Pfizer's Avelumab Makes Its Debut, In Rare Form Of Skin Cancer

Pfizer got Bavencio to market by focusing on an unmet need, but the PD-L1 inhibitor is still a few years behind, competing with other checkpoint inhibitors over more valuable indications.

Despite the recent news of a setback for Pfizer Inc.'s development of Bavencio (avelumab) in lung cancer, the drug giant's strategy of focusing on an unmet need allowed it to get to market in some capacity and will give it a test run with physicians and payers before moving into the larger markets.

The US FDA granted accelerated approval of avelumab March 23 for the lead indication of Merkel cell carcinoma, based on overall response rate and duration of response. The second PD-L1 inhibitor to be approved, Bavencio is the first FDA-approved treatment for the rare form of skin cancer. It had a breakthrough therapy designation and received a priority review.

Roche took a similar tack with its Tecentriq (atezolizumab), the first PD-L1 inhibitor to reach the market, which first received approval for bladder cancer in May 2016. It was cleared for non-small cell lung cancer in October and brought in $158m last year. Roche, however, has a deep development program for the drug alone and in combination. (Also see "Genentech’s Tecentriq Stakes New Claim With FDA Lung Cancer Approval" - Scrip, 19 Oct, 2016.)

Bavencio, which is partnered with Merck KGAA, also beat AstraZeneca PLC's durvalumab to market, which was expected to be the next approved PD-L1 inhibitor. Durvalumab is under review for the treatment of metastatic urothelial cell carcinoma with a decision expected in June or earlier.

Bavencio also is being reviewed for metastatic urothelial carcinoma; the user fee date for the bladder cancer indication is Aug. 27.

Still Lagging Behind Competitors

Despite the approval, Bavencio is still far behind the other PD-1/L1 inhibitors on the market: Bristol-Myers Squibb Co.'s Opdivo (nivolumab), Merck & Co. Inc.'s Keytruda (pembrolizumab) and Tecentriq. All of these treatments are approved for more valuable indications.

Pfizer recently faced a delay in competing with Opdivo and Keytruda in non-small cell lung cancer (NSCLC), the most valuable indication for immuno-oncology, after making major protocol changes to the JAVELIN Lung 100 study. Adjustments to the Phase III study, which tests avelumab as a single agent against chemotherapy, include a large increase in the number of trial participants and a nearly two-year delay in the primary completion date for the study, from August 2017 to April 2019. (Also see "Pfizer Takes Step Back With Avelumab, Step Forward On CAR-T" - Scrip, 9 Mar, 2017.)

Robert Jeng, a Biomedtracker analyst, told Scrip he believes believe the current approval for Bavencio is not significant in the long run.

"Of course, getting a first approval is satisfying, but we already have several examples among the PD-1s where efficacy in one tumor type is not predictive of general efficacy across tumors," Jeng said. "Furthermore, Merkel cell is a fairly small target population," with only about 1,500 cases diagnosed in the US each year.

Jeng touted the drug's broad development program, but added that "the space is getting more and more crowded with little differentiation thus far other than final clinical outcomes."

"Thus, if Bavencio can gain some additional approvals, it should compete reasonably with other PD-1s, although with a strong lag to market in an ever-shrinking pie to split," he said.

Pfizer/Merck KGAA are also studying avelumab in Phase III trials in NSCLC, gastric cancer, ovarian cancer, renal cell carcinoma and squamous cell carcinoma of the head and neck.

Potential For Differentiation

Pfizer has maintained that late-comer avelumab, which marks the company's entrance into the immuno-oncology market, has the potential to stand out compared to the other programmed-death checkpoint inhibitors.

"The antibody has an intact IgG1 Fc domain, which means its effector function is retained, leading to greater cell-based killing (antibody-dependent cell-mediated cytotoxicity, or ADCC)," Bernstein analyst Tim Anderson said in March 23 note.

So far it has not manifested in an efficacy benefit, the analyst observed, but he thinks it might be the cause of a higher rate of infusion-related reactions (IRRs) compared to the other PD-1/L1s. Labeling for Bavencio reports IRRs in about 25% of patients, mostly low-grade. "We recently analyzed the data with competitor products on this metric, and IRRs for them tend to be in the single digit percent range," Anderson said.

Also, Bavencio labeling recommends pretreatment for the first four infusions with acetaminophen and an antihistamine. "Competitor labels lack this," the analyst pointed out. "All labels, however, have some mention of IRRs."

Anderson does not see the IRRs as a major issue, "because the frequency of severe IRRs is still quite low, and all of the other anti-PD[-1/L1] therapies do cause occasional severe IRRs. Where avelumab stands out is the higher frequency of mild IRRs. However, in the tight race among the different PD[-1/L1] companies who are jockeying for mind- and market-share, this may provide at least a bit of ammunition to competitors."