies – offering a staggering number of combination possibilities.

“Not all of those opportunities are likely to ultimately succeed, and it will be important to identify that early,” Chen said. “Others in the pipeline are likely to become good ‘tool molecules’ that themselves may not drive a big breakthrough in the management of cancer patients but could be important tools as we think about how to best manipulate and sensitize the immune system to cancer.”

With one of the biggest tool chests in the industry and a long-term commitment to its science-driven strategy for rational combinations, Roche is in an enviable position to dominate the course of cancer immunotherapy.