FDA's ODAC Supports Proposed Trials for Dostarlimab in dMMR/MSI-H Locally-Advanced Rectal Cancers

The FDA’s Oncologic Drugs Advisory Committee voted 8 to 5 in favor of the development of dostarlimab (Jemperli) for the treatment of human patients with locally advanced, treatment-naïve mismatch-repair deficient (dMMR) or microsatellite-instability-high (MSI-H) rectal cancer.¹

"Patients with dMMR/MSI-H have dramatic response to immunotherapy. There is great promise for immunotherapy in this population, including for the potential to avoid the need for surgery. A study that treats dMMR/MSI-H rectal cancer patients with neoadjuvant immunotherapy would be very attractive, said George J. Chang, MD, MS, FACS, FASCRS, FSSO, Department chair ad interim, Department of Colon and Rectal Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, professor, Department of Colon and Rectal Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, and Associate Vice President, Regional Surgery Strategy, The University of Texas MD Anderson Cancer Center, told Targeted Oncology^TM.

The investigational new drug (IND) application for dostarlimab was brought to the ODAC for discussion around the adequacy of the proposed indication, as well as the adequacy the proposed data package, which will provide a benefit/risk assessment of dostarlimab. Based on this discussion, ODAC was tasked with voting on whether the data from the proposed single-arm trial enrolling 130 patients will be sufficient enough to characterize the benefits and risk of treating dMMR/MSI-H locally advanced rectal cancer (LARC) with dostarlimab.

Discussion followed an explanation of the rectal cancer incidence, the available treatment options from the FDA, as well as the design of the planned study from GlaxoSmithKline, LLC (GSK). Currently, there are approximately 46,050 cases of LARC each year in the United States. Only 2.7%-21% of the LARC cases diagnosed fall under the dMMR/MSI-H subgroup, according to Lola Fashoyin-Aje, MD, MPH.

Before surgery, patients with LARC normally receive chemoradiation or short course radiation with or without neoadjuvant chemotherapy. Then, most patients receive adjuvant chemotherapy. Fashoyin-Aje, a deputy director, Division of Oncology Products 4, Office of Oncologic Diseases, Office of New Drugs, Center for Drug Evaluation and Research, FDA, noted that although standard-of-care (SOC) is effective, the safety is an area of concern.

According to Fashoyin-Aje, these efficacy and safety outcomes of chemoradiation and chemotherapy are the reason for the exploration of new therapies like dostarlimab.

“Interest in a surgery sparing or non-operative management approach has been the subject of ongoing investigation. This approach requires careful monitoring or watchful waiting of patients who have a clinical response to chemotherapy, radiation, or chemoradiation. However, use of a non-operative management strategy is variably implemented largely based on institutional experience and expertise. Due to the limitations of the historical data, that informs current use of this approach,” said Fashoyin-Aje during the FDA’s ODAC presentation “Variability exists with respect to patient selection treatment administered prior to the period of watchful waiting, and in the clinical assessment methods used to determine clinical response.”

Rationale

Dostarlimab is already approved for the treatment of dMMR recurrent or advanced solid tumors, based on results from the phase 1 GARNET study (NCT02715284).^2,3 As previously reported by Targeted Oncology™, treatment with dostarlimab in the GARNET study showed durable activity in 16 different tumor types.⁴

The third interim analysis of GARNET included 153 patients with dMMR/MSI-H endometrial cancer (EC), 210 with dMMR/MSI-H and POLε-mutated solid tumors other than EC.⁴

At a median follow-up of 27.6 months in the endometrial cancer cohort and 27.7 months in the solid tumor cohort, the objective response rate (ORR) was 45.5% (95% CI, 37.1%-54.0%) and 43.1% (95% CI, 36.2%-50.2%), respectively. The median duration of response was not reached in either arm, and responses were ongoing at data cutoff in 83.1% of the EC population and 87.5% of the solid tumor group.

The median progression-free survival (mPFS) was 6.0 months (95% CI, 4.1-18.0 months) in the EC cohort and 7.1 months (95% CI, 3.6-19.5 months) in the solid tumor cohort. The mOS was not reached in either arm.

“Understating dostarlimab’s effectiveness in MSI-H and dMMR tumors, it was also hypothesized that is could also be effective in locally advanced cancers,” said Ivan Diaz-Padilla, MD, PhD, vice president, Clinical Development Head, Immuno-Oncology, GSK, during the ODAC meeting.

Further rationale for the use of dostarlimab in dMMR/MSI-H LARC came from a phase 2 study led by Memorial Sloan Kettering Cancer Center (MSK). Unprecedented efficacy was shown in this study, according to Diaz-Padilla, including clinical CRs (cCR) in all 12 patients treated. Some CRs were sustained beyond 12 months.^1,5

At a median follow-up of 18.3 months (range, 10.0-35.5) and with an additional 30 patients, the cCR remains at 100%, according to study investigator, Andrea Cercek, MD. More data from the MSK study will be presented in the second quarter of 2023.

“Our study at MSK is showing that dMMR/MSI-H LARC is highly sensitive to neoadjuvant monotherapy with dostarlimab. While the short-term benefits appear significant, we need long-term data with additional patients to demonstrate the durability of results and to better understand our ability to successfully retreat in the event that the cancer reappears. This underscores the importance of the proposed GSK study, said Cercek, section head, Colorectal Cancer; co-director, Center for Young Onset Colorectal and Gastrointestinal Cancers, MSK.

Proposed Research

Study 219369 is proposed to be a phase 2 study of dostarlimab 500 mg given intravenously (IV) every 3 weeks in 100 patients with treatment-naïve, dMMR/MSI-H LARC.¹

In the study, tumor assessment will occur at 6 months, followed by cCR at 18 months, and follow-up for 5 years. Patients who recur or develop residual disease will be treated with SOC for 12 consecutive months. However, due to the different in the toxicity of SOC and dostarlimab, a high drop-out rate is anticipated in the control arm.

Patients will be eligible to enroll if they are 18 years of age or older with historically confirmed stage II or III rectal cancer, dMMR/MSI-H status, and do not have metastatic disease or recurrent disease.

GSK plans to conduct the study at more than 45 sites with multidisciplinary teams involved. The study sites will be in the US, Europe, and other countries, according to Diaz-Padilla, vice president, Clinical Development Head, Immuno-Oncology, GSK, dMMR/MSI-H tumors highly express PD-1 and PD-L1 and are therefore susceptible to being treated by immune checkpoint inhibitors. Of the patients enrolled, 347 from either cohort were evaluable for efficacy.

The primary end points of the study are proposed to be cCR at 12 months after 6 months of dostarlimab and event-free survival at 3 years. The key secondary end points will be cCR at 36 months, OS at 5 years, and disease-specific survival at 5 years.

Discussion

During the discussion portion of the meeting, the appewared to be a consensus among ODAC members and temporary voting members, that a randomized trial is not possible for the dMMR/MSI-H LARC population. Therefore, the propsed design of the trial is acceptable.

Regarding the propsed study end points, many of the ODAC members have concerns about the cCR12 end point due to the fact the it will be difficult to see the durability of response. Others think it's suitable. However, additional end point like quality-of-life may be important for this patient population.

The ODAC explained there is unmet need for patients with dMMR/MSI-H LARC. In terms of variability in care, ODAC member agree that most variability will be related to biomarker testing, and it may be a matter of educating the oncology communuity.

The majority voting yes that the proposed single arm trial is sufficient to characterize the benefits and risk of dostarlimab for the proposed indication. This decision was largely due to the unlikeliness of a randomized clinical trial in this patient population.

ODAC Highlights

Discussion Questions:

Discuss the adequacy of proposed single-arm trials to evaluate the efficacy and safety of dostarlimab, including the long-term benefits and risks of treatment
Discuss the adequacy of the proposed clinical endpoints (i.e., cCR rate, EFS), to characterize and verify the benefit of dostarlimab, including the proposed timing of analyses
Discuss the study population with Stage II/III LARC dMMR/MSI-H for a NOM approach.
Discuss the potential impact of the variability in care, expertise, etc., across multi-disciplinary study staff and across study sites on study conduct and ultimately on outcomes

Voting Question:

Will the data from the proposed single arm trials enrolling a total of 130 patients be sufficient to characterize the benefits and risks of dostarlimab in the curative intent setting for patients with dMMR/MSI-H LARC?

During the open public hearing, two experts provided opposing opinions on the issue. First, Diana Zukerman, PhD, president of the National Center for Health Research gave her position against the IND.

“I find the research promising, but there are too many unanswered questions that 2 small single-arm trials can't answer. Designing a randomized control trial now is our best chance to answer these important questions. These questions will be impossible to answer if the drug is approved for this indication, a few years from now, based on the proposed studies because patients are much less willing to participate in a randomized controlled trial for a drug approved for the same indication,” Zuckerman said.

Advocating for further development of dostarlimab to address needs in community oncology was Stephen Cohen, MD, a medical oncologist and chief, Medical Oncology and Hematology Division, Abington Hospital, and vice-chair, Department of Medical Oncology, Sidney Kimmel Cancer Center at Jefferson.

"The treatment of colorectal cancer, in general, has been approved through the use of it's been improved through the use of molecular biomarkers and targeted therapies in metastatic colorectal cancer, Cohen stated... “Given the benefit of immunotherapy in metastatic colorectal cancer patients with dMMR tumors, a natural next step was to evaluate it in the locally advanced setting for patients with deficient mismatch repair rectal cancer, and that was the foundation for the initial dostarlimab experience in dMMR stage 2 and stage 3 rectal cancer and the results in that initial single-arm experience were very provocative, albeit in a relatively small group of patients.”

Cohen also explained the significance of prosed trial sites, which include community centers.

“The selection of community sites is an important aspect of the trial designed to document the generalizability of this approach and findings across practice sites. The majority of cancer care in the US is conducted in Community Oncology practices and the testing for mismatch repair is quite standardized, and local results for mismatch repair testing had been acceptable in US NCI trials evaluating immunotherapy and deficient mismatch repair colorectal cancer. That's as a practicing gi oncologist for 20 years and now with a large community practice I strongly support the GSK phase two design of this trial to evaluate dostarlimab and locally advanced dMMR/MSI-H rectal cancer,” said Cohen.

_{1. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA website. February 9, 2023. Accessed February 9, 2023. https://www.fda.gov/advisory-committees/advisory-committee-calendar/updated-information-february-9-2023-meeting-oncologic-drugs-advisory-committee-meeting-announcement}

_{2. FDA approves immunotherapy for endometrial cancer with specific biomarker. FDA. April 22, 2021. Accessed February 9, 2023. https://bit.ly/3dIIIod}

_{3. FDA grants accelerated approval for GSK’s JEMPERLI (dostarlimab-gxly) for women with recurrent or advanced dMMR endometrial cancer. News release. GlaxoSmithKline plc. April 22, 2021. Accessed February 9, 2023. https://bit.ly/3esABv0}

_{4. Thierry A, Berton D, Curigliano G, et al. Efficacy and safety of dostarlimab in patients (pts) with mismatch repair deficient (dMMR) solid tumors: Analysis of 2 cohorts in the GARNET study. J Clin Oncol. 2022;40(16):2587-2587. doi:10.1200/JCO.2022.40.16_suppl.2587}

_{5. Cercek A, Lumish M, Sinopilu J, et al. PD-1 blockade in mismatch repair–deficient, locally advanced rectal cancer. N Engl J Med. 2022; 386:2363-2376. doi:10.1056/NEJMoa2201445}