A earlier model of this text appeared on OncLive®.
The FDA’s Oncologic Medication Advisory Committee (ODAC) has voted 11 to 0 that the regulatory physique ought to require enough inside trial evaluation of therapy part contribution in new trial design proposals for perioperative regimens for resectable non–small cell lung most cancers (NSCLC).1 The vote was preceded by dialogue of the next query:
Dialogue query: In mild of the uncertainty across the want for each phases of therapy, focus on whether or not an extra trial ought to be carried out to make clear the contribution of therapy part for the durvalumab perioperative routine previous to approval.2
The query was mentioned within the context of the supplemental new drug software (sBLA) submitted by AstraZeneca in search of the approval of durvalumab (Imfinzi) together with platinum-containing chemotherapy as neoadjuvant therapy, adopted by adjuvant durvalumab, for the therapy of grownup sufferers with resectable (tumors ≥ 4 cm and/or node optimistic) NSCLC and no identified EGFR mutations or ALK rearrangements.2
“I voted sure,” Ravi Madan, MD, senior clinician and head of the Prostate Most cancers Medical Analysis Part within the Genitourinary Malignancies Department, Middle for Most cancers Analysis on the Nationwide Most cancers Institute in Bethesda, Maryland, mentioned. “We wrestle with this dilemma due to the success within the subject over the previous a number of years, and that’s a credit score to business, it’s a credit score to the investigators, and it’s of nice profit to sufferers. However with that success now comes the sophisticated path about the best way to transfer ahead. Issues are going to be more durable now as a result of we now have extra therapies. This consideration is essential in that regard.”
“I voted sure,” David Mitchell, performing client consultant and president of Sufferers for Inexpensive Medication in Bethesda, Maryland, mentioned. “We have to know in a scenario like this which part of therapy is contributing what, and particularly the considered giving sufferers a yr of adjuvant remedy, with the dangers concerned and the toxicities concerned, continued therapy for that size of time, not understanding if it’s doing any good in anyway, isn’t acceptable for sufferers. Sooner or later, the FDA ought to be requiring that we now have examine designs that may reply the query so we’re ensuring that we’re giving folks remedies which are protected and efficient, but in addition ensuring that they’re wanted, that they’re doing good, and that sufferers usually are not being subjected to an extended interval of therapy that isn’t essentially serving to them in any respect.”
The worldwide, double-blind, placebo-controlled AEGEAN trial (NCT03800134) enrolled sufferers with treatment-naive, resectable stage IIA to IIIB (N2) NSCLC per American Joint Committee on Most cancers (AJCC) eighth version standards with plans to bear lobectomy, sleeve resection, or bilobectomy. Along with an Japanese Cooperative Oncology Group efficiency standing of 0 or 1, sufferers needed to have confirmed PD-L1 standing and no documented EGFR or ALK aberrations.3
Between January 2, 2019, and April 19, 2022, 802 sufferers had been randomly assigned 1:1 to neoadjuvant remedy consisting of 1500 mg of intravenous (IV) durvalumab plus platinum-based chemotherapy each 3 weeks for 4 cycles or IV placebo plus platinum-based chemotherapy on the identical schedule. After surgical procedure, sufferers acquired an extra 12 cycles of durvalumab or placebo each 4 weeks, relying on randomization. Postoperative radiotherapy was permitted in accordance with native steerage.
Main finish factors had been pathologic full response (pCR) by central laboratory per IASLC 2020 standards and event-free survival (EFS) utilizing blinded unbiased central evaluate (BICR) per RECIST v1.1 standards. Secondary finish factors included main pathologic response (MPR) by central laboratory per IASLC 2020 standards, disease-free survival (DFS) utilizing BICR per RECIST v1.1 standards, and general survival (OS).
Outcomes indicated that the pCR price 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). The MPR charges with durvalumab and placebo had been 33.3% and 12.3%, respectively.
At an information cutoff of November 10, 2022, permitting for median follow-up of 11.7 months (vary, 0.0-46.1) with 31.9% information 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 charges with durvalumab had been 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.
Through the FDA presentation, DFS and OS outcomes had been shared with an information cutoff of Might 10, 2024. The outcomes confirmed that DFS was not statistically vital 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 one perioperative routine to have acquired approval from the FDA is that of pembrolizumab (Keytruda; Merck), which acquired its indication to be used together with platinum-containing chemotherapy as neoadjuvant therapy, and with continuation of single-agent pembrolizumab as adjuvant therapy for resectable (tumors ≥4 cm or node optimistic) NSCLC.4
The approval within the US and Europe was based mostly on information from the part 3 KEYNOTE-671 trial (NCT03425643), which enrolled 797 sufferers with beforehand untreated, resectable stage II, IIIA, or IIIB (N2) NSCLC by AJCC eighth version, randomly assigning them to neoadjuvant pembrolizumab (n = 397) or placebo (n = 400), with platinum-based chemotherapy, each 3 weeks for 4 cycles, adopted by continued single-agent pembrolizumab or placebo within the adjuvant setting, each 3 weeks for as much as 13 cycles.4
At a median follow-up of 29.8 months (vary, 0.4-62.0), the pembrolizumab routine produced a median OS that was not reached (95% CI, NR-NR) vs 52.4 months (95% CI, 45.7-NR) for these within the placebo arm (HR, 0.72; 95% CI, 0.56-0.93; 1-sided P = .00517). Moreover, the pembrolizumab routine 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 routine (HR, 0.59; 95% CI, 0.48-0.72).5
Additional findings confirmed that these within the pembrolizumab arm skilled a considerably increased pCR than these within the placebo arm, at 18.1% vs 4.0% (P < .0001); this was additionally true when it comes to MPR price, at 30.2% vs 11.0% (P < .0001).4
The ODAC voted 11 to 0 for the FDA to require enough inside trial evaluation of therapy part contribution in new trial design proposals for perioperative regimens for resectable NSCLC | Picture Credit score: wladimir1804-stock.adobe.com
The FDA’s Place
Throughout its overview, the FDA cited a number of issues relating to trials containing multiphase regimens, which included the lack of information relating to the relative contribution of every therapy part and the uncertainty round whether or not all sufferers require every part of remedy regardless of EFS being an accepted finish level to assist approvals in early-stage resectable NSCLC.
The company famous that on 2 events––November 2018 and Might 2023––in an end-of-phase 2 assembly and pre-BLA assembly, respectively, they communicated that the proposed examine design wouldn’t isolate the impact of neoadjuvant remedy and advisable an adaptive or factorial examine design and requested a way to judge the contribution of durvalumab within the neoadjuvant and adjuvant settings to the general therapy impact.
Though the FDA acknowledged that it has accepted a complete routine up to now, it said that rising information recommend additional consideration is warranted, noting their advice of 3- or 4-arm trial designs that isolate the contribution of neoadjuvant and/or adjuvant remedy. The company additionally said that such trials would require between 650 and 2400 sufferers, which might on par with accomplished perioperative and adjuvant trials with checkpoint inhibitors in NSCLC.
“It’s going to be extra sophisticated once we transfer ahead, as a result of not solely are there extra therapies, however probably they’re not going to be as nicely tolerated as immune checkpoint inhibitors and the mortality points are going to be increased than the 1% we talked about at this time,” Madan mentioned. “I additionally assume there are other ways to strategy this. The one path isn’t a part 3 trial with an additional 2 arms and additional 1500 sufferers. The opposite path is a extra deliberate, preregistration strategy, whether or not it’s preclinical, or part 2 trials with wealthy correlatives that may higher inform a part 3, such that you just transfer ahead targeted on both neoadjuvant or adjuvant [treatment] with a well-informed rationale. That’s one thing that we overlooked just a little bit on this dialog, however it’s one other option to refocus on getting the solutions that sufferers deserve once they embark on a remedy.”
Following their overview of the AEGEAN information in the course of the assembly, they famous that added uncertainty has been launched by the learn out of the part 3 BR.31 trial (NCT02273375), which did not present a statistically vital DFS profit with adjuvant durvalumab vs placebo in sufferers with stage IB to IIIA, PD-L1–optimistic (≥25% optimistic staining on tumor cells) NSCLC following full tumor resection.6
The FDA concluded that though a statistically vital and clinically significant enchancment in EFS and no obvious detrimental impact on OS was seen, the shortcoming to judge the remoted advantage of the neoadjuvant and adjuvant phases of remedy is trigger for concern.
“We could probably [be] exposing sufferers to pointless remedy with elevated therapy burden and potential for long-term immune-related toxicities in a healing setting,” Erin Larkins, MD, performing director of the Division of Oncology II, Workplace of Oncologic Illnesses, mentioned, additionally noting that 9% of sufferers had been left with unresolved immune-related adversarial results after receiving adjuvant durvalumab in AEGEAN.1
“I voted sure. From the dialogue, I feel we’d all agree it’s an necessary query that must be addressed. Understanding the challenges, future trials can be basically attempting to determine superiority and to some extent noninferiority, all throughout the identical trial. However having mentioned that, I feel the purpose was made that having some data is infinitely higher than no data in any respect, so I feel the trials do want to gather the contribution of part data,” Mark Conaway, PhD, a professor within the Division of Translational Analysis and Utilized Statistics within the Division of Public Well being Sciences on the College of Virginia College of Medication in Charlottesville, concluded.
References
1. July 25, 2024, Assembly of the Oncologic Medication Advisory Committee (ODAC). FDA. https://www.youtube.com/dwell/smUHtK5wdic
2. Oncologic Medication Advisory Committee (ODAC) Assembly. Mixed FDA and Candidates ODAC Briefing Doc. Accessed July 25, 2024. https://www.fda.gov/media/180242/obtain
3. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative durvalumab for resectable non-small-cell lung most cancers. 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 most cancers. Information launch. FDA. October 16, 2023. Accessed July 25, 2024. https://www.fda.gov/medicine/resources-information-approved-drugs/fda-approves-neoadjuvant-adjuvant-pembrolizumab-resectable-non-small-cell-lung-cancer
5. European Fee approves Merck’s Keytruda (pembrolizumab) plus chemotherapy as neoadjuvant therapy, then continued as monotherapy as adjuvant therapy, for resectable non-small cell lung most cancers (NSCLC) at excessive danger of recurrence in adults. Information launch. Merck. March 28, 2024. Accessed July 25, 2024. https://www.merck.com/information/european-commission-approves-mercks-keytruda-pembrolizumab-plus-chemotherapy-as-neoadjuvant-treatment-then-continued-as-monotherapy-as-adjuvant-treatment-for-resectable-non-small-ce/
6. Replace on adjuvant BR.31 part III trial of Imfinzi in non-small cell lung most cancers. Information launch. AstraZeneca. June 25, 2024. Accessed July 25, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/update-on-imfinzi-adjuvant-br31-trial.html
