FDA panel: Benefit of ‘highly anticipated’ lung cancer drug can’t be interpreted reliably
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An FDA advisory committee voted 10-2 that the results of a confirmatory trial for the targeted lung cancer drug sotorasib cannot be interpreted reliably.
The trial showed sotorasib (Lumakras, Amgen) conferred a small but statistically significant PFS benefit compared with docetaxel for patients with locally advanced and unresectable or metastatic KRAS G12C-mutated NSCLC who received at least one prior line of therapy.
However, an FDA briefing document released prior to the Oncologic Drugs Advisory Committee (ODAC) meeting on Oct. 5 raised questions about whether the trial can be considered adequate and well-controlled due to “multiple indications of systemic bias” related to study conduct.
“The question before the committee ... is not one of efficacy of sotorasib in lung cancer, but rather specifically the ability to interpret data from a relatively small clinical trial conducted with a highly anticipated agent in a hyperinformation age where both patients and providers had high expectations,” committee chairman Ravi A. Madan, MD, head of the prostate cancer clinical research section of the Genitourinary Malignancies Branch in NCI’s Center for Cancer Research, said during post-vote discussion. “Given we had hours [of discussions of statistical permutations] that could change interpretations, I had to vote no on the reliability of the PFS benefit.”
Madan noted several factors that contributed to his decision, including the study size, investigator conduct and “the small 5-week PFS benefit” with sotorasib.
"I do think if the PFS benefit was much greater, this would’ve been a much shorter conversation,” Madan added. “But this question will not be limited to this study in the future. Industry and investigators must work together to ensure clinical trials are conducted competently so we can glean the best data to advise our patients based on outcome data, not presumption.”
Confirmatory trial
Sotorasib — an oral, irreversible KRAS inhibitor — received accelerated FDA approval in May 2021 for treatment of adults with KRAS G12C-mutated locally advanced or metastatic NSCLC who received at least one prior systematic therapy.
It became the first approved targeted therapy for tumors with any KRAS mutation.
The agency based accelerated approval on results of the phase 1/phase 2 CodeBreaK 100 trial. The single-arm study showed sotorasib conferred a 41% overall response rate among patients with advanced KRAS G12C-mutated NSCLC, with a 6.3-month median PFS and 12.5-month median OS.
A required confirmatory trial — the randomized phase 3 CodeBreaK 200 trial — included 345 patients with locally advanced and unresectable or metastatic KRAS G12C-mutated NSCLC who received at least one prior line of therapy, including platinum-based chemotherapy and an immune checkpoint inhibitor.
Researchers randomly assigned 171 patients (median age, 64 years; range, 32-88; 36.3% women; 12.3% Asian) to 960 mg sotorasib daily. The other 174 patients (median age, 64 years; range 35-87; 45.4% women;12.6% Asian) received IV docetaxel.
PFS as determined by blinded independent central review served as the trial’s primary endpoint. Median follow-up was 17.7 months.
As Healio previously reported, the trial met its primary endpoint. Researchers reported a small but statistically significant PFS improvement with sotorasib (median, 5.6 months vs. 4.5 months; HR = 0.66; 95% CI, 0.51-0.86). The OS difference between the sotorasib and docetaxel groups did not reach statistical significance (median, 10.6 months vs. 11.3 months; HR = 1.01; 95% CI, 0.77-1.33).
Safety results showed a higher percentage of patients assigned docetaxel experienced any treatment-related adverse events (86.1% vs. 70.4%), grade 3 or higher treatment-related events (40.4% vs. 33.1%) and serious treatment-related events (22.5% vs. 10.7%).
‘Potential systemic bias’
An FDA review team investigated “multiple sources of potential systemic bias” in the open-label trial, according to a briefing document the agency released prior to the ODAC meeting.
The agency cited “asymmetric early dropout,” noting 23 patients assigned docetaxel dropped out after randomization compared with two assigned sotorasib.
The briefing document also highlighted how patients assigned docetaxel had been switched to sotorasib prior to assessment of disease progression by blinded independent central review.
Considerable testimony during the daylong ODAC meeting focused on the potential efficacy and quality-of-life benefits sotorasib may offer vs. standard chemotherapy for patients with KRAS G12C-mutated locally advanced or metastatic NSCLC.
However, FDA briefing documents advised committee members not to base their vote on whether results of CodeBreaK 200 were sufficient to support converting FDA’s accelerated approval of sotorasib to traditional approval.
Instead, the voting question posed to ODAC members focused only on whether they could reliably interpret results from the trial — specifically those related to the primary endpoint of PFS per blinded independent central review — and whether CodeBreaK 200 can be considered an adequate and well-controlled trial.
‘Large number of issues’
The majority of committee members voted “no” to the question.
“All of us want to help [patients with cancer] and improve the way they experience life,” committee member Daniel Spratt, MD, chairman of the department of radiation oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University, said during post-vote discussion. “We typically quantify that as improvement in quality or quantity of life. ... [This] drug did not help patients live longer. ... This study was not designed as a superiority trial for quality of life — quality of life was not even assessed beyond progression, so we do not know what global net long-term quality of life is.”
Spratt emphasized the lack of OS benefit with sotorasib, despite the PFS advantages observed.
“With no further explanation, this leads me to believe — with all of the other discussion we’ve had — that there likely is bias or inaccuracies in the PFS assessment,” Spratt said. “Unfortunately, I lack confidence in the reliability of the PFS endpoint.”
It is unrealistic to expect a perfect randomized controlled trial, according to Mark R. Conaway, PhD, professor in the division of translational research and applied statistics at The University of Virginia School of Medicine.
“What we hope for is a small number of issues in trial conduct and an effect large enough to withstand the uncertainties caused by those issues,” Conaway said. “For this trial, we seem to have the opposite — a large number of issues that cloud interpretation of a small observed effect.”
Madan commended the trial sponsor for choosing an appropriate active control regimen.
“But clinical investigators must comply with the spirit of the protocol and provide necessary education as part of the informed consent process so once enrolled, patients have the comfort and confidence to continue with the study,” Madan said. “Only then can we move forward with new therapies that have demonstrated convincing clinical benefit without question. Data fidelity must begin with the fidelity of the investigators to the protocol.”
Jorge J. Nieva, MD, associate professor of clinical medicine and section head for solid tumors at USC Norris Comprehensive Cancer Center, cast one of the two votes suggesting the CodeBreaK 200 results can be interpreted reliably.
“The study met its primary endpoint based on the intention-to-treat analysis and, ultimately, we have to take the statistical plan as it is written and analyze things according to what was planned,” Nieva said. “The post-hoc analyses are informative but they ultimately don’t change the benefits that were, in fact, observed, and I don’t think a type I error occurred here. Given the corroborating evidence, I have confidence that the drug does have a PFS benefit over the comparator.”
Next steps
The FDA is scheduled to make a decision by late December whether to convert sotorasib’s accelerated approval to traditional approval.
The agency is not required to follow ODAC recommendations, but it often does so.
Given ODAC members voted on evidence reliability rather than approval status, it remains unclear what will happen next.
“We deeply appreciate ... not only the [committee’s] vote but the discussion,” Harpreet Singh, MD, a medical oncologist with FDA, said during post-vote discussion. “We do hear the conflict in [committee members’] thought process around the vote about totality and the desire to keep sotorasib on the market as an option for patients. ...
“It is not our intent to immediately withdraw a drug that has a ‘failed’ confirmatory trial,” Singh added. “[Sotorasib] is under accelerated approval and there are multiple pathways available to us. ... We are taking into account [the committee’s] discussion, and it sounds like we have a call to action, in fact, to discuss conduct and mitigation strategies in open-label trials.”