One-arm trial + ORR may not be enough?

The FDA will convene a meeting of the Oncologic Drugs Advisory Committee (ODAC) on April 21-22 to discuss a vote "on whether companies should be required to pass randomized controlled trial data as substantive evidence to support efficacy and safety.

Two months ago, Cinda PD-1 was blocked by ODAC, which caused an uproar in China (see related information [The FDA's Special Committee Briefing on the Approval of Cinda PD-1 Drugs]), but ODAC kept its pace

Shilin will continue to follow up on this ODAC.

ODAC topics focus on core issues

ODAC topics focus on core issues

The 2-day meeting was originally planned:

Day 1 Discussion: Should companies be required to approve PI3K inhibitors with RCT data as substantial evidence supporting efficacy and safety?

Discussion the next day

– Supplemental New Drug Application filed by TG Therapeutics, Inc.

Discussion of the "umbralisib and ublituximab combination for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma" supplemental application has now been withdrawn, and the TG has withdrawn the supplemental application

ODAC will discuss 4 FDA-approved PI3K inhibitors for various hematological malignancies, including Gilead's Zydelig, Bayer's Aliqopa, SecuraBio's Copiktra and TG's Ukoniq

Deja Vu foreshadowing before the meeting?

Deja Vu foreshadowing before the meeting?

On April 14, Nicholas, an officer of the FDA Oncology Center of Excellence (OCE), and others published an article in The Lancet-Oncology:

The development program of PI3K inhibitors in hematological malignancies highlights the challenges associated with the current paradigm of using overall response rate (ORR) in single-arm trials to support accelerated approval

The paper also summarizes the current status of FDA-approved PI3K inhibitors for hematological malignancies:

Additionally, in the ODAC meeting materials, the FDA submitted a 93-page brief

In the briefing, the FDA noted that the six RCTs showed unprecedented consistency in results -- a decrease in overall survival in the context of a PFS advantage or potential advantage

FDA believes that experience with PI3K inhibitors in hematological malignancies illustrates the challenges of the current paradigm of using ORR in single-arm trials to support preliminary approval:

Dose optimization: There was limited exploration of lower doses in selecting the maximum or near-maximally tolerated dose for subsequent registration trials

Single-arm trial limitations: In some cases, the consequences of not conducting further dose exploration are complicated by the choice of a single-arm study design for initial enrollment

Importance of OS endpoints: OS data should be comprehensively collected and analyzed because OS is an important metric for determining risk to benefit, especially for products with significant toxicity

Original in English: https:// href="https://" target="_blank">https:// 【References】

【References】

[1] FDA Briefing Information for the April21, 2022 Meeting of the Oncologic Drugs Advisory Committee

[1] FDA Briefing Information for the April21, 2022 Meeting of the Oncologic Drugs Advisory Committee

[2] Nicholas C Richards on, et al.

[2] Nicholas C Richards on, et al.

[3] Kyle LaHucik.

[4] Amber Tong.

[1] idelalisib plus bendamustine plus rituximab vs placebo plus bendamustine plus rituximab in untreated chronic lymphocytic leukemia; idelalisib plus rituximab vs placebo Combination with rituximab for relapsed or refractory indolent non-Hodgkin lymphoma; idelalisib plus bendamustine and rituximab vs placebo plus bendamustine and rituximab for relapsed indolent or refractory non-Hodgkin lymphoma
.

[2] Gilead Sciences.
Important drug warning: decreased overall survival and increased risk of serious infections in patients receiving Zydelig(idelalisib).
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http://cllsociety.
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pdf (accessed Feb.
16, 2022).

[2] Gilead Sciences.
Important drug warning: decreased overall survival and increased risk of serious infections in patients receiving Zydelig(idelalisib).
March, 2016.
http://cllsociety.
org/docs/Zydelig%20Safety%20Update.
pdf (accessed Feb.
16, 2022).

[3] Matasar MJ, Capra M, Özcan M, et al.
Copanlisib plus rituximabversus placebo plus rituximab in patients with relapsed indolent non-Hodgkinlymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3trial.
Lancet Oncol 2021; 22: 678–89.

[3] Matasar MJ, Capra M, Özcan M, et al.
Copanlisib plus rituximabversus placebo plus rituximab in patients with relapsed indolent non-Hodgkinlymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3trial.
Lancet Oncol 2021; 22: 678–89.

[4] Secura Bio.
Correction of drug information: updated overallsurvival data for Copiktra (duvelisib) in patients with relapsed/refractory(R/R) chronic lymphatic leukemia (CLL) and small lymphocytic lymphoma (SLL).
March 18, 2022.
https ://copiktrahcp.
com/notice-to-hcps/ (accessed March 18, 2022).

[4] Secura Bio.
Correction of drug information: updated overallsurvival data for Copiktra (duvelisib) in patients with relapsed/refractory(R/R) chronic lymphatic leukemia (CLL) and small lymphocytic lymphoma (SLL).
March 18, 2022.
https ://copiktrahcp.
com/notice-to-hcps/ (accessed March 18, 2022).

[5] Gribben JG, Jurczak W, Jacobs RW, et al.
Umbralisib plusublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) inpatients with treatment naïve (TN) and relapsed/refractory (R/R) chroniclymphocytic leukemia ( CLL): results from the phase 3 Unity-CLL study.
Blood2020;

[5] Gribben JG, Jurczak W, Jacobs RW, et al.
Umbralisib plusublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) inpatients with treatment naïve (TN) and relapsed/refractory (R/R) chroniclymphocytic leukemia ( CLL): results from the phase 3 Unity-CLL study.
Blood2020;

136 (suppl 1): 37–39 (abstr).

136 (suppl 1): 37–39 (abstr).