Improving Oncology Clinical Trials for Accelerated Approval
The FDA issued draft guidance, Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics, regarding clinical trial design considerations to support accelerated approval applications. The accelerated approval pathway is commonly used for approval of oncology drugs in part due to the serious and life-threatening nature of cancer and because of available intermediate clinical endpoints likely to predict clinical benefit.
"The FDA's accelerated approval program has provided patients with cancer earlier access to novel treatments that can be practice-changing," said Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence. "[This] draft guidance provides recommendations to sponsors for designing clinical trials to support accelerated approval. Building quality and efficiency into the design of oncology clinical trials is a crucial component in providing maximum benefit to those living with cancer."
The draft guidance discusses the design of clinical trials and ways to improve the data available at the time of accelerated approval and reduce clinical uncertainty for patients by initiating post-marketing confirmatory studies in a timely manner. Specifically, the draft guidance addresses the design, conduct, and analysis of data through two randomized clinical trial approaches-conducting two separate randomized controlled clinical trials or using one trial for both accelerated approval and to verify clinical benefit. The draft guidance also provides considerations for sponsors to determine the adequacy of single-arm studies to support an application.
For drugs granted accelerated approval, post-marketing confirmatory trials have been required to verify and describe the anticipated clinical benefit. The draft guidance discusses a potential advantage of randomized clinical trials-compared to single-arm trials-by highlighting that use of the one-trial approach, in appropriate cases, which may not require separate clinical trials because longer-term follow-up in the same trial could fulfill a postmarketing requirement to verify clinical benefit. Moreover, confirmatory trials in progress at the time of accelerated approval are more likely to result in timely verification of clinical benefit, therefore minimizing the period of uncertainty for patients.
In a commentary in the New England Journal of Medicine, Oncology Center of Excellence staff outlined the concepts included and expanded upon in the draft guidance (2022; doi: 10.1056/NEJMp2208954). The Oncology Center of Excellence has also launched Project Confirm as an initiative that promotes the transparency of outcomes related to accelerated approval for oncology indications and fosters discussion and research on the accelerated approval program. The project developed a searchable database with information on the status of all oncology accelerated approvals, a model that was then adopted by FDA's Center for Drug Evaluation and Research for all accelerated approvals.
Full Approval of Pembrolizumab for Advanced MSI-H or dMMR Solid Tumors
The FDA has granted full approval to pembrolizumab, an anti-PD-1 therapy for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, who have progressed following prior treatment and have no satisfactory alternative treatment options. The conversion from an accelerated to a full (regular) approval is based on results from the Phase II KEYNOTE-158, KEYNOTE-164, and KEYNOTE-051 trials and includes data in 504 adult and pediatric patients across more than 30 types of cancer. This marks the first full approval for an immunotherapy based on a predictive biomarker, regardless of solid tumor type.
"This approval reinforces the important role of [pembrolizumab] in certain patients with MSI-Hor dMMR solid tumors facing a variety of cancers," said Luis A. Diaz, Jr., MD, Head of the Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center. "These data also further underscore the need for biomarker testing to identify patients who may be eligible for this therapy."
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with pembrolizumab, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of pembrolizumab.
Based on the severity of the adverse reaction, pembrolizumab should be withheld or permanently discontinued and corticosteroids administered if appropriate. Pembrolizumab can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, pembrolizumab can cause fetal harm when administered to a pregnant woman.
The full approval was based on data from three multicenter, non-randomized, open-label multi-cohort trials. KEYNOTE-164 (NCT02460198) enrolled 124 patients with advanced MSI-H/dMMR colorectal cancer that progressed following treatment with fluoropyrimidine and either oxaliplatin or irinotecan with or without anti-VEGF/EGFR mAb-based therapy.
KEYNOTE-158 (NCT02628067) enrolled 373 patients with advanced MSI-H/dMMR non-colorectal cancers who had disease progression following prior therapy. Patients were either prospectively enrolled with MSI-H/dMMR tumors (Cohort K) or retrospectively identified in one of 10 solid tumor cohorts (Cohorts A-J).
KEYNOTE-051 (NCT02332668) enrolled seven pediatric patients with MSI-H/dMMR cancers. All trials excluded patients with autoimmune disease or a medical condition that required immunosuppression. Regardless of histology, MSI or MMR tumor status was determined using polymerase chain reaction (local or central) or immunohistochemistry (local or central), respectively.
Adult patients received pembrolizumab 200 mg administered intravenously every 3 weeks (pediatric patients received 2 mg/kg every 3 weeks) until unacceptable toxicity, disease progression, or a maximum of 24 months. In KEYNOTE-164 and KEYNOTE-158, assessment of tumor status was performed every 9 weeks through the first year, then every 12 weeks thereafter. In KEYNOTE-051, an assessment of tumor status was performed every 8 weeks for 24 weeks, and then every 12 weeks thereafter. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) as assessed by blinded independent central review according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ in KEYNOTE-158) and as assessed by the investigator according to RECIST v1.1 in KEYNOTE-051.
In a pooled analysis of the three trials, pembrolizumab demonstrated an ORR of 33.3 percent (95% CI, 29.2-37.6), including a complete response rate of 10.3 percent and partial response rate of 23.0 percent at a median follow-up time of 20.1 months (range: 0.1-71.4 months). Of the responding patients (n=168), 77 percent had responses lasting 12 months or longer, and 39 percent had responses lasting 36 months or longer. Median DOR was 63.2 months (range, 1.9+ to 63.9+ months).
In patients with MSI-H/dMMR colorectal cancer (n=124), pembrolizumab demonstrated an ORR of 34 percent (95% CI, 26%-43%) with a DOR ranging from 4.4 to 58.5+ months. In patients with other MSI-H/dMMR non-colorectal solid tumors (n=380), pembrolizumab demonstrated an overall ORR of 33 percent (95% CI: 28%-38%) with a duration of response ranging from 1.9+ to 63.9+ months.
These included endometrial cancer, gastric or gastroesophageal junction cancer, small intestinal cancer, brain cancer, ovarian cancer, biliary cancer, pancreatic cancer, sarcoma, breast cancer, cervical cancer, neuroendocrine cancer, prostate cancer, adrenocortical cancer, mesothelioma, thyroid cancer, small cell lung cancer, bladder cancer, salivary cancer, renal cell cancer and other cancers.