FDA Reiterates Preference For Overall Survival Data For Lung Cancer Approvals

FDA’s final guidance on lung cancer trial endpoints says that overall survival is the optimal test of efficacy, but reaffirms that progression-free survival primary endpoint may support approval if the magnitude of effect is “substantial and statistically robust.”

In its latest guidance on trials of drugs for non-small cell lung cancer, FDA continues to stress overall survival as the ideal endpoint for standard drug approvals, but also openness toward progression-free survival to support filings, as long as the benefit is strong enough.

FDA published the “Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and Biologics” final guidance on April 22, roughly four years after the draft guidance released on June 17, 2011.

The final guidance is coming at a crucial time for the industry, as major sponsors work to get the family of PD-1/L1 immune checkpoint inhibitors approved for the valuable lung cancer indication (see related story, (Also see "PD-1 Round-Up: Big Pharmas Talk Competitive Positioning" - Pink Sheet, 4 May, 2015.).

In the draft guidance in 2011, FDA stressed the importance of using overall survival as an endpoint to prove efficacy and made it clear that if a progression-free survival measure is used, a “substantial and robust” effect should be shown (Also see "FDA’s NSCLC Guidance Stresses Overall Survival Endpoint, Sets PFS Standards" - Pink Sheet, 4 Jul, 2011.).

In its final edition, the agency said that based on recommendations from its Oncologic Drugs Advisory Committee in 2003, FDA has continued to “recommend OS as the primary endpoint for NSCLC clinical trials,” but that “a clinical trial demonstrating a large improvement in PFS, with acceptable toxicity, could potentially lead to regular approval, particularly in an unmet medical need population.”

FDA advises that sponsors should justify use of PFS as the primary efficacy endpoint and assess the magnitude of PFS effect considered likely to predict OS versus the risks.

“Because of the subjectivity in the measurement of PFS assessments and the fact that the assessments depend on frequency, accuracy, reproducibility, and completeness, the observed magnitude of effect should be substantial and statistically robust,” the document states.

Overall survival is “optimal,” the final guidance document concludes, in part because it is “definitive and easy to determine.”

The guidance points out that “an observed OS benefit in a well-conducted, randomized trial can be directly attributed to the experimental therapy.”

FDA noted that the commonly used efficacy endpoints in trials assessing lung cancer drugs have been overall survival, time to progression or progression-free survival, and objective tumor response rates.

Most approvals of lung cancer drugs have been based on a significant improvement of OS, the agency said. However, some drugs targeting genetic mutations were initially cleared based on objective response rate or PFS data under the accelerated approval program. For example, Pfizer Inc.’s Xalkori (crizotinib) received accelerated approval from FDA in 2011 for ALK+ NSCLC based on durable response data in a single arm trial.

Parameters For ORR Endpoint

Merck & Co. Inc. recently submitted a supplemental BLA for its PD-1 inhibitor Keytruda (pembrolizumab) for accelerated approval in NSCLC based on Phase I data showing strong objective response rates for a population that had higher PD-L1 expression compared to the general NSCLC population studied (45.2% vs. 19.4%). Researchers reported that responses were durable. Median survival in the PD-L1 selected population was 6.2 months and overall survival data is not ready yet. A companion diagnostic that would allow testing for PD-L1 expression has also been submitted for approval.

Keytruda has “breakthrough therapy” status for advanced NSCLC patients without EGFR and ALK mutations who progressed after platinum-based chemotherapy.

FDA’s latest guidance notes that the ORR endpoint has not been shown to “reliably predict corresponding effects on survival in NSCLC.” ORR alone is a “reasonably likely to predict clinical benefit only when the treatment effect size is large and the responses are durable,” the document states.

“In these circumstances, ORR has been used as the basis only for accelerated approval for NSCLC. In other circumstances, such as when clinical trials have shown that ORR correlated with well-documented improvements in patient tumor-related symptoms (e.g., photodynamic therapy for treatment of obstructing endobronchial therapy), ORR has supported regular approval,” the guidance states.

Merck has a Phase III randomized study in second-line NSCLC called KEYNOTE-010 that features co-primary endpoints of OS and PFS, which is projected to complete in November 2015, according to ClinicalTrials.gov.

Bristol-Myers Squibb Co.’s competing Opdivo (nivolumab) was recently approved for squamous cell NSCLC, regardless of PD-L1 expression, based on results from a single-arm, late-line therapy study as well as a randomized second-line trial demonstrating an overall survival benefit.

On April 17, the company announced the early termination of its Phase III CheckMate 057 study of non-squamous NSCLC, in which Opdivo already demonstrated an overall survival advantage compared to docetaxel chemotherapy. The company plans to get this data to FDA quickly (Also see "Bristol Says It’s Ready For PD-1 Competition In Lung Cancer" - Pink Sheet, 28 Apr, 2015.).

The leading sponsors of PD-1/L1 immunotherapy – Merck, Bristol, AstraZeneca PLCand Roche– use both PFS and OS as primary efficacy endpoints in Phase III NSCLC studies.

Looking at Bristol’s development program of Opdivo, for example, two out of three efficacy studies use OS as the primary endpoint, but a first-line trial in PD-L1+ patients (CheckMate 026) has PFS as the primary endpoint and OS in the secondary position.

In Roche’s development program of the PD-L1 inhibitor MPDL3280A, five out of six Phase III studies have PFS as a primary endpoint, with OS as a secondary endpoint.

“PFS is a standard endpoint in the first-line setting for medicines with selected patient populations. PFS can be useful in this setting because it is not impacted by the confounding effect of subsequent lines of therapy,” Dan Chen, cancer immunotherapy franchise head at Genentech Inc., commented.

According to FDA’s final guidance document, if PFS is the primary endpoint, the “magnitude of the treatment effect” takes into consideration a range of factors, including the drug’s toxicity, the short survival for NSCLC, available therapy and disease subtype.

“Because of the significance of these individual factors, a fixed magnitude of effect that generally will support approval cannot be specified,” the document states.