Jaypirca: what changed in the evidence · Jaypirca · Oct 2021 – Jan 2023
What uncertainty did the FDA's reviewers record when they approved Jaypirca in 2023?
Mainly durability. The review calls the limited follow-up for duration of response “a significant review issue”: most responders were censored within months, so the median duration may not represent the data. It also notes limits on the dose analysis and on safety exposure.
EphemerisX Research · Published · 2 source documents · 1 min read
Short answer
Durability above all. The FDA's 2023 review says the limited follow-up for duration of response was a significant review issue: 61% of censored responders were censored within 6 months, and the median estimate was skewed by outliers. Before submission the FDA had said 65 patients would be insufficient. The review also records limits on the dose analysis and on the length of safety exposure.
What the evidence shows
Before the application, at an October 2021 meeting: The FDA stated that the proposed submission of data from 65 patients with MCL would be insufficient
FDA · Jan 27, 2023 · p. 27 and recommended waiting for increased sample size and adequate follow-up
FDA · Jan 27, 2023 · p. 27.
The review's summary: the data related to durability of response are limited by the degree of early censoring
FDA · Jan 27, 2023 · p. 16. In detail: The limitations with the DOR follow-up were a significant review issue
FDA · Jan 27, 2023 · p. 114. of the responders who were censored (n=36), 61% were censored within 6 months of onset of response and 78% were censored within 9 months
FDA · Jan 27, 2023 · p. 119. the median DOR estimates on their own are not necessarily representative of the data
FDA · Jan 27, 2023 · p. 115.
The figures the review gives: The KM estimates of DOR rate at 6 months and 9 months were 65.3% (95% CI: 49.8%, 77.1%) and 46.4% (95% CI: 28.7%, 62.4%), respectively
FDA · Jan 27, 2023 · p. 186.
On the dose: the Applicant’s exposure-response analyses had significant limitations to determine if 200 mg daily is the optimal dosing regimen
FDA · Jan 27, 2023 · p. 72. On safety: The safety data are limited by the relatively short duration of exposure, particularly in the MCL safety population
FDA · Jan 27, 2023 · p. 185.
The answer the FDA set out to the uncertainty was a randomized trial: The primary endpoint should be progression-free survival as assessed by an independent review committee, with secondary endpoints that include overall survival and objective response rate
FDA · Jan 27, 2023 · p. 3. Where it stands: Where does the confirmatory trial for Jaypirca's first indication stand?
Follow the thread
- What evidence did the FDA rely on when Jaypirca first received accelerated approval?“Limited by the degree of early censoring”
- Where does the confirmatory trial for Jaypirca's first indication stand?Requirement 4389-1
- What stayed the same across Jaypirca's approvals?The 200 mg dose
The documents, by date
The passages quoted
FDA approval letter, January 27, 2023 · page 3
4389-1 Complete a randomized clinical trial to obtain data on the clinical efficacy and safety of pirtobrutinib in patients with mantle cell lymphoma. The trial should compare pirtobrutinib monotherapy to an investigator’s choice of approved BTK inhibitors in patients with mantle cell lymphoma. The primary endpoint should be progression-free survival as assessed by an independent review committee, with secondary endpoints that include overall survival and objective response rate.Open at the source →
FDA Multi-discipline Review, January 27, 2023 · page 16
While the data related to durability of response are limited by the degree of early censoring, the ORR, coupled with demonstration of durability of response in those with adequate follow-up, supports the determination that pirtobrutinib has clinically meaningful activity in a highly refractory, BTK inhibitor-pretreated MCL patient population.Open at the source →
FDA Multi-discipline Review, January 27, 2023 · page 27
The FDA stated that the proposed submission of data from 65 patients with MCL would be insufficient and that responders should have at least 9 months of follow-up for duration of response. The FDA recommended delaying NDA submission until increased sample size and adequate follow-upOpen at the source →
FDA Multi-discipline Review, January 27, 2023 · page 72
the Applicant’s exposure-response analyses had significant limitations to determine if 200 mg daily is the optimal dosing regimenOpen at the source →
FDA Multi-discipline Review, January 27, 2023 · page 114
FDA does not agree that most responders in the originally defined PAS had at least 9 months of follow-up for DOR, as the majority of responders were censored before 6 months as evident in Figure 8. The limitations with the DOR follow-up were a significant review issue.Open at the source →
FDA Multi-discipline Review, January 27, 2023 · page 115
Thus, the median DOR estimates on their own are not necessarily representative of the data and must be interpreted in the context of the limited number of patients with DOR events and the degree of early censoring and early failures.Open at the source →
FDA Multi-discipline Review, January 27, 2023 · page 119
In the primary efficacy population (PAS + SAS1; n=120), of the responders who were censored (n=36), 61% were censored within 6 months of onset of response and 78% were censored within 9 months.Open at the source →
FDA Multi-discipline Review, January 27, 2023 · page 185
The safety data are limited by the relatively short duration of exposure, particularly in the MCL safety population, however there are an adequate number of patients in the safety populations to perform a current assessment of safetyOpen at the source →
FDA Multi-discipline Review, January 27, 2023 · page 186
ORR by IRC per Lugano was 50% (95% CI: 40.7%, 59.3%) and the KM estimate of median DOR by IRC was 8.3 months (95% CI: 5.7, NE) with 24 events observed at a median duration of follow-up of 7.3 months. The KM estimates of DOR rate at 6 months and 9 months were 65.3% (95% CI: 49.8%, 77.1%) and 46.4% (95% CI: 28.7%, 62.4%), respectively.Open at the source →