Future Perioperative Trial Designs in NSCLC Need Adjustments Per FDA ODAC Consensus

John V. Heymach, MD, PhD

After the July 25, 2024, FDA Oncologic Drugs Advisory Committee (ODAC) meeting where the efficacy of neoadjuvant durvalumab (Imfinzi) plus chemotherapy followed by adjuvant durvalumab was discussed in terms of benefit from phase of treatment, the durvalumab regimen received FDA approval for the treatment of patients with resectable non–small cell lung cancer (NSCLC).^1,2

During the ODAC meeting, one discussion question focused on data from the phase 3 AEGEAN trial (NCT03800134) examining the durvalumab regimen, whereas the other concerned clinical trial design to determine benefit from phase of treatment. ODAC voted 11 to 0 that the FDA should require adequate within trial assessment of contribution of treatment phase in new trial design proposals for perioperative regimens in resectable NSCLC.¹

“For future studies, the concern is that over treatment is a possibility. All patients may not require both the neoadjuvant phase and the adjuvant phase [of therapy], and [further] treatment may incur toxicity for patients, additional inconvenience, and cost. [Perioperative therapy] may not bring [patients] adequate benefit to justify that,” John V. Heymach, MD, PhD, said in an interview with OncLive^®.

In the interview, Heymach and Marina Chiara Garassino, MD, professor of medicine and leader of the thoracic program at UChicago Medicine in Illinois, discussed key takeaways from the ODAC meeting and data from AEGEAN. Heymach is the chair of and a professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. He is also the David Bruton, Jr Chair in Cancer Research and a professor in the Department of Cancer Biology.

OncLive: What is key to note about the ODAC decision that the FDA should require adequate within trial assessment of contribution of treatment phase in new trial design proposals for perioperative regimens in resectable NSCLC?

Heymach: It’s important to note that the FDA’s question that was voted [on] was specifically for future trials. They explicitly said this doesn’t apply to AEGEAN or current studies. There was a separate non-voting question about whether additional studies were needed [regarding] AEGEAN, and the consensus of the panel was that additional studies were not needed.

Garassino: The discussion was about the fact that the phase 3 CheckMate 816 trial [NCT02998528] with 358 patients [who received neoadjuvant therapy] showed a HR ratio very similar to [that seen in] a perioperative trial accounting for [a large amount of] patients. We all would like to know if the adjuvant component [of treatment] is helping patients, or if we can select patients for an adjuvant part [of therapy]. Trials in the perioperative settings didn’t answer this question, and now we are at an impasse of having a short regimen that showed very similar results to a longer [regimen].

In the future it will be important to not just work [around the] one size fits all [approach to therapies], but to understand what we can do with more biomarkers and [other factors] to better tailor [treatments]. It is important to address these things in trials.

What position did the FDA take regarding the data from the AEGEAN trial?

Heymach: The FDA acknowledged the efficacy of the AEGEAN regimen. [The trial evaluating] the AEGEAN regimen had 2 primary end points, pathologic complete response [pCR] and event-free survival [EFS], and it hit both end points with clinically meaningful improvements in EFS seen, which [the FDA] acknowledged is an accepted marker for adjuvant studies. There was no debate around whether the regimen was effective.

They also noted that given the design of AEGEAN, just like the design of the phase 3 KEYNOTE-671 [NCT03425643] or CheckMate-77T [NCT04025879] studies, it’s not possible to separate the relative contributions of neoadjuvant therapy from adjuvant therapy. None of those studies can separate the relative contributions [of each treatment phase]. The best we can do is [examine] post hoc analyses or exploratory analyses that give us some hints [on efficacy]. Post hoc analyses suggest that there is benefit from the adjuvant phase but that’s not the same as a study designed specifically to address that question.

Garassino: It’s also important to add that the FDA specified that the overall survival [OS] data were not enough to decide that there was a contribution of phase [of treatment]. I believe that OS is the most important end point in these trials, and only 1 trial for the time being reached the OS [end point]. But it’s important to underline that for the FDA, the OS data were not enough to say that the perioperative trials were superior to the neoadjuvant only [CheckMate 816 trial].

The AEGEAN regimen, which was granted FDA approval after the ODAC meeting, has joined the KEYNOTE-671 regimen as an approved option in this patient population. How will thoughts around those regimens be perceived given this decision by ODAC?

Heymach: Like [with] all our therapies we will have to consider the relative benefits, toxicity, and overall data set in deciding what’s going to be the most appropriate regimen for patients and make our recommendations accordingly. For example, in the metastatic setting, we have at least 10 different approved first-line regimens. But that’s a benefit for patients and providers, because it gives us a lot of different choices that we can tailor, and over time, we learn more about the regimen. Things that were not obvious when the studies were initially done [such as] which regimen might be better for [patients with] brain metastases, squamous [disease], or genomic alterations like STK11 or KEAP1 become clearer over time, and we can take that into account.

In the case of the AEGEAN and KEYNOTE-671 [regimens], at this point the KEYNOTE-671 [data] are a bit more mature [showing both an improvement in EFS and OS], which is wonderful that we have a regimen that has done that for patients. [However,] we also have a lot of experience [using] the phase 3 PACIFIC trial [NCT02125461] regimen with 1 year of adjuvant durvalumab—that’s also something that we have developed a significant degree of comfort with. Keep in mind, for the AEGEAN trial, approximately 70% of patients had stage III disease, which is a population that overlaps with the population from PACIFIC.

Choice of multiple effective regimens is good, and as always physicians and patients will review the data and select the regimen accordingly.

Garassino: I agree, and we have also data for carboplatin and cisplatin. In the KEYNOTE-671 [study,] patients were randomly assigned to receive only cisplatin. We have, for the first time, data on carboplatin [from AEGEAN]. It’s interesting that the trials have a similar HR for EFS [as well suggesting] that [in that respect] they are more or less the same.

References

1. FDA approves neoadjuvant/adjuvant durvalumab for resectable non-small cell lung cancer. FDA. August 15, 2024. Accessed August 15, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvantadjuvant-durvalumab-resectable-non-small-cell-lung-cancer
2. Oncologic Drugs Advisory Committee (ODAC) Meeting. Combined FDA and applicant ODAC briefing document. Accessed August 19, 2024. https://www.fda.gov/media/180242/download