Atezolizumab bests chemo in advanced NSCLC

First-line immunotherapy treatment with atezolizumab – a PD-L1 inhibitor – offers a survival advantage over single-agent chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) who are ineligible for platinum doublets in the phase III IPSOS trial.  

Atezolizumab significantly improved overall survival (OS) vs physician’s choice of single-agent chemotherapy (hazard ratio [HR], 0.78, 95 percent confidence interval [CI], 0.63–0.97; p=0.028), meeting the trial’s primary endpoint. [ESMO 2022, abstract LBA11]

“More importantly, 44 percent of patients in the atezolizumab arm remain alive at 1 year and 24 percent remain alive at 2 years,” reported study investigator Dr Siow Ming Lee, professor of medical oncology and consultant medical oncologist at University College London Hospital, London, UK, at ESMO 2022. “We are talking about one in four NSCLC patients with poor performance status who are unfit for platinum-based treatment but are still alive at 2 years.”

OS benefit was consistent regardless of patients’ age, PD-L1 status, ECOG* performance status (PS), and histology type, he added.

Platinum doublets not for all

Platinum-based chemotherapy (carboplatin or cisplatin) remains the standard first-line treatment for most patients with advanced NSCLC. But many patients with advanced-stage lung cancer cannot tolerate platinum-containing regimens, said Lee.

“For over 2 decades, clinical trials have not brought significant improvement to this neglected population, who are not offered standard immunotherapy,” he continued. “IPSOS is the first randomized trial to show that first-line treatment with atezolizumab significantly improves OS in patients with poor prognosis and no EGFR or ALK alterations. Again, this is regardless of histology, PD-L1 status, and ECOG PS.”

Tremendous breakthrough

ESMO discussant Dr Natasha Leighl of the Princess Margaret Center in Toronto, Canada described the findings as “a tremendous breakthrough.” She noted that along with a doubling of survival at 2 years, patients in the atezolizumab arm had a doubling of response rate, and a near doubling of the duration of response.

“IPSOS enrolled patients that historically are excluded in trials but represent the majority of patients we diagnose and treat each day,” she pointed out.

“These are patients who come to you on a walking stick, with comorbidities such as renal or lung problems, or a cardiac problem, that you would be scared to even put on doublet chemotherapy,” added Lee.

IPSOS population

The trial included 453 patients with treatment-naïve, stage IIIB/IV NSCLC, who were ineligible for platinum-containing chemotherapy due to poor ECOG PS (≥2), or were older and had significant comorbidities. The patients were randomized 2:1 to atezolizumab (n=302) or single-agent chemotherapy with vinorelbine or gemcitabine (n= 151) in 3- or 4-week cycles.

Patients’ median age was 75 years,  31 percent were ≥80 years of age, 72 percent were male, and 83 percent had an ECOG  PS ≥2. Fifty-seven percent of patients had non-squamous histology. Nearly 90 percent were current or former smokers.

At data cut-off on April 30, 2022, the median OS was 10.3 months with atezolizumab vs 9.2 months with single-agent chemotherapy, resulting in a 22-percent reduction in the risk of death with atezolizumab.

Twice as many patients on atezolizumab remained alive at 24 months (24.3 percent vs 12.4 percent with chemotherapy). The 12-month OS rates were 43.7 percent and 38.6 percent, respectively, reported Lee.

There was no significant difference in progression-free survival (PFS) between arms (HR,0.87), although median PFS was numerically higher with atezolizumab (4.2 vs 4.0 months with chemotherapy). The 12-month PFS rates were 19.7 and 14.2 percent; the 24-month PFS rates were 8.9 percent and 1.6 percent, respectively.

Overall response rates (ORRs) were 16.9 percent and 7.9 percent with the atezolizumab and chemotherapy arms. The median DoR was 14.0 months and 7.8 months, respectively. Overall, there were more patients in the chemotherapy arm who went on to receive subsequent treatment (29.8 percent vs 20.2 percent with atezolizumab). While crossover was not allowed, 19 percent of patients in the chemotherapy arm ultimately received a checkpoint inhibitor.

Additionally, meaningful changes were reported across disease-and treatment-related symptoms, including improved time to confirmed deterioration of chest pain and improvement in appetite loss and cough with atezolizumab.

Grade 3 or 4 treatment-related adverse events (TRAEs) were less frequent with atezolizumab (16.3 percent vs 33.3 percent), and so were serious adverse events (12 percent vs 16 percent).

“I think patients felt better on atezolizumab than chemotherapy, with fewer TRAEs, and numerically lower rates of toxic deaths,” said Leighl.

“There weren’t any new or unexpected safety signals with atezolizumab,” added Lee. “This is important as we wanted to do no harm to these patients. Reassuringly, we do not see any added toxicity compared with the historical control or what had been published in pivotal studies.”

Expert perspectives

Dr Lizza Hendriks of Maastricht University Medical Center, Netherlands, who is not affiliated with the trial, said the results are “reassuring” because the median OS for the atezolizumab arm in the IPSOS trial is comparable to that seen from the PePS2 trial of pembrolizumab monotherapy in PS2 patients with NSCLC. [Lancet Respir Med 2020;8:895-904]

“This confirms that for select patients with PS ≥2 and those aged ≥70 years with comorbidities, immunotherapy is a good option. We know these patients were historically excluded from pivotal clinical trials, so this is really a patient population with an unmet therapeutic need.”

She explained that PS ≥2 can be a result of cancer or multiple comorbidities, making it more difficult to determine the optimal management strategy for these patients. “If you have a rapidly deteriorating patient, it would be quite difficult to derive benefit from any treatment, including immunotherapy,” she added.