NSCLC: Immune-Related AEs May Predict Survival Outcomes

Andrew D. Bowser

June 07, 2021

Experiencing an immune-related adverse event during checkpoint inhibitor treatment may predict outcomes in patients with non-small cell lung cancer, exploratory analyses of phase 3 trials suggest.

Immune-related adverse events (irAEs) were tied to longer overall survival (OS) in exploratory pooled analyses of three phase 3 clinical trials evaluating atezolizumab-based regimens, according to investigator Mark A. Socinski, MD, of AdventHealth Cancer Institute, Orlando, Fla.

Median OS approached 26 months for patients who received first-line atezolizumab and experienced an irAE, compared with just 13 months for those who did not experience an irAE, according to results reported at the American Society of Clinical Oncology Annual Meeting (Abstract 9002).

Atezolizumab-treated patients with grade 3 or greater irAEs had the shortest OS, shorter than those atezolizumab-treated patients who experienced grade 1-2 irAEs or no irAEs at all. That short OS may be due to treatment interruptions or discontinuations, said Socinski.

"Data from these analyses suggest an association between irAEs and efficacy in patients with [non-small cell cancer] NSCLC," he stated in his presentation of the results.

A Lot More to Learn About irAEs

Similar linkages between irAEs and outcomes were observed in pooled analyses of patients enrolled in the control arms of the phase 3 trials, with a median OS of about 20 months for control patients experiencing an irAE, versus about 13 months for those who did not.

That linkage in the control arm prompted a question from an ASCO attendee about why an effect of irAEs, commonly associated with immune checkpoint inhibitor therapy, would be evident in analyses of patients who did not receive those agents.

In his response, Socinski characterized the finding as "a surprise" and said the finding may either reflect how adverse events are characterized or how chemotherapy impacts the immune system.

"I don't know that our definition of irAEs is perfect," he said, "and maybe we don't understand what impact chemotherapy may have on the immune system, and may actually engender what historically we've always seen as an adverse event, but didn't necessarily classify as an immune-related adverse event."

More work is needed to better understand the connection between irAES and outcomes, and whether anything can be done as a result of that improved understanding, said discussant Mary Weber Redman, PhD.

"The question is, 'what is actionable?'" added Redman, a biostatistician at the Fred Hutchinson Cancer Research Center, Seattle.

A firmer understanding of the relationship between irAEs and outcomes could change how clinicians monitor patients for irAEs, lead to better prediction of which patients may experience higher grade irAEs, and ultimately impact treatment selection potentially to avoid those higher grade events, Redman said in her remarks.

"Doing these types of analyses are quite important, because we have to look at the breadth of information that we have to be able to interpret that and think about what are future questions," she said in the question-and-answer session accompanying Socinski's presentation.

"I think the key is that we shouldn't use these analyses to be definitive, but we should use them as to be hypothesis generating," she added.

More Evidence to Link irAEs and Outcomes

Immune-related AEs caused by off-target immune and inflammatory activity have been reported in up to 80% of patients receiving immune checkpoint inhibitors as monotherapy and up to 95% in combination regimens, Socinski said in his presentation.

"Increasing evidence suggests that the occurrence of immune-related adverse events with PD-L1 or PD-1 inhibitor therapy may be predictive of improved outcomes in cancers such as NSCLC, " he added.

In their exploratory pooled analyses, Socinski and co-investigators looked at data from the phase 3 IMpower130 and IMpower132 trials, which evaluated first-line atezolizumab and chemotherapy for NSCLC, and the phase 3 IMpower150 trial, which evaluated atezolizumab plus chemotherapy with or without bevacizumab.

In all, they analyzed data for 1,557 atezolizumab-treated patients, and 900 patients who had been in the control arms of the studies.

Forty-eight percent of atezolizumab-treated patients experienced irAEs of any grade, while 11% experienced irAEs of grade 3-5, according to the presented data. In the control arm, 32% experienced irAEs of any grade and 5% experienced grade 3-5 irAEs.

The most common irAEs of any grade were rash, hepatitis, and hypothyroidism, occurring in 28%, 15%, and 12% of atezolizumab-treated patients, respectively.

Median OS in the atezolizumab arm was 25.7 months for patients with irAEs and 13.0 for patients with no irAEs, with a hazard ratio (HR) of 0.69 using a time-dependent Cox model.

Median OS in the control arm was 20.2 months for patients with irAEs and 12.8 months for patients with no irAEs, with an HR of 0.82.

The overall response rate (ORR) in the atezolizumab arm was 61.1% for patients with irAEs and 37.2% for those without irAEs; in the control arm, ORR was 42.2% for patients with irAEs and 34.0% for those with no irAEs.

Atezolizumab-treated patients who experienced grade 3-5 irAEs had the shortest OS, according to Socinski. The HRs for OS at 1, 3, 6, and 12 months in atezolizumab-treated patients with grade 3-5 irAEs (compared with those without irAEs) ranged from 1.25 to 0.87. By contrast, HRs at those time points for patients with grade 1-2 irAEs ranged from 0.78 to 0.72, Socinski said.

Socinski reported disclosures related to AstraZeneca/MedImmune, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech, Guardant Health, Janssen, Lilly, Merck, Novartis, Roche/Genentech, and Spectrum Pharmaceuticals. Redman reported a consulting or advisory role with AstraZeneca.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.


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