Roche may not be the first entrant in the immune checkpoint inhibitor field, but it intends to win in the end.

The company's long-term oncology strategy includes maximizing the potential of its PD-L1 inhibitor atezolizumab, as it has with Avastin, and turning the expected blockbuster into a cornerstone of combinations. And while Roche has emphasized the potential for immunotherapy combinations since checkpoint inhibitors came into play, the data presented at the American Society of Clinical Oncology annual meeting are starting to put evidence behind the potential.

Roche Pharmaceuticals Chief Operating Officer Daniel O’Day opened the firm’s May 31 on-site analyst meeting by noting that the data coming out of ASCO, including the POPLAR results for atezolizumab (MPDL3280A) stratified by PD-L1 expression, were “proof of concept” for its biomarker-driven strategy.

The current boom in precision medicine plays directly to Roche's complementary strengths in diagnostics and pharmaceuticals. "The value of understanding patient responses using biomarkers, and then using those biomarkers to help understand what combinations to use, is really critical and very, very exciting," Genentech Inc. VP-Cancer Immunology Ira Mellman told the briefing.

Rather than using immune biomarkers to select patients, with a rule in/rule out mindset, the firm sees the information as guiding toward appropriate treatment, “as perhaps how we can best identify the patients who best respond to a monotherapy immuno-agent versus those patients who respond better or get a best response from combinations,” O’Day explained.

“This year, both from our data and from our competitors, it’s really starting to appear that that strategy is supported by clinical results very broadly,” Mellman said.

There is no small element of theater in the investor presentations the major players stage alongside ASCO every year. The choice of speakers can underline how companies envision their strengths. At Roche, the annual presentation has moved away from highlights of specific trial results, discussed by clinical investigators, in favor of bringing out executives in charge of early stage research to discuss broader clinical strategy ([A#00140609013]). This year, for the first time, a diagnostics exec also presented at Roche's ASCO event: Genentech VP-Biomarker Development and Companion Diagnostics Garrett Hampton.

"Comprehensive Diagnostics"

Hampton discussed Roche's move toward "comprehensive diagnostics," a strategy that got a big boost in early 2015 when Roche acquired a majority stake in the molecular information and genomic analysis firm Foundation Medicine Inc. – a stake reminiscent of Roche's early relationship with Genentech Also see "Roche Could Repeat Genentech Success With Foundation Medicine Partnership" - Pink Sheet, 12 January, 2015..

Roche has long been a major in vitro diagnostics presence. When the rise of targeted cancer therapies created demand for companion diagnostics based on histopathology, the company aggressively pursued tissue-based cancer test maker Ventana Medical Systems Inc., finally succeeding in acquiring Ventana in 2008.

Roche's diversified organization stands out in an increasingly specialized and focused pharma sector. Partnering is the more common route for therapeutics firms looking to incorporate biomarkers into immuno-oncology R&D, either around specific drugs or through wider-ranging master collaboration agreements. Novartis and Astellas inked master collaboration agreements with diagnostics specialist Qiagen NV in late 2014, for example. Amgen Inc. has a master collaboration agreement with Dako AS. And Dako is also a major player in PD-1/L1 inhibitor companion diagnostics, partnering with both Merck & Co. Inc. and Bristol-Myers Squibb Co.

AstraZeneca PLC stands out in following in Roche's footsteps in bringing oncology diagnostics expertise in-house, buying "tissue phenomics" company Definiens AG in late 2014 Also see "Companion Diagnostics Come Of Age" - Medtech Insight, 28 April, 2015..

Roche now sees itself as uniquely well-positioned not only to offer patients a wide range of oncology drugs but the ability to guide therapy and develop drugs more efficiently.

Roche has considerable experience using companion diagnostics to rule patients in or out for targeted therapy based on cancer cell markers like HER2 (for Herceptin, Perjeta, and Kadcyla) and BRAF (Zelboraf). And immuno-oncology opens up new horizons for use of tumor microenvironment biomarkers – and, by extension, diagnostic tests.

“Every single molecule that we work on has a biomarker program,” Hampton reminded investors. “Where the science tells us that we're likely to understand which patients will benefit, then we trigger diagnostics development at a very early stage.”

Foundation Medicine's tumor profiling technology, which can analyze a single tissue sample for a large number of biomarkers, addresses one of the challenges of precision medicine: limited availability and volume of patient tissue for testing.

Preclinical models are "actually very limited for immunotherapy," Hampton said. "Ultimately, we think the types of experiments we do in the clinic and the types of tumor tissues we get from patients become exceptionally important to understand this area."

For most Phase I trials "we take pre-biopsies, post-biopsies, progression biopsies," he said. "We're really using patient materials to understand exactly what's happening." Roche oncology trials are designed to continually feed information back to the company so trial design and strategy can adapt in response ([A#00140609013]).

Part of that developing understanding is learning how to use biomarkers. PD-L1 is the first frontier for immunotherapy companion diagnostics, and questions about the role of PD-L1 testing were a major topic of controversy throughout the ASCO meeting ([A#00150608008]). Roche presented its first clinical trial results showing a correlation between PD-L1 expression measured by its proprietary assay and clinical response from the POPLAR trial of atezolizumab in second- and third-line non-small cell lung cancer.

Roche’s assay, developed through Ventana, differs from other assays by measuring PD-L1 expression both on the tumor cell and on infiltrating immune cells in the tumor microenvironment ([A#14150601001]). The firm believes that specificity will be an advantage moving into other tumor types, where immune cell expression might be more relevant.

Genentech Chief Medical Officer Sandra Horning stressed that Roche is "not looking at the assay in an exclusionary manner," but as a way to determine the best course of therapy for the patient, be it atezolizumab monotherapy or combination regimens.

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"Not all patients are going to respond" to immuno-oncologics, "because they may not have adequate T-cell responses," Mellman said. Roche came to understand "very, very early on that we're going to have to combine [drugs] to see if we can accentuate these kinds of responses." O'Day suggested that about 80% of cancer patients will require combination therapy of some type.

Many Drugs For Many Targets

With its broad internal pipeline and wide array of marketed oncologics, Roche can be much quicker to respond to emerging data about what combinations could work in which patients. Roche still plays the deal-making game along with everyone else; during the ASCO meeting, for example, it announced a deal to combine atezolizumab with Amgen's oncolytic immunotherapy T-VEC. But with deal-making less of a necessity for Roche, the company can be more flexible and nimble on the clinical trial front.

"The ability to have critical mass around going after actionable targets, either alone or in combination, and being able to react quickly on that is a unique competitive advantage for us," O'Day said.

Roche pRED Global Head Oncology Discovery and Translational Area William Pao described a drug discovery operation that could well be called a drug design operation. Discoveries come from the company's "deep understanding of disease biology," informed not only by bench research but by information feeding back from ongoing clinical trials that extensively monitor patient responses. The company has identified a library of targets so big that Roche has used the "kid in a candy store" metaphor to describe it ([A#06140601009]).

The company then aims to "design the right drug with the right format for the right target," Pao said. "We want fit-for-purpose technology." When a drug with the desired attributes is produced, "we want precision medicine algorithms so we can deliver the right drug to the right patient at the right time."

In pursuit of that goal, Roche has brought seven immuno-oncology molecules into the clinic, each in a range of trials – including, Horning said, 11 Phase III studies. "This kind of breadth in our portfolio means that we are in an extraordinary position to pursue combination therapies …. within our portfolio, in our specific franchises, across our immunotherapy program with our targeted agents, with chemotherapy, and certainly with immune doublets," Horning declared.

Chemotherapy is an area where Roche is ahead of the pack. While Bristol has avoided chemo combinations with Opdivo (nivolumab), based on early data, Roche presented data on atezolizumab plus carboplatin/paclitaxel, carboplatin/pemetrexed or carboplatin/nab-paclitaxel in lung cancer. “The bottom line for this, and really important, is that the combination was well tolerated,” Horning said, with “no unexpected toxicities other than what is customarily seen with combination chemotherapy.” With the caveats that the trial was small and data are early, she said the efficacy data are “highly encouraging.” The firm is moving rapidly into Phase III chemo combination studies in lung cancer, including adding Avastin, with data expected in 2017-2018.

Bristol has taken an early lead with immune doublets, presenting at ASCO the first data on an immune checkpoint combination, with its CTLA-4 inhibitor Yervoy (ipilimumab) and PD-1 inhibitor Opdivo ([A#00150615010]). AstraZeneca is fast on its heels, looking at its anti-PD-L1 MEDI4736 with its investigational CTLA-4 inhibitor tremelimumab. But Roche has big plans there as well.

Roche's Network Effect

The promising activity of PD-1/L1 inhibitors has made them the central hub of big pharma's immuno-oncology efforts. Merck, Bristol and AstraZeneca, like Roche, described extensive clinical trial programs in multiple cancer types at ASCO, with eligible combination partners arrayed around a central anti-PD-1 candidate like the spokes of a wheel. Merck even has a mantra: "great drugs build great franchises" ([A#00150608002]).

Roche's Web Of Oncology Therapies

Roche analyst presentation, May 31, 2015

Roche certainly is positioning atezolizumab as the foundation of a great franchise. The company has a successful historical record of nourishing blockbuster franchises – indeed, while immuno-oncology took control of the headlines, O'Day noted that Roche's venerable Avastin (bevacizumab) was the most cited drug at the ASCO meeting.

"We draw some parallels to the fact that Avastin, as a multi-tumor product, has been very successful, now for more than a decade," O'Day said. "We see now our immunotherapy program as another way to look at a pan-tumor approach to improving the standard of care across many tumor types."

But Roche is also looking beyond atezolizumab to an entire network of immuno-oncologics, connected not just to atezolizumab like the spokes of a wheel but to each other, like a spider web (see related story on Roche's early-stage immuno-oncology pipeline, [A#00150615012]). Roche wants to combine its drugs "again and again," Mellman said, in a "directed fashion informed by biomarkers."

The scale and complexity of the immuno-oncology programs presented at ASCO may offer unprecedented therapeutic potential, but they also reinforce the dominance of a few big players.

In the early days of biotechnology, specialist boutiques could gradually grow into "big biotech" firms, remaining independent like Amgen or Biogen or becoming innovation engines for big pharma, like Genentech after its acquisition by Roche or Genzyme after its purchase by Sanofi.

Today it will be harder to grow to the next level with any degree of independence; small firms must enter into deals with companies that have the resources and experience to mount R&D programs of great scale and complexity. And Roche, as a heavyweight in both pharma development and marketing and diagnostics, is aiming to have the biggest, broadest, and deepest program around.

Roche's Oncology Strategy: The Long Game Comes Into Focus

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