AstraZeneca Sees Strength In Small Molecules, Starts Building Oncology Franchises

With its first oncology approval in 15 years, an imminent submission for its next cancer drug and a slew of trials starting by the end of the year, AstraZeneca is starting to show how oncology will be a growth platform.

Last year at the American Society of Clinical Oncology meeting, AstraZeneca PLC’s oncology business review was pitched to investors largely as a defense against a takeover by Pfizer Inc. This year, the focus was on the company’s progress in the therapeutic area.

In 2014, CEO Pascal Soriot attended ASCO as a show of how integral oncology was to the company’s stand-alone strategy (Also see "ASCO Boosts AstraZeneca’s Standings, And Options" - Pink Sheet, 3 Jun, 2014.). He was in attendance again this year, but to highlight the milestones the company has reached, like the fact that oncology was officially established as one of the company’s five growth platforms late in 2014 (Also see "AstraZeneca Staking Its Growth On Oncology; Now It Needs Cancer Drugs" - Pink Sheet, 24 Nov, 2014.).

The firm has a goal of bringing six new oncology drugs to market in the next five years. In January, Lynparza (olaparib) became the first oncology approval for AstraZeneca since Iressa, almost 15 years ago. It was approved to treat advanced ovarian cancer associated with defective BRCA genes (Also see "With Oncology Drugs On The Way, AstraZeneca Sets The Stage For New Launches" - Pink Sheet, 26 Jan, 2015.).

The first-in-class PARP inhibitor is “a very important milestone” for the company, Head of Oncology-Global Product and Portfolio Strategy Mondher Mahjoubi told the June 1 analyst briefing, but it also will be an important test of the company’s ability to fully develop an oncology asset.

“Lynparza is at the beginning of a long journey. We started with a very limited indication, but we're going to build on that. We're going to build in ovarian cancer, earlier lines of treatment, various combinations,” Soriot said. “We're going to build this product into breast cancer, prostate cancer, pancreatic cancer. And I think it is important to keep in mind this could be a – or this will be a blockbuster.”

“The same is true of [AZD]9291,” the firm’s third-generation EGFR inhibitor, he added, “that has enormous potential.”

Laying The Foundation For Franchises

AstraZeneca is on track to complete its submission of AZD9291 for lung cancer by the end of the month, which it believes will make it “the fastest drug development in oncology ever.”

With the additional data released at ASCO, the competition between ‘9291 and Clovis Oncology Inc.’s rociletinib is a sharp area of focus (Also see "ASCO Resets Stage For Third-Generation EGFR Contest: May Come Down To Safety Or Resistance" - Pink Sheet, 8 Jun, 2015.). In an interview at ASCO, Bahija Jallal, exec VP of AstraZeneca’s MedImmune LLC subsidiary, pointed out that the efficacy holds up from the early progression-free survival data presented last year and the drug is well-tolerated. Since its mechanism is slightly different from rociletinib, ‘9291 doesn’t hit IGF and thus doesn’t cause hyperglycemia. “That’s baggage we don’t have,” she said.

Mahjoubi’s discussion of AstraZeneca’s expansion plans for ‘9291 offer another example of the firm’s thoughtful approach to lifecycle management, similar to the plans for Lynparza.

The initial filing will be in second-line lung cancer patients with the T790M mutation, who have developed resistance to older EGFR inhibitors, but the firm is “building out that program with first-line data,” he noted. Phase I data presented at ASCO showed progression-free survival rates at 12 months “in excess of 70%, compared to 50%-55% for first-generation TKIs,” he said. AstraZeneca is also testing the drug in combination with a cMet inhibitor to overcome resistance to ‘9291.

It is also progressing another EGFR inhibitor, AZD3759, out of its innovation center in Shanghai that “was specifically designed to have good characteristics across the blood-brain barrier and also to penetrate into CSF,” Head of Oncology-Innovative Medicines Biotech Unit Susan Mary Galbraith noted. The goal is to treat patients with brain metastases. The company is running a Phase I trial with both compounds that should answer questions about the relative positioning of ‘3759 and ‘9291.

AstraZeneca’s ambition is to have an entire franchise to treat EGFR-mutant lung cancer, akin to Roche’s HER2+ breast cancer franchise. The company’s expertise in the area stems from its experience with Iressa, which debuted before the EGFR pathway was well understood. Iressa's accelerated approval was later restricted in the U.S., though AstraZeneca went on to identify the patients most likely to respond and secure approval of Iressa in Europe. The company only recently resubmitted an NDA for Iressa (Also see "Regulatory Briefs: Ebola Trials Protocol, AstraZeneca Resubmits Iressa" - Pink Sheet, 8 Dec, 2014.).

Iressa stands to be well positioned in the first-line setting, though Roche/Astellas Pharma Inc.’s Tarceva (erlotinib) also competes in the space. The plan is for ‘9291 to enter the market to treat second- and third-line and eventually move up to first-line treatment, Galbraith noted. The next steps will be combining the assets with its PD-L1 inhibitor MEDI4736, with the idea of using immunotherapy to build on the response achieved with targeted therapy to improve response rate and prolong the duration of response. It is starting a trial of ‘4736 plus AZD9291 in second-line T790 mutant lung cancer patients.

The firm is moving Iressa plus ‘4736 into a Phase III trial in first-line EGFRm+ lung cancer and has been studying ‘9291 with ‘4736 in the TATTON trial, a basket trial, after progression on a prior EGFR inhibitor. While previous data have indicated there would be about a 60%-70% response in T790M+ patients and 23% in T790M-, the addition of the PD-L1 inhibitor achieved 85% in T790M+ patients and 43% in T790M-, Galbraith said.

Mixing It Up

More so than some oncology players, AstraZeneca is still heavily focused on small molecules. “We have a deep expertise and for sure the broadest pipeline of small molecules, which of course strengthens our ability to develop combinations, and that’s what makes us unique,” Mahjoubi stated.

A big part of that mix will be combinations with its immunotherapy assets, like ‘4736 and CTLA-4 inhibitor tremelimumab. The firm is also aggressively pursuing all-immunotherapy combinations (see related story, (Also see "AstraZeneca’s Oncology Strategy: It’s All About The End Results" - Pink Sheet, 22 Jun, 2015.)). But small molecules could be a way for AstraZeneca to differentiate in a crowded market.

“Are we just doing it because we've got these things in our portfolio? No, actually. That's not the rationale. The rationale is that we know we can achieve a high and durable response rate with targeted therapies when you've got a tumor that's addicted to signaling through that particular mechanism,” Galbraith said. When you have a drug that kills cancer cells through a specific mechanism and add an immunotherapy, “you can further improve the durability of the responses and depth of responses and lead to an improvement in overall survival,” she explained.

Galbraith acknowledged that tolerability has been a concern with the TKI/checkpoint inhibitor approach, but she cited data showing tolerability at full doses of both ‘9291 and ‘4736 across different settings. They also have in vivo models showing ‘9291 is not inhibiting the immune stimulatory effect, so there is good preclinical rationale for the trial.

Better understanding of disease biology is suggesting that immunotherapy would be a good addition in tumors with high mutational load, and that certain mechanisms can prime for immune action – which is why AstraZeneca is combining ‘4736 with Lynparza, a DNA damage response inhibitor, in ovarian as well as DNA damage repair deficient SCLC, triple-negative breast cancer, bladder, gastric, lung, head and neck, cervical and pancreatic cancer.

“The intent in all of these trials is if the doublet is well-tolerated, then we will be adding in tremelimumab at the dose and schedule … already demonstrated is well-tolerated as a combination,” Galbraith added.

In metastatic bladder cancer, the firm is running an innovative trial that segments patients by genetic drivers, Galbraith noted, “so patients that have got an FGFR mutation will get our FGFR inhibitor together with ‘4736. And patients that have P10 deficiency will get our PI3 kinase beta delta inhibitor together with ‘4736, [in addition to] other segments in that study.”

It is also planning trials with its STAT3 and CXCR2 agents in solid tumors.

Leerink analyst Seamus Fernandez assessed the PD-L1/small molecule combination work as “interesting,” noting the firm already has evidence of tolerability for ‘4736/’9291 from TATTON and for ‘4736 plus BRAF and MEK from a triple combination study presented at ASCO (Also see "PD-1 Progress May Shorten The Life Of Other Drugs" - Pink Sheet, 22 Jun, 2015.).

The small molecule-IO combination work isn’t limited to in-house assets, Galbraith noted. AstraZeneca is testing ‘4736 with an IDO inhibitor and with Johnson & Johnson’s BTK inhibitor Imbruvica (ibrutinib) in hematology and solid tumors. It is starting trials with PI3 kinase inhibitors, its own and with Gilead Sciences Inc. in hematology.

With the new combination work, “we think we could broaden the range of tumor types and the range of tumors that might response to immunotherapy combinations,” Galbraith said.

The small molecule portfolio also holds promising combinations apart from adding immunotherapy. With Lynparza, AstraZeneca has demonstrated that homologous recombination deficiency is relevant across a number of tumor types, and preclinical evidence is showing the WEE1 inhibitor AZD1775 has activity in a broader sample of HRD cells. “The natural next step is a combination study with olaparib, which AstraZeneca is just starting,” Bernstein analyst Tim Anderson said in a June 6 pipeline note.

All of these additional combination trials started in the last six months or will be started in the next six months. With even more data maturing in the rest of the year, it seems like AstraZeneca will have even more progress to report at the next ASCO.

Source: AstraZeneca ASCO analyst briefing, June 1, 2015