ODAC Votes in Favor of Continued Development of Dostarlimab for dMMR/MSI-H Locally Advanced Rectal Cancer

In an 8 to 5 vote, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted that data from two proposed single-arm trials will provide adequate means of characterizing the risk-benefit profile of dostarlimab-gxly (Jemperli) for the treatment of patients with mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) locally advanced rectal cancer.¹

“I voted yes,” Christopher Lieu, MD, co-director, GI Medical Oncology Program and associate director for clinical research, at the University of Colorado Cancer Center, said.

“In this setting, I don’t think a randomized study is feasible, given the existing data and patients’ overall goals and expectations. I do have some concerns about the use of complete clinical response at 12 months as the definitive end point mainly because I don’t think that there’s a clear correlation [there], although there’s a suggestion that there’s a correlation between complete clinical response and disease-free survival and distant metastasis. The end point of event-free survival [EFS] at 3 years, which is the secondary end point of the study, will be critically important to show that correlation. But overall, I believe the study as designed will provide the data needed for accelerated approval.”

"I voted yes," Kristen Ciombor, MD, MSCI, associate professor of medicine, Division of Hematology/Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, said. "While the proposed studies certainly won't answer all of our questions about the optimal use of immunotherapy in MSI-H locally advanced rectal cancer, I think they'll provide additional data to determine whether the initial pilot results are generalizable, given the multi-institutional, multi-national nature of the proposed studies, the longer follow-up, and increased sample size."

Dostarlimab is a PD-1 monoclonal antibody that received accelerated approval for the treatment of patients with dMMR recurrent or advanced solid tumors and dMMR recurrent or advanced endometrial cancer.^2,3

During the meeting, the committee discussed whether data from the proposed single-arm trials enrolling a total of 130 patients are sufficient to characterize the benefits and risks of dostarlimab in the curative-intent setting for patients with dMMR/MSI-H locally advanced rectal cancer.¹ Four topics served as the basis for discussion:

1. Adequacy of proposed single-arm trials to evaluate the efficacy and safety of dostarlimab, including the long-term benefits and risks of treatment
2. Adequacy of the proposed clinical end points (clinical complete response [cCR] rate, EFS) to characterize and verify the benefit of dostarlimab
3. Study population with stage II/III dMMR/MSI-H rectal cancer for a nonoperative management approach
4. Potential impact of the variability in care, expertise, etc., across multidisciplinary study staff and across study sites on study conduct and ultimately on outcomes

The two established standards of care for locally advanced rectal cancer, regardless of dMMR/MSI-H status, are neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy, and chemoradiation and neoadjuvant chemotherapy up front (TNT) followed by surgery. However, approximately 1/3 of these patients will die of distant metastases, and up to 30% of patients will require permanent colostomy following total mesorectal excision, a procedure that is associated with social and physiological dysfunction, depression, and stoma complications. Additionally, data indicate that most patients with locally advanced rectal cancer are not candidates for nonoperative management and those with dMMR/MSI-H disease have reduced sensitivity to chemotherapy.

“We need a more efficacious treatment for this biomarker-selected population with reduced morbidities and the potential for organ preservation with nonoperative management,” Andrea Cercek, MD, head of the colorectal cancer section and co-director of the Center for Young Onset Colorectal and GI Cancers at Memorial Sloan Kettering Cancer Center in New York, New York, said.

Prior findings from the phase 2 OPRA trial (NCT02008656) showed that the 3-year total mesorectal excision–free survival rate was 53% (95% CI, 45%-62%) in patients with stage II/III rectal adenocarcinoma who received induction chemotherapy followed by chemoradiotherapy compared with 41% (95% CI, 33%-50%) of patients who received chemoradiotherapy followed by consolidation chemotherapy and either total mesorectal excision or watch-and-wait on the basis of tumor response. Additionally, data suggested no detriment in disease-free survival (DFS) with TNT,⁴ as well as a positive correlation between cCR and DFS; however, the surrogacy between cCR, DFS and OS outcomes has not been definitively shown.⁵

More recently, findings from a phase 2 trial (NCT04165772) demonstrated that dostarlimab led to a 100% cCR rate with no evidence of residual tumor among 14 patients with stage II/III dMMR locally advanced rectal cancer.^6,7 Most patients had T3/T4 disease (78%) and positive nodes (94%), said Cercek, which is “representative of the locally advanced dMMR/MSI-H rectal cancer population.”

Patients enrolled on the trial received 500 mg of dostarlimab intravenously every 3 weeks for 6 months. If patients achieved cCR they entered a nonoperative follow-up window and underwent evaluation every 4 months. Patients with residual disease would proceed to chemoradiation until cCR was observed. If cCR was not achieved patients would undergo surgery.

To date all patients have completed the full 6 months of therapy, Cercek said. Additionally, no patients have required chemotherapy, radiation, or surgery. Moreover, all adverse effects were grade 1 or 2, and the safety profile was in line with that of other checkpoint inhibitors.

The data, which were presented at the 2022 ASCO Annual Meeting and simultaneously published in the New England Journal of Medicine with a median follow-up of only 6.8 months (range, 0.7-23.8), generated “enthusiasm and caution in equal measure,” Lola Fashoyin-Aje, MD, MPH, deputy director in the Division of Oncology III/Office of Oncologic Disease, FDA, said.¹

“Evidence for nonoperative management [is limited], there’s major risk for non-salvageable local regrowth or metastases, and [we’re] uncertain of long-term outcomes,” Sandra J. Casak, MD, Division of Oncology 3/Office of Oncologic Disease, FDA, added. ODAC members added, “We’re heaping uncertainty onto uncertainty…This is a curable population, so the bar needs to be high.”

Mark Conaway, PhD, professor and director of Translational Research, Division of Translational Research and Applied Statistics, Department of Public Health Sciences at the University of Virginia echoed similar concerns. “Despite the extraordinary promise of the agent and concerns about the feasibility of doing a randomized trial, I voted no, because of the difficulty in interpreting results of noncomparative trials and the uncertainty around the long-term applicability of the end point.”

Ivan Diaz-Padilla, MD, PhD, vice president and clinical development head of Immuno-Oncology at GSK, stated that in the absence of a randomized, phase 3 trial against the current SOC, which would likely be “unfeasible” given the high cCR rate with dostarlimab demonstrated to date, the company will pool updated results from the MSK trial with those from the planned Study 219369 prior to its supplemental biologics license application submission.

The primary end point of the multi-site, single-arm, pivotal, phase 2 study, which will begin enrolling in April 2023, will be the proportion of patients who maintain cCR for 12 months after 6 months of dostarlimab treatment via independent central review. Secondary end points include cCR at 36 months and 3-year EFS.

To account for the potential effects of inter-site variability on outcomes, GSK will employ protocol standardization and training and enable consensus evaluation of cCR with a multidisciplinary approach. During the discussion, ODAC member Jorge Nieva, MD, section head of solid tumors at the University of Southern California Norris Comprehensive Cancer Center, emphasized “safeguards have to be put in place to prevent biases.”

To be eligible for enrollment, patients must be at least 18 years of age with histologically confirmed, stage II or III (T3-T4, N0 or T any, N+), dMMR/MSI-H rectal cancer via local or central testing. Evidence of metastatic or recurrent disease will preclude enrollment. Notably, patients who do not achieve cCR after dostarlimab will still be eligible to receive SOC therapy, Cercek said.

References

1. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. February 9, 2023. Accessed February 9, 2023. https://www.youtube.com/watch?v=-iHseGn2LhQ
2. FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. FDA. Updated February 1, 2022. Accessed February 9, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dostarlimab-gxly-dmmr-advanced-solid-tumors
3. FDA grants regular approval to dostarlimab-gxly for dMMR endometrial cancer. News release. FDA. February 9, 2023. Accessed February 9, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
4. Aguilar JC, Patil S, Gollub MJ, et al. Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy. J Clin Oncol. 2022;40(23):2546-2556. doi:10.1200/JCO.22.00032
5. Thompson H, Kim JK, Yuval JB, et al. Survival and organ preservation according to clinical response after total neoadjuvant therapy in locally advanced rectal cancer patients: A secondary analysis from the organ preservation in rectal adenocarcinoma (OPRA) trial. J Clin Oncol. 2021;39(15):3509. doi:10.1200/JCO.2021.39.15_suppl.3509
6. Cercek A, Lumish MA, Sinopoli JC, et al. Single agent PD-1 blockade as curative-intent treatment in mismatch repair deficient locally advanced rectal cancer. J Clin Oncol. 2022;40(suppl 17):LBA5. doi:10.1200/JCO.2022.40.17_suppl.LBA5
7. Cercek A, Lumish MA, Sinopoli JC, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. Published online June 5, 2022. doi:10.1056/NEJMoa2201445