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CHICAGO -- An FDA meta-analysis supported response rate as a surrogate endpoint in metastatic non-small cell lung cancer (NSCLC), but others said it's time to look beyond conventional measures.
The correlation of overall response rate with progression-free survival (PFS) was high, with an R-squared value of 0.89, across all 14 trials received by the agency for metastatic NSCLC since 2003, Gideon Michael Blumenthal, MD, of its Center for Drug Research and Evaluation, reported here at the American Society of Clinical Oncology meeting.
The meta-analysis results came as no surprise but were "very comforting because the FDA has approved a lot of drugs based on very impressive response rates," commented Mark G. Kris, MD, chief of thoracic oncology at Memorial-Sloan Kettering Cancer Center in New York City.
Those agents include the ALK inhibitors ceritinib (Zykadia), which got accelerated approval based on overall response rate in NSCLC earlier this year, and crizotinib (Xalkori) which received accelerated approval based on overall response in NSCLC in 2011.
However, while response rates provide an objective, measurable, and highly reproducible early indication of efficacy, there's room for improvement, argued study discussant Lawrence H. Schwartz, MD, of Columbia University Medical Center in New York City.
It's time to challenge the definition of response, which doesn't adequately capture response on cytostatic therapy, depth of response, or alternative types of responses, like when a tumor loses density and becomes "ghosted" on imaging but doesn't shrink, he told attendees.
He pointed to sorafenib (Nexavar) in renal cell carcinoma as a classic case, where the benefit to PFS was significant despite only a 2% response rate.
The threshold for what is considered response is also fairly arbitrary, he pointed out.
Volumetric CT could provide an alternative, he noted. It is being studied in the VOL-PACT study with simulations of randomized phase II trial data to look at a spectrum of measurement data beyond "best response."
Such new metrics could make clinical trials and drug development more efficient to get treatments to patients faster, Schwartz said.
"We have not tapped into all we can do to precisely, quickly evaluate response," Kris agreed. "We have imaging data in every CT scanner that could be mined and used to predict response better."
However, surrogates have been under siege in other areas of medicine.
Lung cancer should take a lesson from breast cancer, said Edith Perez, MD, of the Mayo Clinic in Jacksonville, Fla., and the Alliance for Clinical Trials in Oncology.
"Survival is still what matters most for our patients regardless of what cancer we're talking about," she told MedPage Today. "Look at what's happening with pathologic complete response in breast cancer. It's really not been corroborated for disease-free survival."
And things got ugly when bevacizumab (Avastin) lost its accelerated approval in breast cancer after overall survival results failed to substantiate the early promise seen in PFS.
In NSCLC, the epidermal growth factor receptor (EGFR)-targeted drug gefitinib (Iressa) received accelerated approval on the basis of a modest tumor response rate, but two trials subsequently failed to show a survival benefit and the approval in that indication was later withdrawn.
Kris argued that this example may not apply to molecularly-targeted drugs given to populations enriched with those targets.
But overall survival differences are increasingly hard to achieve because of crossover, he told MedPage Today, and it's entirely likely that no such difference will be found for the ALK inhibitors in clinical trials for that reason.
In Blumenthal's trial-level meta-analysis with a total of 12,567 patients across 14 actively-controlled trials submitted to the FDA since 2003 (about half of which led to regulatory approval), neither PFS nor overall response rate correlated well with overall survival.
That is likely due to confounding from high crossover, underpowered trials, and long survival after progression in the three small targeted therapy trials in molecularly-defined populations, Blumenthal suggested.
But response is still meaningful for these patients with advanced disease, Kris said. "Our surrogates have direct symptomatic benefit for patients."
Will accelerated approvals be pulled for newer agents or does the FDA ascribe to the argument about it being unethical to deny crossover opportunity?
"We don't know," Blumenthal told MedPage Today. He said the agency is still operating under the "presumption that it will prolong patient survival, but it may not in the constructs of patient care."
The FDA can’t comment on specific results, a spokesperson for the agency told MedPage Today, “but according to law and regulations, a drug must demonstrate clinical benefit.”
At the same time, “regarding crossover, we think it should not be withheld for therapies with large magnitudes of response in patients with limited options,” she said.
In the FDA analysis, the correlation between response rate and PFS was particularly strong within the seven head-to-head trials, with an R-squared value of 0.94.
That might reflect some bias if head-to-head designs reflect sponsors' greater confidence in the superiority of their compound going into phase III, Blumenthal suggested.
Larger trials tended to yield modestly better correlations between overall survival and the surrogate endpoints. R-squared values were 0.33 in the trials with more than 500 participants versus 0.07 overall for PFS and 0.40 versus 0.09, respectively, for response rate.
UPDATE: This article, originally published June 1, 2014, at 9:43 a.m., was updated with new material (June 1, 2014, at 7:15 p.m.).
Blumenthal and Perez disclosed no relationships with industry.
Schwartz disclosed relationships with Merck and Pfizer.
American Society of Clinical OncologySource Reference: Blumenthal GM, et al "Overall response rate (ORR) as a potential surrogate for progression-free survival (PFS): A meta-analysis of metastatic non-small cell lung cancer (mNSCLC) trials submitted to the U.S. Food and Drug Administration (FDA)" ASCO 2014; Abstract 8012.