Failed confirmatory trial raises questions about atezolizumab for advanced urothelial cancer
The future of atezolizumab as second-line treatment for urothelial cancer is in question after results of a confirmatory trial indicated the agent failed to extend survival.
A phase 2 study showed atezolizumab (Tecentriq, Genentech) — a monoclonal antibody designed to bind with PD-L1 — improved tumor response rate and duration of response compared with chemotherapy among patients with locally advanced or metastatic urothelial carcinoma who progressed after prior chemotherapy.
Based on these data, the FDA last year granted accelerated approval to atezolizumab for use in the second-line setting. The drug became the first FDA–approved anti–PD-L1 therapy, as well as the first drug approved to treat bladder cancer since 1998.
However, Genentech last month announced the confirmatory randomized phase 3 IMvigor211 trial — designed to convert the accelerated approval to full approval — failed to meet its primary endpoint.
“Will the FDA continue to grant approval to atezolizumab for this space?” Terence Friedlander, MD, assistant clinical professor at the division of hematology/oncology at UCSF’s Helen Diller Family Comprehensive Cancer Center, told HemOnc Today. “Most oncologists who treat bladder cancer are very used to using atezolizumab, so it may take some time for the data to disseminate once they are presented. Then, will it change practice patterns?”
HemOnc Today spoke with Genentech officials and the FDA about their next steps, and to urologic oncologists about the implications of the IMvigor211 results.
The IMvigor211 trial evaluated the efficacy and safety of atezolizumab compared with chemotherapy administered every 3 weeks in 931 patients with locally advanced or metastatic urothelial cancer whose disease progressed during or after treatment with platinum-based chemotherapy.
OS — tested in a successive fashion in study populations defined by PD-L1 expression — served as the primary endpoint.
A Genentech press release issued May 9 indicated atezolizumab did not significantly extend OS compared with chemotherapy, but that atezolizumab’s safety profile appeared consistent with previous studies of the drug.
Genentech officials indicated they intend to further examine the data, including the initial observation that efficacy results in the chemotherapy arm appeared better than study design assumptions.
“We are committed to helping patients with advanced bladder cancer and believe that Tecentriq will continue to play an important role in the treatment of people with advanced bladder cancer,” Austine Graff, senior manager of corporate relations at Genentech, told HemOnc Today. “We will apply insights to the continued development of Tecentriq. We will discuss these data with health authorities, and share next steps when available.”
FDA officials declined to discuss this situation specifically. However, a statement provided to HemOnc Today offered insights into the agency’s processes.
“Generally speaking for postmarketing requirements, a company first submits full data from the trial to the agency and discusses the findings in detail with the review division,” the statement read. “If — after a review of the data and consideration of the totality of evidence — a clinical benefit is not demonstrated or the applicant fails to perform required postmarketing studies with due diligence, the FDA may withdraw approval, following an open public hearing.”
Friedlander described the confirmatory trial results as “perplexing” considering the clinical activity atezolizumab demonstrated in phase 1 and phase 2 studies, as well as the OS benefit observed in a phase 3 trial of pembrolizumab (Keytruda, Merck) — an anti–PD-1 antibody — in the same setting.
“A lot of oncologists expected atezolizumab would show similar benefit based on the fact that the phase 2 studies and earlier-phase studies of these drugs all showed somewhat similar efficacy as determined by response rate,” he added. “We were rather surprised that the atezolizumab phase 3 study failed to meet its primary endpoint.”
Petros Grivas, MD, PhD, assistant professor in the department of medicine at Cleveland Clinic Lerner College of Medicine and staff genitourinary oncologist at Cleveland Clinic’s Taussig Cancer Institute, recalled similar reactions among his colleagues.
“This press release generated a significant amount of discussion amongst academic circles about the potential causes of this negative result,” Grivas told HemOnc Today. “However, I think we all need to see the actual data.”
Until complete data are released, oncologists are left to wonder whether they clearly show no survival advantage, or whether the survival outcomes were a “close miss,” Friedlander said.
“Did they miss [the target HR] by just a small fraction, and did that make the study negative?” he said. “How did this agent perform against chemotherapy?”
That question — in addition to uncertainty about how well chemotherapy performed in the study — are the primary questions to which oncologists are seeking answers, Friedlander said.
“It would be interesting to see if patients receiving chemotherapy in the control arm in this study had a similar response rate compared with earlier studies, if atezolizumab didn’t perform as well, or if chemotherapy, in fact, performed better than expected,” he said. “If so, that may make it more difficult for the investigators to achieve the primary endpoint.”
The sequential design of the study, potential subsequent therapies, PD-L1 protein expression and differences between arms also could have affected outcomes.
Bladder cancer landscape
The negative trial does not necessarily mean patients with previously treated locally advanced or metastatic urothelial cancer are without treatment options.
Until complete data are presented, use of atezolizumab may not change.
“When decisions are being made by health care providers, parameters may include efficacy, safety, level of evidence, frequency of administration, patient convenience and cost in regard to value-based care,” Grivas said. “So far, the checkpoint inhibitors in phase 2 trials have shown comparable safety and efficacy, and I think the more data and specific details we get, the more insight we will have for more discussion.”
Sandy Srinivas, MD, professor of oncology at Stanford University Medical Center, has used atezolizumab in clinical trials in both the postplatinum second-line setting and the cisplatin-ineligible patient population.
“It doesn’t really mean that this drug is ineffective. It just didn’t meet its endpoint,” she told HemOnc Today. “I’m not willing to make a judgement until I actually see those results. Having said that, there are other checkpoint inhibitors that have gained FDA approval for the identical indication.”
Since the approval of atezolizumab, four additional checkpoint inhibitors have entered the treatment landscape for advanced bladder cancer: nivolumab (Opdivo, Bristol-Myers Squibb), durvalumab (Imfinzi, AstraZeneca), avelumab (Bavencio; EMD Serono, Pfizer) and pembrolizumab.
“If you look at all five of the drugs, there is nothing really that distinguishes one from the other, whether it is in terms of response rate, number of complete responses, durability of response, OS and even toxicity,” Srinivas said. “With that in mind, I can’t think there is something unique about atezolizumab that didn’t lead to a positive outcome compared with pembrolizumab, which demonstrated superiority compared with chemotherapy.”
Although no differences have been observed between checkpoint inhibitors, the number of agents now available may affect the FDA’s decision about what action — if any — it will take on atezolizumab’s accelerated approval.
Rapid changes likely will not occur until data from the trial are presented and reviewed thoroughly, Grivas said.
“With the exception of pembrolizumab — which had an OS benefit in a large phase 3 randomized trial — the other four have comparable levels of evidence based on phase 2 trials,” he said. “It will be important to take this into account. We will see how the FDA and the oncology community react to the data when they become available, and how they may affect practice patterns.”
Two months ago, the FDA granted accelerated approval to atezolizumab for first-line treatment of patients with locally advanced or metastatic urothelial cancer who are not eligible for cisplatin chemotherapy. The phase 3 IMvigor130 study is ongoing to confirm the benefit in this population.
Thirty other trials are underway to evaluate atezolizumab alone or in combination for the treatment of lung, kidney, skin, breast, colorectal, prostate, ovarian, bladder and blood cancers.
If the FDA decides to withdraw its accelerated approval of atezolizumab for use in the second-line setting, the implications may not be dramatic for patients and clinicians.
“It may be that it is not such a big deal because they have other options,” Srinivas said. “If the FDA comes back and says this drug will be withdrawn, it will be a shame for the company and for the other trials that are all looking at atezolizumab, but from a patient and physician point of view, there are four other choices.”
Despite the uncertainty surrounding atezolizumab, Grivas expressed excitement about bladder cancer treatment advances made in the past 2 years.
“It is very encouraging and exciting to have options for patients with bladder cancer,” Grivas said. “After so many years of research efforts, we now have options with five agents, and hopefully more to come in the future. Promising clinical and translational research is ongoing, and trial accrual remains critical to make further progress.” – by Kristie L. Kahl
Balar AV, et al. Lancet Oncol. 2016;doi:10.1016/S0140-6736(16)32455-2.
Genentech. Genentech provides update on phase III study of Tecentriq (atezolizumab) in people with previously treated advanced bladder cancer. 2017. Available at: www.gene.com/media/press-releases/14665/2017-05-09/genentech-provides-update-on-phase-iii-s. Accessed on June 7, 2017.
Rosenberg J, et al. Eur J Cancer. 2015;doi:10.1016/S0959-8049(16)31942-6.
For additional reading on the FDA approval process:
FDA. CFR — Code of Federal Regulations Title 21. Available at: www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.150. Accessed on June 7, 2017.
For more information:
Terence Friedlander, MD, can be reached at 1825 4th St., San Francisco, CA 94158; email: firstname.lastname@example.org.
Austine Graff can be reached at email@example.com.
Petros Grivas, MD, PhD, can be reached at Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195; email: firstname.lastname@example.org.
Sandy Srinivas, MD, can be reached at Stanford University, 875 Blake Wilbur Drive, Palo Alto, CA 94304; email: email@example.com.
Disclosures: Friedlander reports advisory board roles with AstraZeneca and Genentech. Graff reports employment with Genentech. Grivas reports consultant roles with AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis Oncology, Dendreon, EMD Serono, Exelixis, Genentech and Merck. Srinivas reports advisory board roles with AstraZeneca, Bristol-Myers Squibb and Genentech.