Roche’s Immuno-Oncology Arsenal: PD-L1 And Beyond

Roche may be playing catch-up to Bristol-Myers Squibb and Merck & Co in the PD-1/PD-L1 checkpoint development space, but it believes its unique in-house strengths in diagnostics and molecular biology, coupled with partnering, will enable it to play a major role in immuno-oncology.

BASEL – Showcasing 20 therapies for personalized cancer treatment, Roche has emphasized its breadth and depth in the space at a media briefing on its oncology efforts held at its Basel headquarters on Sep. 8, 2015.

Although it may be behind at the moment, Roche believes its PD-L1 checkpoint inhibitor atezolizumab (aPDL1) will act as a launch pad that will propel it into a dominant position in the race.

The Swiss firm believes that combining the single agent with multiple therapies while leveraging its own diagnostics assets and partnerships will enable it to quickly capture territory in the red hot immuno-oncology arena.

Leveraging its strength in diagnostics and molecular biology is crucial in the effort, said CEO Severin Schwan as he opened the company's Oncology Medial Day.

"It's absolutely crucial to find the elements through biomarker analysis [to develop good immunology therapies]," Schwan told participating journalists from around the world. He added that diagnostics and drug development "go hand in hand."

Diagnostics, in effect, go across the entire healthcare spectrum, from screening to prognosis to patient selection and therapy monitoring, explained Roland Diggelmann, Roche Diagnostics COO.

Speaking at the same forum, Diggelmann said that the role of predictive diagnostics was especially important for cancer immunology, in which the right patients need to be identified for the different therapies.

So far, four cancer therapies from Roche have gained breakthrough designations (BTDs) by US FDA: alectinib for non-small lung cancer (NSCLC) patients with ALK mutations; the anti-PD-L1 antibody atezolizumab for NSCLC and bladder cancer; and venetoclax for chronic lymphoma leukemia (CLL) with 17p deletion.

BTDs are established to speed up the review and approval of drugs with substantial improvements over current treatment for serious diseases.

"The four BTDs in oncology were supported by having a diagnostic that identified patients most likely to benefit," Diggelmann said.

Combos And Durable Outcomes

Out of the 20 therapies Roche has in development for personalized cancer treatment, seven are in clinical development and one, atezolizumab, is close to market, Roche Pharmaceuticals COO Daniel O'Day told reporters.

Atezolizumab is an antibody of IgG1 isotype against the protein programmed cell death ligand 1 (PD-L1).

During a data presentation at the American Society of Clinical Oncology (ASCO) meeting in June, the anti-PD-L1 was shown to have a strong response to PD-L1 expression in cancer patients (Also see "Beyond PD-1: Roche Maps Further Checkpoints On Cancer Immune Cycle" - Pink Sheet, 15 Jun, 2015.).

Calling it Roche's "foundation of cancer immunology", Daniel Chen, Head of Roche's Cancer Immunology Franchise, said there were over 20 combinations with Avastin (bevacizumab) and chemotherapies centered on the single agent.

Also an adjunct faculty member at Stanford University, Chen co-authored a widely-cited article, Oncology Meets Immunology: The Cancer-Immunity Cycle, published in Immunity in 2013.

While the single agent is for inflamed tumor cells, the aim in combining it with other products is to deepen the responses, the scientist explained. He added that while PD-L1 expressed on immune cells and tumor cells can inhibit auto-immune response, the anti-PD-L1 agent only drives anticancer response and is very easy to turn off, so it should not cause autoimmune-like diseases.

Currently, the combination aPDL1 (atezolizumab) therapies include those with Avastin for non-squamous NSCLC and with chemotherapies for renal cell carcinoma and NSCLC.

Additional combinations include with aOX40, aCSF-1R, aCEA-IL2v and IDO for solid tumors including lung, bladder, kidney and breast cancer. The study for hard-to-treat triple negative breast cancer is particularly notable, as the company hopes for higher response and long durability.

The purpose of the combo therapies is to achieve long-term durable outcomes, noted O'Day.

O'Day added that the company would provide updates to the bladder cancer data soon, during the coming European Cancer Congress meeting in late September.

"A lot of data readout will be in the next 12 and 24 months," said O'Day. The data include atezolizumab Phase II results in bladder cancer, two Phase II trials for NSCLC and an alectinib Phase II update.

Further data readouts include aPDL1 for melanoma, to be released in November during the Society for Melanoma Research meeting in San Francisco, and Phase II results for venetoclax PII in chronic lymphocytic leukemia in December during the American Society of Hematology meeting.

In addition, selective ALK inhibitor alectinib has shown to shrink tumors in NSCLC patients with ALK rearrangement. Globally, 19,000 patients are diagnosed with this type of mutation each year, and brain metastasis accounts for over 50% of the patients.

Oral small molecule BCL-2 inhibitor venetoclax, studied for hard-to-treat CLL, is planned for US and EU regulatory filings by the end of 2015, he said.

Meanwhile, MEK inhibitor cobimetinib in combination use with BRAF inhibitor Zelboraf (vemurafenib) for melanoma patients with BRAF V600 mutation has been filed for US and EU approval.

Cobimetinib was recently approved in Switzerland under the brand name Cotellic.

The firm that sells the most cancer drugs in the world looks at two key criteria for operating in a therapy area: substantially better results and critical diseases, pointed out Dietmar Berger, Head of Product Development Oncology. Bladder cancer meets both of these criteria.

There has been no new treatment for bladder cancer - a condition that mainly affects older men - for the past 30 years, he noted.

Compared with 2014 when it initiated seven Phase III studies, Roche has begun 11 Phase III studies in 2015 so far, and 10 of these are immunology therapies, highlighting the company's "belief in the promise of immunology," Berger emphasized.

And 70% of Roche Phase II and Phase III products in oncology have a personalized component, he added.

Study Design Shift, More Accurate Testing

One aspect of personalized cancer treatment is categorization not by organs, but molecular characteristics, Berger noted.

To that end, Roche is changing to new study designs and clinical endpoints, he added.

The design has shifted from umbrella trials to basket trials, where a patient with a rare blood disorder could be potentially treated with a melanoma drug, for example, if the patient is found to have the BRAF mutation.

Meanwhile, new clinical endpoints are used. Although patients with BRAF E600 mutations only account for roughly 1% of NSCLC patients, the patient group is included in the study. "Bringing the treatment to a smaller group of patients to get effective results," O'Day explained.

Roche also highlighted its collaboration with Foundation Medicine to strengthen molecular information.

The partnership allows Roche to enhance DNA sequencing panels, and use blood testing to identify all relevant gene mutations at the same time, noted Miro Venturi, Global Head, Diagnostics Biomarkers.

"It's not about one simple test, but multiple tests, which is more accurate," Venturi told journalists, adding that, for instance, lung cancer can be classified into multiple subsets based on molecular alterations.

The current gold standard is tissue biopsy, in which multiple tissues are taken out for molecular tests, leaving, in the end, no tissues left.

Roche, however, is working on “liquid biopsy” technology to analyze nucleic acids, cells and proteins released by a tumor into the blood, thus making series testing possible, and leaving sufficient sample volume for next-generation sequencing (NGS) and other analysis.

In one study, EGFR liquid biopsy was found to detect cancer progression much earlier than a CAT scan, Venturi explained. Using the technology, the patient was found to have progression at 230 days, whereas the CAT scan detected progression at 574 days, or nearly one year later.

Early detection enables physicians to adjust therapy early and achieve better outcomes, he explained.

This emphasis on earlier detection appears to have rubbed off on Roche's approach to discussing its oncology work, with the company fielding executives in charge of early-stage research to discuss broader clinical strategy, instead of primary investigators (Also see "Roche's Oncology Strategy: The Long Game Comes Into Focus" - Pink Sheet, 15 Jun, 2015.).

(This article also appears in Scrip Intelligence. PharmAsia News brings selected complementary coverage from our sister publications to subscribers.)