ODAC Weighs In on the Future of Perioperative Trial Designs in Resectable NSCLC

John V. Heymach, MD, PhD

Adjusting clinical trial designs to examine the benefit from phase of treatment will be a focus in the future, as data from the phase 3 AEGEAN trial (NCT03800134) have sparked conversations on where the efficacy of a perioperative regimen is coming from in patients with resectable non– small cell lung cancer (NSCLC). Findings from the trial did not clearly show whether the positive event-free survival (EFS) outcomes seen with neoadjuvant durvalumab (Imfinzi) plus chemotherapy followed by adjuvant durvalumab were a result of the PD-L1 inhibitor’s use in the neoadjuvant phase of therapy, adjuvant phase, or both.¹

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 11 to 0 that the FDA should require that new trial design proposals for perioperative regimens in resectable NSCLC include adequate within-trial assessment of contribution of treatment phase (Figure).¹

NSCLC, non–small cell lung cancer;

ODAC, Oncologic Drugs Advisory Committee.

“It’s important to note that the FDA’s question that was voted [on during the meeting] was specifically for future trials. They explicitly said this doesn’t apply to AEGEAN or current studies. There was a separate nonvoting question about whether additional studies were needed [regarding] AEGEAN, and the consensus of the panel was that additional studies were not needed,” John V. Heymach, MD, PhD, said in an interview with OncologyLive.

Following the ODAC meeting held on July 25, 2024, durvalumab received FDA approval in combination with platinum-containing chemotherapy as neoadjuvant treatment and then as single-agent adjuvant treatment for adult patients with resectable NSCLC with no known EGFR mutations or ALK rearrangements. The August 15, 2024, approval was based on findings from AEGEAN, and resectable disease was defined as tumors 4 cm or larger and/or node-positive disease.²

“For future studies, the concern is that over-treatment is a possibility,” Heymach added. "All patients may not require both the neoadjuvant phase and the adjuvant phase [of therapy], and [further] treatment may incur toxicity, additional inconvenience, and cost. It may not bring [patients] adequate benefit to justify that.”

Unpacking the First ODAC Discussion Question: AEGEAN Trial Data

The first of 2 discussion topics focused on the adequacy of efficacy and safety data from the AEGEAN trial, which supported the then-proproposed perioperative indication. In addition to concerns about the potential for overtreatment of patients with perioperative immune checkpoint inhibitor regimens, the FDA noted that AEGEAN was unable to determine whether the efficacy seen with durvalumab in patients with resectable NSCLC was a result of the agent’s administration in the neoadjuvant, adjuvant, or perioperative phases of treatment.³

“The best we can do is post hoc analyses or exploratory analyses that give us some hints [on efficacy],” Heymach said. “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.”

Findings from AEGEAN revealed that patients with previously untreated stage IIA to IIIB resectable NSCLC with no EGFR/ALK alterations achieved a median EFS that was not reached (NR; 95% CI, 31.9-NR) in the durvalumab plus chemotherapy arm (n=366) vs 25.9 months (95% CI, 18.9-NR) in the chemotherapy alone arm (n=374; HR, 0.68; 95% CI, 0.53-0.88; P=.0039).⁴

The FDA acknowledged that the trial met its primary end point with a statistically significant and clinically meaningful improvement in EFS seen, but the design of the trial did not allow for a within-trial assessment of the individual contributions of durvalumab in combination with chemotherapy in the neoadjuvant phase and durvalumab in the adjuvant phase.³

Additionally, there was not a statistically significant difference in disease-free survival, a key secondary end point at the first interim analysis, which was required to formally test overall survival (OS). However, a descriptive analysis showed that there was no clear detriment from treatment.³

“It’s important that the FDA specified that the 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 an OS [end point],” Marina Chiara Garassino, MD, said in the dual interview with OncologyLive. “For the FDA, the OS data were not enough to say that the perioperative trials were superior to the neoadjuvant only [phase 3 CheckMate 816 (NCT02998528) trial].”

A 4-year data update from CheckMate 816 presented at the 2024 American Society of Clinical Oncology Annual Meeting showed an OS benefit for patients with stage IB to IIIA resectable NSCLC and no EGFR/ALK alterations who received neoadjuvant nivolumab (Opdivo) plus chemotherapy vs chemotherapy alone. The median OS was NR in the nivolumab plus chemotherapy arm (n=179) vs NR in the chemotherapy arm (n=179; HR, 0.71; 98.36% CI, 0.47-1.07; P=.0451). Four-year OS rates were 71% vs 58%, respectively. Investigators noted that this reinforces the doublet as a standard of care for patients with resectable disease.⁵

“Findings from the CheckMate 816 trial with 358 patients [who received neoadjuvant therapy] showed a HR very similar to findings from 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],” Garassino said. “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].”

Voting Question: Adjusting Clinical Trial Criteria Has Several Implications

The ODAC vote, which centered on the need for adequate within-trial assessment of contribution of treatment phase in the design of new trial proposals for perioperative regimens in resectable NSCLC, also highlighted a few concerns regarding time taken to conduct trials.³

“The FDA raised concerns that they were going to make [the process of] trials much slower, which may not be beneficial, and they raised the possibility of novel designs or using other markers as potential end points, which is a wonderful suggestion,” Heymach said. “If we’re mandating that studies require understanding of the contribution of phase [of treatment] but we’re potentially accelerating research using biomarkers such as pathologic complete response, then it may not delay development so much. It may give us more information.”

He noted that perioperative studies may take 5 to 8 years to read data out and that pros and cons should be weighed when designing future trials. Although focusing on contribution of phase of therapy studies would help answer the question of whether certain phases are benefiting patients, Heymach suggested that newer regimens may then miss the opportunity for investigation.

“Given that at least 60% of this population [will experience] recurrence and that PD-1 inhibitors are generally well tolerated in the adjuvant setting, that makes this a cost/benefit question,” he noted. “Is the field better off investing resources in figuring out the optimum duration of a drug that’s relatively well tolerated or trying to move forward with new combinations that will increase cure rates?”

Garassino added that she agrees, noting that “taking advantage of liquid biopsy, radiomics, patients’ conditions, and many other things [is important so that] it’s possible that we [can] personalize the adjuvant component of therapy more in the future. I have been in Italy for most of my life, [and] I believe that it will be very difficult for European countries and socialized countries like Canada where there are full reimbursements to accept continuously adding clinical trials. These kinds of trials will help a lot, particularly [for] those countries where it is possible [that they won’t have access to perioperative regimens].”

Where Does Durvalumab Stand Based on This Approval and Discussion?

The only other currently FDA-approved perioperative regimen in resectable NSCLC is pembrolizumab (Keytruda) plus platinum-containing chemotherapy as neoadjuvant treatment followed by adjuvant single-agent pembrolizumab.⁶

Data from the pivotal phase 3 KEYNOTE-671 trial (NCT03425643), upon which the approval was based, revealed that at a median follow-up of 29.8 months (range, 0.4-62.0), the median OS was NR (95% CI, NR-NR) in the pembrolizumab arm (n = 397) vs 52.4 months (95% CI, 45.7-NR) in the chemo- therapy/placebo arm (n = 400; HR, 0.72; 95% CI, 0.56-0.93; 1-sided P = .00517). Median EFS was also improved with the pembrolizumab regimen vs chemotherapy alone arm, as the risk of disease recurrence, progression, or death was reduced by 41% (HR, 0.59; 95% CI, 0.48-0.72).⁷

“In the case of the AEGEAN and KEYNOTE-671 [regimens], at this point the KEYNOTE-671 [data] are a bit more mature, [showing improvement in both 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... Choice of multiple effective regimens is good, and as always, physicians and patients will review those data and select the regimen accordingly.”

References

1. FDA. July 25, 2024 meeting of the Oncologic Drugs Advisory Committee (ODAC). YouTube. Accessed August 19, 2024. bit.ly/4dRLWCb
2. FDA approves neoadjuvant/adjuvant durvalumab for resectable non-small cell lung cancer. FDA. August 15, 2024. Accessed August 15, 2024. bit.ly/3MbKzlT
3. Oncologic Drugs Advisory Committee (ODAC) Meeting: Combined FDA and Applicant ODAC Briefing Document. FDA. July 25, 2024. Accessed August 19, 2024. bit.ly/3ArzZVo
4. Imfinzi. Prescribing information. AstraZeneca; 2024. Accessed August 19, 2024. bit.ly/4cx8Ltu
5. Spicer JD, Girard N, Pulla MP, et al. Neoadjuvant nivolumab (NIVO)+chemotherapy (chemo) vs chemo in patients (pts) with resectable NSCLC: four-year update from CheckMate 816. J Clin Oncol. 2024;42(suppl 17):LBA8010. doi:10.1200/ JCO.2024.42.17_suppl.LBA8010
6. FDA approves neoadjuvant/adjuvant pembrolizumab for resectable non-small cell lung cancer. FDA. October 16, 2023. Accessed August 19, 2024. bit.ly/3YRPZtQ
7. European Commission approves Merck’s Keytruda (pembrolizumab) plus chemotherapy as neoadjuvant treatment, then continued as monotherapy as adjuvant treatment, for resectable non-small cell lung cancer (NSCLC) at high risk of recurrence in adults. News release. Merck. March 28, 2024. Accessed August 19, 2024. bit.ly/4cx9gnm