Cancer combos key to AstraZeneca success, but rivals have long lead

The rapid commercial emergence of cancer immunotherapy over the past half-decade has excited both the biopharma industry and the public alike, offering tantalizing results in treating a number of common cancers such as melanoma or lung cancer.

Immuno-oncology drugs promise a selective, but still systemic, approach to treating cancer and clinical evidence of strong responses in some patients has quickly catapulted drugs like Merck’s Keytruda (pembrolizumab) and Bristol-Myers Squibb’s Opdivo (nivolumab) to blockbuster sales.

That surge in optimism, though, belies the fact that many patients don’t respond as well or at all, leaving researchers puzzled over how to identify the patients most likely to benefit.

One approach that pharma companies have pegged as a way to expand the number of patients who actually benefit from immunotherapy is pairing drugs into combinations targeting multiple pathways used by tumor cells to escape detection.

"More recently, it has become evident that a given cancer cell is not just able to utilize one mechanism but that in a given cancer you may actually find multiple different pathways employed by the tumor cells to evade immune attack," explained Ronald Herbst, VP of R&D in cancer biology at AstraZeneca’s subsidiary MedImmune.

Primary strategy

For AstraZeneca, success with combination therapy likely will be the only way it can quickly catch up to current immuno-oncology leaders such as Merck and Bristol-Myers.

"Our primary strategy will be around combinations," Jamie Freedman, head of oncology global at AstraZeneca, said at a recent briefing with media.

One such combination, using AstraZeneca’s experimental PD-L1 inhibitor durvalumab together with its anti-CTLA4 drug tremelimumab, is expected to read out data in the middle of this year in the all-important non-small cell lung cancer (NSCLC) market. A lineup of other late-stage studies testing the combo as well as durvalumab monotherapy fills out AstraZeneca’s late-stage pipeline in immuno-oncology.

"Core to our strategy is combination therapy because we need to be able to target multiple different pathways to fully engage the immune system, so that we can get rid of the cancer," explained Herbst further.

Playing catch-up

Four so-called checkpoint inhibitors are already on the market: Keytruda, Opdivo, Roche’s Tecentriq (atezolizumab) and Pfizer/Merck KGaA’s recently approved Bavencio (avelumab).

Battered by patent expiries, AstraZeneca has been working to join the field in hopes of bolstering its oncology portfolio – a key pillar to its hope of reaching $45 billion in sales by 2023. Last year, for example, the British pharma sunk 40% of its overall R&D investment into its oncology pipeline.

"Our immuno-oncology portfolio, our IO/IO combination of durvalumab and tremelimumab, can position us in front-line lung cancer, bladder cancer and head and neck cancer over the next couple years, propelling us into a leadership role in immuno-oncology," Freedman said.

But that hope remains just an ambition, for now. Bristol-Myers and Merck both have a lengthy head start commercially and have carved out growing market positions in the largest cancer types (even factoring in the damaging setback to Bristol-Myers in NSCLC last summer).

And AstraZeneca isn’t the only one looking at combinations. Bristol-Myers’ combo of Opdivo plus Yervoy (ipilimumab) has become a standard treatment for certain advanced melanoma patients, while Merck surprised markets in January by securing a speedy review from the Food and Drug Administration for its combo of Keytruda and chemotherapy in first-line lung cancer.

That stiff competition has raised the stakes for AstraZeneca, which will need a hit from its closely watched MYSTIC study testing durvalumab and tremelimumab in NSCLC. (The FDA is also set to decide on approval for durvalumab monotherapy in bladder cancer in the second quarter.)

Jefferies, an investment firm, recently downgraded AstraZeneca’s stock to a “hold” rating, citing in part lower peak sales estimates for durvalumab and tremelimumab due to chemo-I/O combinations.

Complement to targeted therapy

Success with durvalumab will also have an impact on AstraZeneca’s existing cancer portfolio, led by the lung cancer drug Tagrisso (osimertinib) and the PARP inhibitor Lynparza (olaparib).

Tagrisso is currently approved in second-line NSCLC for those patients who have EGFR T790M mutations after progression from treatment with an EGFR tyrosine kinase inhibitor like AstraZeneca’s older Iressa (gefitinib).

By year end, AstraZeneca hopes to submit Tagrisso for approval as a first-line therapy for patients with advanced EGFR mutated NSCLC. Data from the FLAURA trial in that setting is expected in the second half of this year.

Add in an approval for durvalumab and AstraZeneca would have a flexible portfolio of lung cancer treatments that could apply to a broader range of patients.

"If we are successful there, we will actually own the whole lung cancer space in first line with immuno-oncology and Tagrisso," declared Freedman.

Immuno-oncology acts more systemically than targeted therapy and the hope is drugs like durvalumab and tremelimumab will be active across a range of tumor types, complementing the laser-like focus of drugs like Tagrisso on certain subsets of patients.

"[I/O and targeted therapy] together really complement each other and there are also opportunities to combine together and extend the population from the targeted agent to a broader population with the immunotherapy," Freedman said.

While sales of Tagrisso and Lynparza have grown quickly and represent strong market opportunities, durvalumab will enable AstraZeneca to compete with rivals in larger markets and anchor new combinations down the road. 

CEO Pascal Soriot has flagged the next 12 to 18 months as a key inflection point for the company to pivot from managing patent losses to new growth. One way or the other, oncology will be a big part of whether AstraZeneca handles that transition smoothly.

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