AstraZeneca lands narrow Imfinzi nod in endometrial cancer. Where’s Lynparza?

Phase 3Clinical ResultDrug ApprovalPriority ReviewImmunotherapy
AstraZeneca lands narrow Imfinzi nod in endometrial cancer. Where’s Lynparza?
Source: FiercePharma
With the narrowed label, AstraZeneca said it's still working with the FDA to determine next steps to potentially bring Imfinzi with or without Lynparza to a broader endometrial cancer population.
AstraZeneca’s Imfinzi has followed GSK’s Jemperli into endometrial cancer. And like its compatriot competitor, the FDA approval is limited to a subgroup of patients.
The new approval is for Imfinzi, used in combination with chemotherapy followed by Imfinzi alone, to treat certain patients with primary advanced or recurrent endometrial cancer. In a key limitation, the cancer must be mismatch repair deficient (dMMR), a type of genetic abnormality, AZ said Monday.
The dMMR-only nod matches the first immunotherapy approval that the FDA handed to GSK’s Jemperli as an add-on to chemotherapy in July 2023.
Although AZ’s oncology business chief Dave Fredrickson in a Monday statement touted Imfinzi as “an important new option” for the first-line treatment of dMMR endometrial cancer, two questions remain for the PD-1/L1 inhibitorPD-1/L1 inhibitor class in the broader endometrial cancer field.
First of all, the FDA seemed to have turned away AZ’s proposed combination that further adds the Merck & Co.-partnered PARP inhibitor Lynparza on top of Imfinzi during the maintenance phase. In AZ’s most recent investor updates, the company has been listing the Imfinzi-Lynparza regimen as awaiting an FDA decision in first-line endometrial cancer.
In response to a Fierce Pharma inquiry, an AZ spokesperson didn’t directly answer whether the company had filed the Imfinzi-Lynparza combo with the FDA and got a rejection.
“We are continuing to assess overall survival (OS) for both [Imfinzi] monotherapy and [Imfinzi] plus [Lynparza] as maintenance therapy in the overall trial population and are working with the U.S. FDA to determine next steps to provide additional treatment options to even more patients,” the spokesperson said.
The spokesperson was referring to the phase 3 DUO-E trial. In a prespecified subgroup analysis, Imfinzi and chemo cut the risk of tumor progression or death by 58% compared with chemo alone in dMMR patients. The Imfinzi-chemo regimen also slashed the risk of death by 66% in this subgroup at the interim analysis. Those data formed the basis of the current approval.
Imfinzi and chemo also offered a 23% improvement in progression-free survival (PFS) in the larger mismatch repair proficient group (pMMR), and a marginal 9% reduction in the risk of death. It’s not clear whether AZ had sought a broader indication that included the pMMR population for Imfinzi and chemo.
The Imfinzi-Lynparza-chemo regimen appeared to have offered limited additional benefit in the dMMR population with very similar PFS and OS improvements compared with the Imfinzi-chemo pairing. AZ has also acknowledged that the incremental benefit for Lynparza was more pronounced in the pMMR group, in which it has shown PFS and OS benefits at 43% and 31%, respectively, compared with chemo alone at the interim analysis.
The FDA has become very cautious with PAPR inhibitors after some long-term data in ovarian cancer pointed to potential harm to certain later-line patients without BRCA mutations. AZ and Lynparza felt that extra scrutiny last year when the FDA restricted an approval in metastatic prostate cancer to only BRCA-mutated tumors.
Now, it appears that AZ will need longer follow-ups to convince the FDA of Lynparza’s use in endometrial cancer as well.
The second question concerns AZ’s PD-1 competitors: GSK’s Jemperli and Merck’s Keytruda.
Although Jemperli and chemo’s initial nod in first-line endometrial cancer was only for dMMR patients, GSK has followed the phase 3 RUBY trial longer and recently got FDA priority review for its new application in the overall population. The target decision date is August 23.
However, GSK has yet to make a move for its combination that includes the PARP inhibitor ZejulaPARP inhibitor Zejula. Part 2 of GSK’s RUBY trial showed a similar pattern as AZ’s DUO-E, as the addition of Zejula to Jemperli and chemo only appeared to have meaningful benefits in pMMR tumors.
As to Merck, the New Jersey pharma has its application for Keytruda and chemo in first-line endometrial cancer under FDA priority review, with a target action date of June 21.
Data from the phase 3 NRG-GY018 trial released last year showed the Keytruda-chemo combo improved PFS by 46% in pMMR patients and by 70% in dMMR. However, investigators of the study noted back then that the follow-up time for pMMR patients was too short.
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