At a session of the American Association for Cancer Research Virtual Annual Meeting II, multiple FDA regulators gave presentations on various topics to help drug companies understand the ever-evolving oncology regulation.

A hot topic with the FDA has been the recent approvals for tissue-agnostic oncology drugs: Keytruda (pembrolizumab, Merck & Co. Inc.) for microsatellite instability-high or mismatch repair deficient and more recently, for tumor mutational burden-high, as well as Rozlytrek (entrectinib, Roche Holding AG) and Vitrakvi (larotrectinib, Bayer AG) for cancers with NTRK gene fusions.

"In the tissue-agnostic approvals to date, we believe that based on the biology and clinical results, that we can infer clinical effects across a wide variety of tumors. The chance of each rare biomarker-positive tumor responding will be higher than the chance that a specific tumor type will be inherently resistant," Steven Lemery, acting director of the division of oncology at the FDA, told the audience, noting that the if a resistance was found in a certain tumor type, the label could be modified to note the exception.

Patients with rare mutations clearly benefit from the tissue-agnostic approvals. For example, Lemery estimates there are only 12 patients a year with cholangiocarcinoma with NTRK gene fusions. Enrolling a tissue-specific clinical trial would be impossible.

Patient-reported outcomes

The FDA is studying the use of patient-reported outcomes (PRO), especially for adverse events, because the data can be recorded more often than for physician-reported events.

Jeanne Fourie Zirkelbach, a lead clinical pharmacologist at the FDA's Office of Clinical Pharmacology, performed a retrospective analysis of diarrhea for 120 patients in a clinical trial who had drug exposure rate (ER) data as well as physician-reported Common Terminology Criteria for Adverse Events (CTCAE) and PRO-CTCAE data for diarrhea.

CTCAE was measured every three weeks for the first 21 weeks and then every six weeks thereafter, while PRO-CTCAE was measured weekly for 18 weeks then every three weeks. The CTCAE was a binary event, either the patient had the adverse event (AE) or they didn't. The PRO-CTCAE cutoff for whether the patient had diarrhea was whether the patient reported that the diarrhea was frequent or almost constant, while reports of never, rarely or occasionally were deemed as not having the AE.

Using logistic regression, CTCAE showed drug ER was associated with diarrhea but the effect was shallower compared to PRO-CTCAE and not statistically significant (p=0.49 vs. p=0.0284).

"The PRO data may be more sensitive to identifying this known ER relationship for diarrhea in a small 120-patient dataset compared to CTCAE. This could be due to the larger amount of data available with PRO-CTCAE within the same treatment time frame or because patient responses had more range, particularly with the lower-grade CTCAE patients," Fourie Zirkelbach said.

The FDA is set to launch a new website by early July called Project Patient Voice that will present PRO AEs at baseline and over the first six months of treatment. Paul Kluetz, deputy director of the Oncology Center for Excellence, noted that the baseline data are important and "not typically known in standard safety analyses that we have on FDA labels."

Immunotherapies: Combinations and neoantigens

Since 2011, there have been 73 new or supplemental approvals for the seven approved immune checkpoint inhibitors targeting PD-(L)1 in 17 cancer types and a tissue agnostic approval. Combinations accounted for 20 of those 73 approvals, with many of them coming over the last year or so.

When testing combinations, sponsors have multiple options for clinical trial design. The ideal design, assuming both drugs have activity, would have four arms: the combination, each single agent and a placebo control. "In order to expose the fewest patients to a less effective therapy, the trial could include an interim examination plan to discontinue accrual to one or both of the arms – if clearly less active than the combination," Marc Theoret, acting deputy director at the FDA's Office of Oncologic Diseases, told the audience.

If one drug is active, a three-arm trial with the combination, the active drug and a placebo is preferred. If both drugs had already been proved to not be active on their own, the FDA is okay with testing the combination against a placebo control.

Interestingly, of the 20 combination approvals, only one study used the ideal four-arm study, one study used the three-arm design and eight only tested the combination without any single-agent arms. The other 10 were add-ons to the standard of care (SOC) and compared to combination to SOC.

"I encourage trial sponsors to meet with the FDA as early as possible in development, especially concerning considerations for demonstration of contribution effect," Theoret noted.

There haven't been any FDA-approved treatments for neoantigens; all 33 active INDs are in phase I or phase II, but Ke Liu, associate director for cell and gene therapy at the FDA's Oncology Center of Excellence and the chief of the oncology branch of the Office of Tissues and Advanced Therapies, is already thinking about the challenge of writing an indication statement for the vaccines or cell therapies that train the immune system to attack tumor-specific antigens.

Typically, the statement would describe the drug class and which diseases the drug is indicated for.

"It is challenging to describe an indication statement for a neoantigen-based therapy because a patient may receive a mixture of different products based on the patients' own neoantigens, which in most cases we only know the mutated proteins but do not know what they are or what their functions are, not alone, what drug classes they belong to," Liu noted.

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