Adaptive NSCLC Study Fails to Produce Improved Results, Clinical Benefits in Some

Long-term benefits were improved in some patients with advanced non-small cell lung cancer (NSCLC) enrolled in experimental combination groups, although none of the groups met the study’s desired result, according to data presented at the 2024 ESMO Congress.

Of these combinations, Imfinzi (durvalumab) plus monalizumab and Imfinzi plus ceralasertib were the stand-out treatments in terms of benefit, according to Dr. Pascale Tomasini, an associate professor of thoracic oncology in the Multidisciplinary Oncology and Therapeutic Innovations Department of the Cancer Research Center in Marseille, France.

In a live presentation, Tomasini explained that the PIONeeR trial “used an innovative and adaptive design to identify signal of efficacy of new types of immunotherapy combinations.”

To explore new ways to overcome PD-(L)1 inhibitor resistance, 114 patients with advanced NSCLC were randomly assigned to one of four experimental groups or a control group. Patients on group A received Imfinzi plus monalizumab (28 patients), group B received Imfinzi plus oleclumab (MEDI9447; three patients), group C received Imfinzi plus ceralasertib (32 patients), group E received Imfinzi plus Orpathys (savolitinib; 20 patients), and the control group, group D, received Taxotere (docetaxel) (31 patients).

For this trial, the primary goal was the 12-week disease control rate (DCR; the proportion of a population that is protected against a specific disease), and secondary goals included objective response rate (ORR; the percentage of people whose disease shrinks or disappears after treatment), overall survival (OS; the time from the start of treatment when a patient with cancer is still alive), progression-free survival (PFS; how long a person lives without their disease getting worse), duration of response (DOR; the length of time a person's disease remains in remission after treatment) and safety and tolerability. The adaptive design of the trial was to let investigators stop groups quickly when there was a lack of efficacy and open new combination groups when data emerged.

The mean estimated 12-week DCR was 24.1% in group A, 50% in group C, 13.6% in group E, and 54.5% in the control group. The ORR, consisting of all partial responses, was 17.9% (five patients) in group C and 25% (five patients) in the control group in the evaluable population. In the total intention-to-treat population, the ORR was 15.6% in group C and 16.1% in the control group, respectively. Stable disease was observed in 42.9% of patients in group A, 66.7% in group B, 57.1% in group C, 30% in group E, and 50% in the control group.

“In the control [group] with [Taxotere], 31 patients were enrolled, but only 23 were treated mainly due to consent withdrawal,” Tomasini said. “Two [groups] had to be closed prematurely during the trial. [Group] B with the oleclumab was closed after only three patients enrolled because of lack of efficacy shown in a concomitant trial, the HUDSON study. In [group] E with Orpathys was closed after 20 patients enrolled because of lack of efficacy shown in the first interim analysis of the PIONeeR trial.”

The secondary goals of PFS and OS were available for groups A, C, E, and the control group. The median PFS was 1.6 months in group A, 4.1 months in group C, 1.4 months in group E, and 4.4 months in the control group. In these respective groups, the median OS was 11.7 months, 17.4 months, 7.1 months, and 13.8 months, although group C’s median OS was biased based on length of follow-up.

In terms of safety, treatment-related side effects were observed in 82.1% of group A, 100% of group B, 93.5% of group C, 95% of group E and 100% of the control group. Grade 3 (severe) or worse side effects related to treatment occurred in 7.1% of patients in group A, 33.3% in group B, 54.8% in group C, 30% in group E, and 43.5% in the control group. There was one treatment-related death, which occurred in group C.

There were three treatment interruptions and two discontinuations in group A, one each in group B, 10 interruptions and eight discontinuations in group C, nine interruptions and seven discontinuations in group E, and six each in the control group.

All the patients enrolled on PIONeeR had disease progression after more the six 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, most patients were male (61.4%), 53.5% had ECOG performance status of 1 (meaning patients were able to complete most daily tasks independently), and 46.5% had a status of 0 (completing daily tasks entirely independently). A small number of patients had liver (10.5%) or brain (7.9%) metastases. Sixty-six percent of patients experienced disease worsening or spreading on a prior line of therapy for more than 24 weeks before enrollment.

“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 group 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.”

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