NBCC has made Food and Drug Administration (FDA) reform a priority, which you can read about here. NBCC believes it is important to educate our members about how the FDA works and where NBCC advocates can play a role. Here, we focus on a recent meeting of the FDA Oncologic Drugs Advisory Committee (ODAC). ODAC is an external advisory committee charged to review and evaluate data concerning the safety and effectiveness of marketed and investigational human drug products for use in the treatment of cancer and make recommendations to the Commissioner of Food and Drugs.1 ODAC meetings are open to the public and are an important way for NBCC advocates to make their voices heard.
The FDA made an atypical move in the most recent ODAC meeting on February 9th, 2023.2 The purpose of this meeting was to discuss an investigational new drug application (IND), for dostarlimab (Jemperli; a PD-1 immune checkpoint inhibitor) for the treatment of patients with a certain type of locally advanced, treatment-naïve rectal cancer. While not breast cancer related, the implications of this meeting are noteworthy and of importance to NBCC.
Why was this ODAC meeting notable?
Instead of being asked to assess the merits of data from a clinical trial of a new cancer treatment, ODAC was asked to consider the adequacy of a proposed trial design that would later be used to evaluate efficacy of the drug in approval for a type of rectal cancer. Currently, the drug is only approved in the advanced/metastatic setting for endometrial cancer.
Why is the trial design so controversial?
First, the proposed trials (one of which is already underway) are single-arm trials (not randomized controlled trials), meaning there is no meaningful control group to compare the drug to. Second, the current standard of care (SOC) for this type of rectal cancer (i.e., chemotherapy, radiation, and surgery) is curative, meaning these patients can be cured with the current SOC. Third, the proposed primary endpoint is complete clinical response rate (cCR) at 12 months, which arguably means very little in terms of actual benefit to the patient over the long term. Fourth, the two trials combined only seek to enroll a total of 130 patients, and previously-published preliminary data are available for only 12 patients.3
With all of the aforementioned limitations in the trial designs, why is the FDA even considering this request?
First, the specific type of rectal cancer being addressed is rare, meaning that recruiting higher numbers of patients is difficult. Second, preliminary data showed that 100% of the 12 patients receiving the experimental drug have achieved complete clinical response, and none of the 12 have needed surgery or chemoradiotherapy to date. These preliminary results are certainly impressive.3 Third, the current SOC for this form of rectal cancer causes significant, long-term quality-of-life issues, including infertility, decreased sexual function, and decreased bowel function. Because the SOC causes these severe side effects, investigators believe patients would be hesitant to join a trial where they could be randomized into the SOC arm instead of the experimental arm which doesn’t require surgery and the associated quality of life issues. Fourth, while the primary endpoint (cCR) is not very meaningful in terms of long-term benefit to the patient, one of the proposed studies plans to analyze event-free survival (EFS) at 3 years and overall survival (OS) at 5 years.
What did ODAC ultimately decide?
After over 6 hours of discussion, ODAC voted 8-5 in support of the proposed trial design. Supporters acknowledged their concerns, but ultimately voted yes because they believe a randomized trial is not feasible in this specific scenario and they believe the data will be sufficient assuming that the proposed trials continue to show substantial clinical response rates. Those who voted no acknowledged the drug’s promise but said the flaws in the design and suboptimal primary endpoints have major consequences for data interpretation and long-term applicability. Ultimately, the final decision is up to the FDA.
NBCC applauds FDA for bringing this question to ODAC and pursuing transparency and a high bar for clinical trial designs. However, if FDA chooses to accept this design, it will set a dangerous precedent that lowers the bar for FDA approval in future trials in the curative setting. While this particular ODAC meeting did not deal with a breast cancer drug, both the unprecedented nature of the meeting and FDA’s ultimate decision will mold the future of the drug approval process, including the potential for breast cancer drugs to be approved on the basis of weakly-designed, nonrandomized clinical trials. Patients should be able to make decisions based on meaningful outcomes from robustly-designed and conducted clinical trials. Without an appropriate control arm, it is not possible to generate the type of evidence required to support informed decision-making.
Do Breast Cancer Patients Always Need Radiotherapy?
We all want to see less toxic treatment. Less treatment overall, with the same outcome, is an important goal. New research suggests irradiation/radiotherapy can be safely omitted in certain breast cancer patients.
The PRIME II trial is a phase 3, randomized clinical trial that is investigating if radiotherapy can be omitted in node-negative breast cancer patients who are older than 65 years of age with small (≤3 cm in the largest dimension), HR-positive tumors that have been treated with breast-conserving surgery (with clear excision margins) and endocrine therapy. Ten-year outcomes were recently reported in the New England Journal of Medicine.4
The key takeaway from this study is that in these older, low-risk, HR-positive breast cancer patients, the omission of radiotherapy results in no differences in overall survival. While there was an increased incidence of local recurrence (9.5% versus 0.9%) among those not receiving radiation, there were no differences noted between the two groups for distant (metastatic) recurrence (1.6% versus 3.0%), regional recurrence (data not shown), contralateral breast cancer (data not shown), overall survival (80.8% versus 80.7%), or breast cancer-specific survival (97.4% versus 97.9%). In this specific cohort of breast cancer patients, the PRIME II trial suggests that omitting radiation is a safe way to de-escalate treatment without jeopardizing survival.
FDA Approval of Trodelvy in Hormone Receptor Positive Breast Cancer
The FDA recently approved sacituzumab govitecan-hziy (Trodelvy) for unresectable, locally advanced or metastatic HR+ HER2- breast cancers that had previously received endocrine therapy and 2+ systemic therapies in the metastatic setting. Trodelvy was investigated in the TROPiCS-02 trial, where it improved both progression-free survival (5.5 versus 4 months) and overall survival (14.4 versus 11.2 months).5 NBCC has previously written about Trodelvy here. While NBCC applauds trials that show an overall survival benefit, we must ask, is the scope of the benefit worth the scope of the physical and financial toxicities?
(1) Research, C. for D. E. and. Oncologic Drugs Advisory Committee. FDA. https://www.fda.gov/advisory-committees/human-drug-advisory-committees/oncologic-drugs-advisory-committee (accessed 2023-02-10).
(2) FDA. UPDATED INFORMATION: February 9, 2023: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement – 02/09/2023. FDA. https://www.fda.gov/advisory-committees/advisory-committee-calendar/updated-information-february-9-2023-meeting-oncologic-drugs-advisory-committee-meeting-announcement (accessed 2023-02-10).
(3) Cercek, A.; Lumish, M.; Sinopoli, J.; Weiss, J.; Shia, J.; Lamendola-Essel, M.; El Dika, I. H.; Segal, N.; Shcherba, M.; Sugarman, R.; Stadler, Z.; Yaeger, R.; Smith, J. J.; Rousseau, B.; Argiles, G.; Patel, M.; Desai, A.; Saltz, L. B.; Widmar, M.; Iyer, K.; Zhang, J.; Gianino, N.; Crane, C.; Romesser, P. B.; Pappou, E. P.; Paty, P.; Garcia-Aguilar, J.; Gonen, M.; Gollub, M.; Weiser, M. R.; Schalper, K. A.; Diaz, L. A. PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer. N. Engl. J. Med. 2022, 386 (25), 2363–2376. https://doi.org/10.1056/NEJMoa2201445.
(4) Kunkler, I. H.; Williams, L. J.; Jack, W. J. L.; Cameron, D. A.; Dixon, J. M. Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer. N. Engl. J. Med. 2023, 388 (7), 585–594. https://doi.org/10.1056/NEJMoa2207586.
(5) U.S. Food and Drug Administration (FDA). FDA Approves Sacituzumab Govitecan-Hziy for HR-Positive Breast Cancer. FDA 2023.