ESMO 2023: LBA41
AstraZeneca is exploring a potentially powerful approach in the fight against endometrial cancer, suggesting that combining their drug Imfinzi with Merck-partnered Lynparza may offer a promising new avenue.
Results from the phase 3 DUO-E trial, unveiled at the European Society for Medical Oncology (ESMO) 2023 Congress in Madrid, reveal a significant reduction in the risk of disease progression or death when Imfinzi and Lynparza are added to chemotherapy for patients with newly diagnosed advanced or recurrent endometrial cancer. The risk decreased by an impressive 45% with the triplet combination, while the addition of Imfinzi alone to chemotherapy still cut that risk by a notable 29%.
Dr. Cristian Massacesi, Chief Medical Officer and Chief Development Officer in Oncology at AstraZeneca, stated that the DUO-E study achieved its primary endpoint for both the doublet and triplet regimens across the overall trial population. However, some patients appeared to benefit more than others, depending on their specific characteristics.
Notably, Imfinzi has a strong track record against tumors with mismatch repair deficiency (dMMR). In these cases, Imfinzi combined with chemotherapy reduced the risk of progression or death by 58%. Surprisingly, the addition of Lynparza did not provide an extra benefit, as the triplet combination achieved the same risk reduction of 59% compared to chemotherapy alone.
In the pMMR subgroup, the Imfinzi-chemo combo reduced the risk of progression or death by 23% compared to chemotherapy alone. However, the Lynparza-containing triplet significantly improved this figure to 43%.
Dr. Massacesi acknowledged that the primary potential of the doublet and triplet combination lies in the MMR-proficient population, where immunotherapies have less influence.
For the dMMR population, the Imfinzi-chemo combo’s progression-free survival (PFS) benefit of 58% was slightly lower than the impressive 70%-plus benefit seen with other drugs in separate first-line endometrial cancer trials.
In the pMMR subgroup, the Imfinzi-chemo combo’s risk reduction of 23% was similar to what was observed in other trials. Although the median PFS improvement was only 0.2 months, Dr. Massacesi pointed out that Imfinzi’s benefits often manifest later in the treatment process.
Regarding regulatory plans, Dr. Massacesi did not comment on AstraZeneca’s strategy, leaving the question open as to whether they will seek FDA approval for both the doublet and triplet for all patients, regardless of dMMR or pMMR status. He referred to GSK’s recent success with Jemperli, which received fast FDA approval for first-line dMMR endometrial cancer while awaiting more data for the pMMR population.
Merck’s Keytruda has also shown promise with a 46% PFS improvement in the pMMR population in the NRG-GY018 trial. However, more data is needed for a definitive decision on FDA approval for a first-line endometrial cancer indication.
The FDA has raised concerns about PARP inhibitors like Lynparza, particularly in late-stage treatment, as some data has suggested that these drugs may lead to long-term harm to patient survival, especially in tumors without specific genetic mutations, despite initial benefits in disease progression.
The DUO-E trial showed a 23% reduction in the risk of death with the Imfinzi-chemo combination, and a 41% reduction with the Imfinzi-Lynparza-chemo regimen, although the data remains somewhat immature.
Moreover, researchers are still investigating why Asian patients, constituting around one-third of the DUO-E population, did not seem to benefit from the Imfinzi-chemo doublet.
The question of whether Imfinzi is the best immunotherapy partner for Lynparza in the context of endometrial cancer remains open. Dr. Massacesi noted that, for now, Imfinzi is the only one with relevant data in this regard.
Conclusion
AstraZeneca’s phase 3 DUO-E trial has demonstrated a significant reduction in the risk of disease progression or death in patients with advanced or recurrent endometrial cancer when Imfinzi and Lynparza are added to chemotherapy. The triplet combination showed an impressive 45% risk reduction, while Imfinzi alone cut the risk by 29%. Notably, Imfinzi’s strength lies in tumors with mismatch repair deficiency (dMMR), while Lynparza did not provide additional benefits in this context. The primary potential of these combinations appears to be in the MMR-proficient population. However, regulatory plans for these combinations remain unclear, with further data and FDA considerations needed. The question of the best immunotherapy partner for Lynparza in endometrial cancer treatment is still open.
