A recent report highlighting FDA subgroup approval by the American Association for Cancer Research offers perspective into regulatory science and policy summarizing the key findings of benefit-risk assessment of cancer drugs and highlighting how the FDA considers the appropriate patient population for cancer drug approval.
The report was authored by Anup K. Amatya, PhD, a Statistician for the Office of Biostatistics at the Center for Drug Evaluation and Research for the US Food and Drug Administration along with Mallorie Fiero, PhD, the Statistical Team Leader for Division V of the FDA’s Biostatistics Office and other experts from the Office of Biostatistics in addition to FDA members including Office of Hematology and Oncology Products, Office of New Drugs, Center for Drug Evaluation and Research, Office of Oncologic Diseases, Oncology Center of Excellence, and Division of Oncology.
Many of the authors are regular participants at Food and Drug Administration Center for Drug Evaluation and Research Oncologic Drug Advisory Committee (ODAC) meetings and are true experts on the subject.
The primary focus of the report is on subgroup analyses and how they demonstrate evidence of the effects of treatment. Subgroup analyses are the treatment effects based on certain patient characteristics with a larger group of data from the total clinical study population. In the past, these have been important for interpreting trials; however, in regards to regulatory decision-making and product labeling, these analyses have been challenging.
The ability to produce the desired results for the total population and the subgroups are important for the labeling, justification, data and external information. Patients must know that for their specific population a drug is both safe and effective.
Regulators have broken the intent of subgroup analyses into:
- Inferential: establishing the desires of the population
- Supportive: investigating consistency of the treatment
- Exploratory: used to gain further insight into biological characteristics of the disease
FDA Approved Drugs with Failed Clinical Trials
FDA drug approvals in intent to treat populations have been approved on multiple occasions despite not meeting a primary endpoint. One of those examples is KEYTRUDA (pembrolizumab), which has become a foundational cancer treatment across 25 different cancer types and has been projected to generate $22.5 billion in revenue by 2025. Through its 4.6-month trial, the results raised uncertainty regarding the benefit to the subgroup, as it was not possible to draw definitive conclusions. It was later approved in combination with chemotherapy.
The approval of LYNPARZA (olaparib) came from an exploratory subgroup analysis along with HAlAVEN, which found its exploratory subgroup analysis was driven by a large treatment effect in a small group of patients—less than one-third of the total testing population. The approval of TECENTRIQ atezolizumab for the studies subgroup was based on the favorable trend of the subgroup population trends.
While there is little known about how the determination is made in what population to include in a new drug indication, some of this recent insight, as well as the studies cited, help provide perspective on recent failed trials that could still reach FDA approval. Below we take a look at a few top prospects and major focuses.
Failed Clinical Trials with Potential FDA Approvals
Calithera Biosciences – Telaglenastat Approval
Calithera Biosciences’ telaglenastat missed its primary endpoint in a phase 2 clinical trial of renal cell carcinoma. The failure of the glutaminase inhibitor to improve progression-free survival (PFS) also led to a reduction in staff at Calithera of 35% in an attempt to stretch cash reserves beyond future readouts.
Further trials are underway, including KEAPSAKE, which is assessing telaglenastat in KEAP1/NRF2 mutant non-small cell lung cancer (NSCLC) patients. Calithera is continuing the NSCLC trial despite the failure of CANTATA in hopes of a strong, distinct rationale for targeting the patient population. The staff layoffs are intended to keep the company cash-positive into 2022 when the trial is expected to deliver results.
Merck KGaA GlaxoSmithKline – M7824 (Bintrafusp alfa) Approval
The pair of GSK and Germany Merck halted their trial INTR@PID Lung 037 based on the feedback from an Independent Data Monitoring Committee. The trial was testing the drug in patients with stage IV non-small cell lung cancer, with high expression of the PD-L1 biomarker, a mutation that tends to make tumours more susceptible to immunotherapy.
The group is continuing development in other forms of cancer despite the results that cast doubt on the future of the bintrafusp alfa drug. Trials include cervical cancer and NSCLC along with newly initiated monotherapy studies that include a Phase II study in patients with triple-negative breast cancer (INTR@PID BREAST 020) and a Phase I monotherapy study in locally advanced/metastatic urothelial cancer (INTR@PID UROTHELIAL 152).
Cel-Sci Corporation – Multikine Approval
Cel-Sci Corporation recently completed the largest ever phase 3 clinical trial for head and neck cancer patients though the primary endpoint was not met. Patients treated with the Multikine treatment regimen plus SOC vs. SOC alone had an overall survival benefit of 14.1% at five years, which exceeded the predefined 10% overall survival benefit set out for the study population as a whole.
Cel-Sci plans to file for FDA approval based on the group of participants who did not receive chemotherapy as part of their treatment. That subgroup demonstrated a positive overall survival at five years for 14% higher in the Multikine group, 62.7%, than in the control cohort, 48.6%.
The company released a statement confirming the positive data and their plans for the future. “The analysis of this separate group is expected to meet regulatory requirements for FDA submission based on the protocol and Statistical Analysis Plan, which were prospectively concluded before database lock and unblinding,” said Cel-Sci Corporation. The company also stated that “the chemotherapy, cisplatin, was given intravenously and may have negated the survival benefit imparted by Multikine immunotherapy in these patients.” Cel-Sci’s phase 3 clinical trial reported no safety issues found for Multikine in the treated population during or as a result of administration. There were also no late effects of the overall treated population.
Recent Failed Clinical Trials
Odonate Therapeutics – Tesetaxel Failure
Odonate Therapeutics ended the development of its oral chemotherapy drug and ceased operations after the FDA stated the drug’s clinical data was “unlikely to support FDA approval.” Odonate was developing tesetaxel for the treatment of metastatic breast cancer as a taxane in the same drug class as paclitaxel and docetaxel. Unlike the latter, tesetaxel is delivered orally rather than intravenously.
Tesetaxel was in multiple phase 2 studies testing it alone and in combination with other medicines, including the chemo drug capecitabine in HER2-negative breast cancer and checkpoint inhibitors in triple-negative breast cancer. In its phase 3 study, the combination treatment delayed cancer progression for a median of 9.8 months versus 6.9 months for capecitabine alone, top-line data. Despite meeting its primary endpoint, the 2.9-month difference in progression-free survival was disappointing and likely was a factor in the FDA statement.
Polyphor – Balixafortide Failure
Swiss biotechnology company Polyphor did not meet the co-primary endpoint of the study, which was objective response rate (ORR) (13% versus 13.7%) in a third-line setting. The phase 3 clinical trial dubbed Fortress featured Polyphor’s drug balixafortide in over 400 patients with late-stage HER2-negative breast cancer. The trial combined balixafortide along with Eisia’s Halaven (eribulin) and compared against the use of Halaven on its own.
The primary endpoint of the study progression free survival (PFS) was not met, and the company also stated in a release on August 3 that prespecified interim analysis of overall survival (OS) showed no statistically significant differences between study groups. The board of directors has extended the period for strategic evaluation of all options for the future of the Company by no later than the end of August.