Pfizer Halts Sutent's Phase III in Hepatocellular Carcinoma

Failure is the second in two months for Sutent, which is a lynchpin of Pfizer's oncology strategy.

Pfizer has discontinued its Phase III trial comparing Sutent (sunitinib) in advanced hepatocellular carcinoma to Nexavar (sorafenib) because of a higher incidence of unexpected serious adverse effects.

In addition, the randomized, open-label study of more than 1,000 patients did not meet the criteria showing that sunitinib was either superior or non-inferior to sorafenib in survival.

The company could not provide detailed comment on the adverse events at this time because they require further review, Maria Lechuga, MD, Pfizer's director of Sutent clinical programs, said in an interview, a day after the announcement on April 22. The trial, which was conducted in Europe and Asia, was discontinued after a review by an independent Data Monitoring Committee.

Sunitinib is approved for renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor, or GIST and it's hard to say how adverse events in earlier trials compare, if at all, to the discontinued liver cancer trial.

In trials for other indications, the drug has caused a range of side effects, including high blood pressure, nausea, abdominal pain, diarrhea, low blood sugar, and swelling of feet and hands, stomatitis, and skin discoloration. In an earlier and ultimately successful Phase III renal cancer trial with sunitinib, 19 percent of patients had to stop taking the drug due to adverse events, and in a Phase III study of GIST, 20 percent of patients had a serious adverse effect.

In contrast, in Nexavar's Phase III trials in HCC (these were not head to head), the most common adverse reactions (greater than 20 percent) were fatigue, weight loss, rash, hand-foot syndrome, alopecia, diarrhea, anorexia, nausea and abdominal pain.

Sutent: A Lynchpin Of Pfizer's Oncology Strategy

Pfizer made the announcement April 22, just as the American Association for Cancer Research concluded its annual meeting in Washington DC. The AACR has become a showcase for companies' early-stage efforts in cancer and Pfizer held a press conference there to discuss the wide range of oncology compounds it has in early-stage development.

But events earlier in the week couldn't mitigate the blow from the latest failure of Sutent, which is by far the company's bestselling cancer drug and linchpin of its evolving oncology program. Pfizer has stressed its plans to become a dominant player in the increasingly competitive oncology market, and in spring 2008 set up a separate business unit focused on the therapeutic area (Also see "With A Novel Pipeline, Pfizer Tries A New Oncology Business Unit Too" - Pink Sheet, 23 Jun, 2008.). In 2009, Sutent had sales of roughly $1 billion, and analysts believe that with additional indications, sales could reach $1.5 billion by 2015.

An oral multi-targeted tyrosine kinase inhibitor, Sutent specifically inhibits receptors for VEGF and PGDF, which are involved in angiogenesis, as well as kit, FLT-3, and RET. As part of its push in oncology, Pfizer is aggressively testing sunitinib in a number of other indications for which angiogenesis is known to play a key role, including non-small cell lung cancer, prostate cancer, and kidney cancer.

"The disappointing outcome of this trial challenges all of us to work harder to understand the complex biology of this disease," said senior vice president of clinical development and medical affairs for Pfizer's oncology business unit, Mace Rothenberg in a statement. "The result of this trial does not diminish our confidence in Sutent for the treatment of renal cell cancer and GIST. We continue to study the potential role of Sutent in the treatment of various cancer types in late-stage trials," Rothenberg said.

"We think Pfizer's overall R&D program has been disappointing, with over 10 setbacks in recent years," Herman Saftlas, a pharmaceuticals industry analyst at Standard & Poor's, wrote on April 23 in a note in which he downgraded the stock to "hold" from a "buy." "Without major new products, we see more challenges by the impending loss of patent protection on Lipitor , and health care reform pressures." He did note that merger synergies and cost restructurings will aid the company.

Other Setbacks, New Questions

The failure of SUN-1170 is the most recent disappointment in a string of Sutent setbacks, however. Just last month, the drug failed a Phase III trial against Roche's Avastin (bevacizumab) plus chemotherapy in advanced breast cancer, after showing good activity in a Phase II as a single-agent. Sunitinib had also tested poorly against Roche's Xeloda .

In July 2009, Pfizer's trial with Sutent and chemotherapy in colon cancer ended early, as it was not more effective than chemotherapy alone. Pfizer's Jamie Christensen has observed that those breast cancer trials had begun three to four years ago, before it had revamped its oncology strategy.

Recently, Pfizer has revamped its research strategy in cancer to match drugs more closely to the precise underlying genetic pathways driving each cancer type. Fruits of these efforts composed many of its AACR submissions, but Pfizer is still testing Sutent in a multitude of other cancers.

"We recognize the role of angiogenesis varies in the progression of different cancers including breast cancer and that the utility of sunitinib in this treatment setting may not have been ideal," said Christensen. He observed that breast cancer is currently not understood to be driven primarily by angiogenesis but rather by other factors.

The current trial outcome is puzzling because hepatocellular carcinoma, like renal cell cancer, is largely driven by angiogenesis. Moreover, the population in the Phase II trial was sicker and more diverse than that of the Phase III trial and received a range of doses of the drug. In contrast, Phase III patients received only the lower dose, 37.5 mg, and were healthier.

"Advanced liver cancer is a challenging cancer to treat because it develops in livers which are often diseased due to underlying cirrhosis or hepatitis," said Lechuga. "Therefore, based on the Phase II results, we enrolled patients in the Phase III study who had adequate liver function."

On the upside, Sutent has shown strong activity in (neuroendocrine) pancreatic islet cell cancer, a rare form of pancreatic cancer, affecting only about five percent of those with the disease. In results released last June of a Phase III trial, Sutent extended patients' lives 5 months longer than placebo, with progression-free survival 11.4 months vs. 5.5 on placebo for patients whose disease had progressed after first-line treatment. In NSCLC, the drug also tested well in a Phase II study.

Competition with Nexavar

Until the current Phase III trial, Sutent would have been Nexavar's main competition for HCC, with both drugs aimed at the very large, unmet need in Asia in hepatitis B and C, and liver cancer. "Sutent's surprise failure in HCC very good news for Nexavar," wrote RW Baird analyst Christopher J. Raymond in an April 23 note. Sutent's failure in the HCC trial alone is likely to increase Nevavar's sales going forward, and increase scrutiny of Sutent's performance in RCC.

Nexavar, which is sold by Bayer and Onyx, had sales of $843 million in 2009, based largely on its approved indications for advanced renal cell carcinoma and hepatocellular carcinoma. It also remains Sutent's "foremost competitor" in RCC, Raymond observed. "Many investors had anticipated similar competitive pressure in HCC by 2012, so this failure - especially this early on is a big surprise," he added.

RCC, however, is an increasingly crowded marketplace, relatively limited in size, with Wyeth's - now Pfizer's -- Torisel (temsirolimus), GlaxoSmithKline's Votrient (pazopanib), and Novartis' Afinitor (everolimus) joining Nexavar and Sutent. Nexavar, Votrient and Sutent are all multi-kinase angiogenesis inhibitors targeting VEGF and PDGF, while Affinitor and Torisel inhibit mammalian target of rapamycin, mTOR. Genentech/Roche's Avastin (bevacizumab) more recently added a kidney cancer indication (Also see "RCC Market Snapshot: In A Crowded Field, What's Next?" - Pink Sheet, 5 Apr, 2010.).

Sutent has been the winner in first-line RCC treatment, accounting about 61 percent of sales of all angiogenesis inhibitors. However, renal cell carcinoma (RCC) is a relatively small market as compared to liver cancer - RCC accounting for only 3 percent of all adult cancers, though it is expected to grow to 7 percent by 2013, then slow. Sales last year for kidney cancer drugs only hit $950 million in 2009 for the US, Europe and Japan.

Pfizer is also developing another VEGF inhibitor, axitinib, to treat RCC, and is now testing it against Nexavar in patients, including in those whose disease has progressed on Sutent. And to make things more interesting, an investigational drug, tivozanib, by Aveo Pharmaceuticals in Cambridge, MA, is also going head-to-head against Nexavar in a Phase III RCC trial.

--Vicki Brower ([email protected])