Several IO Combos Miss Efficacy Target in NSCLC, But Clinical Benefit Seen With 2 Combos

Durvalumab plus monalizumab and durvalumab plus ceralasertib showed promising long-term benefits in advanced NSCLC.

Certain patients with advanced non–small cell lung cancer (NSCLC) experienced benefit when treated with various combination therapies in the phase 2 PIONeeR trial (NCT03833440), specifically those given durvalumab (Imfinzi) plus monalizumab (IPH2201) and durvalumab plus ceralasertib (AZD6738). However, no arms of the trial met the efficacy target, according to data presented at the 2024 ESMO Congress.1

To explore new ways to overcome PD-(L)1 inhibitor resistance, 114 patients with advanced NSCLC were randomly assigned to 1 of 4 experimental arms or a control arm. Patients on arm A received durvalumab plus monalizumab (n = 28), arm B received durvalumab plus oleclumab (MEDI9447; n = 3), arm C received durvalumab plus ceralasertib (n = 32), arm E received durvalumab plus savolitinib (Orpathys; n = 20), and the control arm, arm D, received docetaxel (n = 31).

In a presentation of the data, Pascale Tomasini, MD, MSc, an associate professor of thoracic oncology in the Multidisciplinary Oncology and Therapeutic Innovations Department of the Cancer Research Center in Marseille, France, explained that the PIONeeR trial “used an innovative and adaptive design to identify signal of efficacy of new types of immunotherapy combinations.”

The mean estimated 12-week DCR was 24.1% in arm A (95% CI, 10.7%-41.0%), 50.0% in arm C (95% CI, 33.1%-66.9%), 13.6% in arm E (95% CI, 3.0%-30.4%), and 54.5% (95% CI, 34.0%-74.3%) in the control arm. The ORR, consisting of all partial responses, was 17.9% (n = 5) in arm C and 25.0% (n = 5) in the control arm in the evaluable population. In the total intention-to-treat population, the ORR was 15.6% in arm C and 16.1% in the control arm, respectively. Stable disease was observed in 42.9% of patients in arm A, 66.7% in arm B, 57.1% in arm C, 30.0% in arm E, and 50.0% in the control arm.

“In the control arm with docetaxel, 31 patients were enrolled, but only 23 were treated mainly due to consent withdrawal,” Tomasini said. “Two arms had to be closed prematurely during the trial. Arm B with oleclumab was closed after only 3 patients enrolled because of lack of efficacy shown in a concomitant trial, the phase 2 HUDSON study [NCT03334617]. Arm E with savolitinib was closed after 20 patients enrolled because of lack of efficacy shown in the first interim analysis of the PIONeeR trial.”

For this trial, the primary end point was the 12-week disease control rate (DCR) by RECIST 1.1 criteria, and secondary end points included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), duration of response (DOR), and safety and tolerability. The adaptive design of the trial was to let investigators stop arms quickly when there was a lack of efficacy and open new combination arms when data emerge.

The secondary end points of PFS and OS were available for arms A, C, E, and the control group. The median PFS was 1.6 months in arm A (95% CI, 1.5-2.1), 4.1 months in arm C (95% CI, 2.8-7.2), 1.4 months in arm E (95% CI, 1.3-2.9), and 4.4 months in the control arm (95% CI, 1.6-7.8). In these respective arms, the median OS was 11.7 months (95% CI, 6.6-13.7), 17.4 months (95% CI, 5.5-21.7), 7.1 months (95% CI, 3.3-12.6), and 13.8 months (95% CI, 11.5-not evaluable), although arm C’s median OS was biased based on length of follow-up.

In terms of safety, treatment-related adverse events AEs were observed in 82.1% of arm A, 100% of arm B, 93.5% of arm C, 95.0% of arm E, and 100% of the control arm. Grade 3 or higher AEs related to treatment occurred in 7.1% of patients in arm A, 33.3% in arm B, 54.8% in arm C, 30.0% in arm E, and 43.5% in the control arm. There was 1 grade 5 AE related to treatment, which occurred in arm C.

There were 3 treatment interruptions and 2 discontinuations on arm A, 1 each on arm B, 10 interruptions and 8 discontinuations on arm C, 9 interruptions and 7 discontinuations on arm E, and 6 each on the control arm.

All the patients enrolled on PIONeeR had disease progression after more the 6 weeks of anti–PD-(L)1 therapy in the second or third line or more than 12 weeks of anti–PD-(L)1 plus platinum-based chemotherapy, and ECOG performance status of 0 or 1. Patients were stratified by center, squamous vs non-squamous histology, and progression on prior treatment before or after 24 weeks.

In the intention-to-treat population, the median age was 63 years (range, 32.0-85.0), most patients were male (61.4%), 53.5% had ECOG performance status of 1, and 46.5% had a status of 0. Only 12.3% of patients were non-smokers and most had non-epidermoid histology. A small number of patients had liver (10.5%) or brain (7.9%) metastases. Sixty-six percent of patients progressed on a prior line of therapy over 24 weeks before enrollment.

For the experimental arms, the investigators used Bayesian decision rules to decide whether an arm was not effective and should be closed. The futility rule at interim analysis meant the arm closed if there was a 90% or higher probability that estimated the 12-week DCR is less than or equal to 30%. The efficacy rule at final analysis considered further evaluation for an arm if there was a 90% or higher probability that the 12-week DCR was greater than or equal to the 12-week DCR in the control arm.

“In conclusion, the PIONeeR trial is an academic collaborative success in exploring how to overcome resistance to PD-1 and PD-L1 inhibitors in advanced NSCLC,” Tomasini said. “[While] no experimental arm formally met the efficacy target, we observed that some patients derived a long-term clinical benefit from some combinations, especially including ceralasertib and monalizumab and comprehensive biomarker analysis are ongoing to be able to predict among the patients who are likely to have this long-term clinical benefit.”

Reference

  1. Tomasini P, Cropet C, Jeanson A, et al. Precision immuno-oncology for advanced non-small cell lung cancer (NSCLC) patients with PD-(L)1 inhibitors resistance (PIONeeR): A phase Ib/IIa clinical trial targeting identified resistance pathways. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA8.