ODAC Votes to Require Within Trial Assessment of Neoadjuvant vs Adjuvant Treatment Benefit in Perioperative Trial Protocols in Resectable NSCLC

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 11 to 0 that the regulatory body should require adequate within trial assessment of contribution of treatment phase in new trial design proposals for perioperative regimens for resectable non–small cell lung cancer (NSCLC).¹ The vote was preceded by discussion of the following question:

Discussion Question: In light of the uncertainty around the need for both phases of treatment, discuss whether an additional trial should be conducted to clarify the contribution of treatment phase for the durvalumab perioperative regimen prior to approval.²

The question was discussed in the context of the supplemental new drug application (sBLA) submitted by AstraZeneca seeking the approval of durvalumab (Imfinzi) in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by adjuvant durvalumab, for the treatment of adult patients with resectable (tumors ≥ 4 cm and/or node positive) NSCLC and no known EGFR mutations or ALK rearrangements.²

“I voted yes,” Ravi Madan, MD, senior clinician and head of the Prostate Cancer Clinical Research Section in the Genitourinary Malignancies Branch, Center for Cancer Research at the National Cancer Institute in Bethesda, Maryland, said. “We struggle with this dilemma because of the success in the field over the past several years, and that’s a credit to industry, it’s a credit to the investigators, and it’s of great benefit to patients. But with that success now comes the complicated path about how to move forward. Things are going to be harder now because we have more therapies. This consideration is very important in that regard.”

“I voted yes, David Mitchell, acting consumer representative and president of Patients for Affordable Drugs in Bethesda, Maryland, said. “We need to know in a situation like this which phase of treatment is contributing what, and especially the thought of giving patients a year of adjuvant therapy, with the risks involved and the toxicities involved, continued treatment for that length of time, not knowing if it’s doing any good whatsoever, is not acceptable for patients. In the future, the FDA should be requiring that we have study designs that will answer the question so we’re making sure that we’re giving people treatments that are safe and effective, but also making sure that they’re needed, that they’re doing good, and that patients are not being subjected to a long period of treatment that isn’t necessarily helping them at all.”

A Quick Look at the AEGEAN Trial: Perioperative Durvalumab in Resectable NSCLC

The global, double-blind, placebo-controlled AEGEAN trial (NCT03800134) enrolled patients with treatment-naive, resectable stage IIA to IIIB (N2) NSCLC per American Joint Committee on Cancer (AJCC) 8th edition criteria with plans to undergo lobectomy, sleeve resection, or bilobectomy. In addition to an ECOG performance status of 0 or 1, patients had to have confirmed PD-L1 status and no documented EGFR or ALK aberrations.³

Between January 2, 2019, and April 19, 2022, 802 patients were randomly assigned 1:1 to neoadjuvant therapy consisting of 1500 mg of intravenous (IV) durvalumab plus platinum-based chemotherapy every 3 weeks for 4 cycles, or IV placebo plus platinum-based chemotherapy on the same schedule. After surgery, patients received an additional 12 cycles of durvalumab or placebo every 4 weeks, depending on randomization. Post-operative radiotherapy was permitted in accordance with local guidance.

Primary end points were pathologic complete response (pCR) by central laboratory per IASLC 2020 criteria and event-free survival (EFS) using blinded independent central review (BICR) per RECIST v1.1 criteria. Secondary end points included major pathologic response (MPR) by central laboratory per IASLC 2020 criteria, disease-free survival (DFS) using BICR per RECIST v1.1 criteria, and overall survival (OS).

Results indicated that the pCR rate with durvalumab (n = 366) was 17.2% (95% CI, 13.5%-21.5%) vs 4.3% (95% CI, 2.5%-6.9%) with placebo (n = 374), reflecting an absolute difference of 12.9% (95% CI, 8.7%-17.6%; P < .001). The MPR rates with durvalumab and placebo were 33.3% and 12.3%, respectively, reflecting an absolute difference of 21.0% (95% CI, 15.1%-26.9%; P < .001).

At a data cutoff of November 10, 2022, allowing for median follow-up of 11.7 months (range, 0.0-46.1) with 31.9% data maturity, the median EFS was not reached (NR; 95% CI, 31.9-NR) with durvalumab vs 25.9 months (95% CI, 18.9-NR) with placebo (stratified HR, 0.68; 95% CI, 0.53-0.88; P = .004). The 12- and 24-month EFS rates with durvalumab were 73.4% (95% CI, 67.9%-78.1%) and 63.3% (95% CI, 56.1%-69.6%), respectively, vs 64.5% (95% CI, 58.8%-69.6%) and 52.4% (95% CI, 45.4%-59.0%) with placebo.

During the FDA presentation, DFS and OS results were shared with a data cutoff of May 10, 2024. The results showed that DFS was not statistically significant with durvalumab vs placebo (HR, 0.66; 95% CI, 0.47-0.92), thereby prohibiting the formal testing of OS (HR, 0.89; 95% CI, 0.70-1.14).¹

Precedent for Perioperative Approval: Pembrolizumab in Resectable NSCLC

The only perioperative regimen to have received approval from the FDA is that of pembrolizumab (Keytruda), which received its indication for use in combination with platinum-containing chemotherapy as neoadjuvant treatment, and with continuation of single-agent pembrolizumab as adjuvant treatment for resectable (tumors ≥4 cm or node positive) NSCLC.⁴

The approval in the US and Europe was based on data from the phase 3 KEYNOTE-671 trial (NCT03425643), which enrolled 797 patients with previously untreated, resectable stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8th edition, randomly assigning them to neoadjuvant pembrolizumab (n = 397) or placebo (n = 400), with platinum-based chemotherapy, every 3 weeks for 4 cycles, followed by continued single-agent pembrolizumab or placebo in the adjuvant setting, every 3 weeks for up to 13 cycles.⁴

At a median follow-up of 29.8 months (range, 0.4-62.0) the pembrolizumab regimen produced a median OS that was not reached (NR; 95% CI, NR-NR) vs 52.4 months (95% CI, 45.7-NR) for those in the placebo arm (HR, 0.72; 95% CI, 0.56-0.93; 1-sided P = .00517). Additionally, the pembrolizumab regimen elicited a median EFS of 47.2 months (95% CI, 32.9-NR) vs 18.3 months (95% CI, 14.8-22.1) with the placebo regimen (HR, 0.59; 95% CI, 0.48-0.72).⁵

Further findings showed that those in the pembrolizumab arm experienced a significantly higher pCR than those in the placebo arm, at 18.1% vs 4.0%, respectively (P < .0001); this was also true in terms of MPR rate, at 30.2% vs 11.0%, respectively (P < .0001).⁴

FDA’s Position

During their overview the FDA cited several concerns regarding trials containing multi-phase regimens, which included the lack of understanding regarding the relative contribution of each treatment phase and the uncertainty around whether all patients require each phase of therapy despite EFS being an accepted end point to support approvals in early-stage resectable NSCLC.

The agency noted that on two occasions––November 2018 and May 2023––in an end of phase 2 meeting and pre-BLA meeting, respectively, they communicated that the proposed study design would not isolate the effect of neoadjuvant therapy and recommended an adaptive or factorial study design and requested a method to evaluate the contribution of durvalumab in the neoadjuvant and adjuvant settings to the overall treatment effect.

Although the FDA acknowledged that they have approved an entire regimen in the past they stated that emerging data suggests further consideration is warranted, noting their recommendation of 3- or 4-arm trial designs that isolate the contribution of neoadjuvant and/or adjuvant therapy. The agency also stated that such trials would require between 650 and 2400 patients, which would be comparable to completed perioperative and adjuvant trials with checkpoint inhibitors in NSCLC.

“It’s going to be more complicated when we move forward, because not only are there more therapies, but likely they’re not going to be as well tolerated as immune checkpoint inhibitors and the mortality issues are going to be higher than the 1% we talked about today,” Madan said. “I also think there are different ways to approach this. The only path isn’t a phase 3 trial with an extra two arms and extra 1500 patients. The other path is a more deliberate, preregistration approach, whether it’s preclinical, or phase 2 trials with rich correlatives that can better inform a phase 3, such that you move forward focused on either neoadjuvant or adjuvant [treatment] with a well-informed rationale. That’s something that we lost sight of a little bit in this conversation, but it’s another way to refocus on getting the answers that patients deserve when they embark on a therapy.”

Following their overview of the AEGEAN data during the meeting they noted that added uncertainty has been introduced by the read out of the phase 3 BR.31 trial (NCT02273375), which failed to show a statistically significant DFS benefit with adjuvant durvalumab vs placebo in patients with stage IB to IIIA, PD-L1–positive (≥25% positive staining on tumor cells) NSCLC following complete tumor resection.⁶

The FDA concluded that although a statistically significant and clinically meaningful improvement in EFS and no apparent detrimental effect on OS was seen the inability to evaluate the isolated benefit of the neoadjuvant and adjuvant phases of therapy is cause for concern. “We may potentially [be] exposing patients to unnecessary therapy with increased treatment burden and potential for long-term immune-related toxicities in a curative setting,” Erin Larkins, MD, acting director of the Division of Oncology 2 Office of Oncologic Diseases, said, also noting that 9% of patients were left with unresolved immune-related adverse effects after receiving adjuvant durvalumab in AEGEAN.¹

“I voted yes. From the discussion, I think we’d all agree it’s an important question that needs to be addressed. Understanding the challenges, future trials will be essentially trying to establish superiority and to some extent noninferiority, all within the same trial. But having said that, I think the point was made that having some information is infinitely better than no information at all, so I think the trials do need to collect the contribution of phase information,” Mark Conaway, PhD, a professor in the Division of Translational Research and Applied Statistics in the Department of Public Health Sciences at the University of Virginia School of Medicine in Charlottesville, concluded.

References

1. July 25, 2024, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. https://www.youtube.com/live/smUHtK5wdic
2. Oncologic Drugs Advisory Committee (ODAC) Meeting. Combined FDA and Applicants ODAC Briefing Document. Accessed July 25, 2024. https://www.fda.gov/media/180242/download
3. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative durvalumab for resectable non-small-cell lung cancer. N Engl J Med. 2023;389(18):1672-1684. doi:10.1056/NEJMoa2304875
4. FDA approves neoadjuvant/adjuvant pembrolizumab for resectable non-small cell lung cancer. FDA. October 16, 2023. Accessed July 25, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-adjuvant-pembrolizumab-resectable-non-small-cell-lung-cancer
5. 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 July 25, 2024. https://www.merck.com/news/european-commission-approves-mercks-keytruda-pembrolizumab-plus-chemotherapy-as-neoadjuvant-treatment-then-continued-as-monotherapy-as-adjuvant-treatment-for-resectable-non-small-ce/
6. Update on adjuvant BR.31 phase III trial of Imfinzi in non-small cell lung cancer. News release. AstraZeneca. June 25, 2024. Accessed July 25, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/update-on-imfinzi-adjuvant-br31-trial.html