ALRN-6924 Shows Improved Chemotherapy Cycle Completion Vs Placebo in p53-Mutated NSCLC

Results from a phase 1b chemoprotection trial (NCT04022876) indicated that patients with p53-mutated non–small cell lung cancer (NSCLC) undergoing treatment with first-line carboplatin plus pemetrexed with or without immune checkpoint inhibitors who were given ALRN-6924 were able to stay on treatment longer compared with the placebo, according to a press release from Aileron.

Ninety-three percent of patients in the ALRN-6942 arm completed the first 4 cycles of treatment vs 78% of those in the placebo arm. Additionally, when evaluating the completion rate up to cycle 6, investigators reported that 79% in the ALRN-6942 arm stayed on treatment longer vs 57% in the placebo arm.

“We remain passionate about advancing ALRN-6924 for patients with p53-mutated cancer, and these interim NSCLC findings have significantly helped to clarify our development path toward that goal. We are very encouraged by the finding that ALRN-6924-treated patients were able to complete more cycles of chemotherapy in the NSCLC trial, but unfortunately, it also appears that this may have worked against us given the nature of the exploratory composite primary endpoint. The more cycles patients completed, the more opportunity they had to experience toxicities. This introduced an imbalance of toxicities between the active and placebo arms and, may have resulted in a bias against ALRN-6924 on the composite primary endpoint,” Manuel Aivado, MD, PhD, president and chief executive officer at Aileron, said in the press release.

A total of 20 patients were included in the interim analysis who received either 0.3 mg/kg of ALRN-6924 plus carboplatin plus pemetrexed (n = 11) or placebo plus carboplatin and pemetrexed (n = 9). Investigators noted that the imbalance of completed cycles between treatment arms may have led to bias of ALRN-6924 of the composite primary end point.

The median progression-free survival was 4.6 months in the ALRN-6942 arm and 3.2 months in the placebo arm.

Adverse effects (AEs) of grade 3 or higher included neutropenia (45% vs 22%), thrombocytopenia (45% vs 44%), and anemia (9% vs 22%) in the ALRN-6924 and placebo arms, respectively. Other grade 3 or higher AEs of note were blood transfusions, the use of growth factors, and dose reductions or delays during the first 4 cycles of treatment in 56% of cycles for the ALRN-6924 vs 50% in the placebo arm. Grade 4 hematologic AEs occurred in 3 patients, including 1 patient in the ALRN-6924 arm and 2 in the placebo.

Investigators believe that a higher dose of ALRN-6924 will provide more durable cell cycle arrest and more chemoprotection again chemotherapy. Patients had increased p53 activation which correlated to cell cycle arrest in the bone marrow. Key ideas that were learned from this trial will be applied to the phase 1b breast trial, where the primary end point will be updated to the duration of severe neutropenia during cycle 1, and adjusting the chemotherapy regimen to allow for simultaneous administration of doxorubicin, cyclophosphamide, and docetaxel.

“By stopping the NSCLC trial, we plan to fully focus our resources on our Phase 1b breast cancer trial to continue our development of ALRN-6924 to protect patients with p53-mutated cancer from chemotherapy-induced [adverse] effects. Neoadjuvant chemotherapy for breast cancer is associated with frequent severe neutropenia in cycle 1, and we believe this offers a well-established end point, which has been used to secure FDA approval of multiple supportive care drugs. This end point also obviates any potential imbalance in the number of cycles completed on ALRN-6924 vs placebo. The breast cancer trial also gives us the ability to evaluate protection against alopecia, which occurs in more than 90% of patients with breast cancer on neoadjuvant chemotherapy compared to less than 10% of patients receiving carboplatin/pemetrexed,” Aivado concluded.

Reference

Aileon Therapeutics announces interim data from phase 1b chemoprotection trial of ALRN-6924 in patients with p53-mutated non–small cell lung cancer (NSCLC) and confirms development path for ALRN-6924 focused on p53-mutated breast cancer. News Release. Aileron. June 29, 2022. Accessed June 30, 2022. https://bit.ly/3yuTfxv