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PARIS -- Treatment with a PD-L1 inhibitor held a survival advantage over single-agent chemotherapy for unfit non-small cell lung cancer (NSCLC) patients ineligible for platinum doublets, findings from the IPSOS trial showed.

The randomized study met its primary endpoint, showing that atezolizumab (Tecentriq) significantly improved overall survival (OS) compared with physician's choice of chemotherapy (HR 0.78, 95% CI 0.63-0.97, P=0.029), reported Siow-Ming Lee, MD, PhD, of University College London, at the annual European Society for Medical Oncology (ESMO) congress.

While there was only a 1-month improvement in median OS (10.3 vs 9.2 months), landmark analyses showed that twice as many patients treated with the PD-L1 inhibitor were alive at 2 years:

• OS at 1 year: 44% vs 39%
• OS at 2 years: 24% vs 12%

"IPSOS is the first randomized study to show that first-line treatment with atezolizumab improves overall survival in this poor-prognosis NSCLC population," said Lee, noting that the population excluded those with EGFR or ALK alterations, and that the OS benefit was observed regardless of histology, PD-L1 status, or patients' performance status.

He added that the survival benefit achieved with atezolizumab rivals that of a fit NSCLC population treated with platinum doublets, as seen in the (31-36% at 1 year, 10-13% at 2 years). "You have to take this into perspective," he said.

ESMO discussant Natasha Leighl, MD, of the Princess Margaret Cancer Centre in Toronto, called the findings "a tremendous breakthrough" for this unfit group of patients, and noted that along with the "amazing" doubling of survival at 2 years, patients in the atezolizumab arm had a doubling of response rate (16.9% vs 7.9%), and a near doubling of the duration of response (14 vs 7.8 months).

"This study has enrolled patients that historically are excluded or underrepresented in trials, and yet really represent the majority of patients that we diagnose and treat around the world," she said.

Numerous trials have demonstrated the benefit of anti-PD-1/L1 in NSCLC, either as single agents or in combination with platinum-based chemotherapy, but most only opened up enrollment to fitter patients, meaning those with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

For the IPSOS trial, patients were considered platinum ineligible if they had an ECOG performance status of 2 or 3, while those with a score of 0 or 1 were only allowed if they were 70 or older and had substantial comorbidities.

Lee described the type of unfit patient clinicians should now be looking to treat with a checkpoint inhibitor: "They come to you on a walking stick, with a comorbid problem -- renal impairment, a lung problem, a cardiac problem -- you would be scared to even try doublet chemotherapy."

No significant difference in progression-free survival was seen in the study (HR 0.87, 95% CI 0.70-1.07), though landmark analysis showed numerically more patients alive and without progression in the atezolizumab arm at both 1 and 2 years.

Investigators found no significant improvement in quality of life with atezolizumab, but also no deterioration.

"On balance, I think patients felt better on atezolizumab than chemotherapy, with fewer treatment-related adverse events, and some numerically lower rates of toxic deaths," said Leighl.

On the ESMO benefit scale, the treatment ranked a "perfect" five out of five, said Leighl, but she cautioned that giving all unfit patients atezolizumab upfront could come with financial toxicity. The PD-L1 inhibitor lists at $13,805, as compared with $4,000 for gemcitabine and $260 for vinorelbine, the two chemotherapy options allowed in the trial.

"If we're now going to treat everyone with atezolizumab, I think the budget impact of this is going to be huge," said Leighl.

From 2017 to 2019, IPSOS randomized 453 treatment-naive stage IIIB/IV NSCLC patients 2:1 to either atezolizumab or physician's choice of chemotherapy.

Participants had a median age of 75 years (about 30% were 80 or older), and about two-thirds were white. Three-fourths had an ECOG performance status of 2, and 8% had an ECOG score of 3. The trial included patients with both squamous (43%) and non-squamous (57%) histology, and 9% had treated asymptomatic brain metastases. Slightly more patients in the chemotherapy arm had a PD-L1 expression level of 1% or greater (52% vs 42% in the atezolizumab arm).

Overall, more patients in the chemotherapy arm went on to receive subsequent treatment (30% vs 20%), and while crossover was not allowed, 19% of patients in the chemotherapy arm ultimately received a checkpoint inhibitor.

Grade ≥3 treatment-related adverse events occurred half as frequently in the atezolizumab arm (16% vs 33%), and serious adverse events were also less frequent with the PD-L1 inhibitor (12% vs 16%).

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