Initial results from the phase 3 IPSOS trial (NCT03191786) showed that frontline atezolizumab improved the 24-month overall survival (OS) to 24.3%, compared with 12.4% for single-agent chemotherapy in patients with stage IIIB/IV non-small cell lung cancer (NSCLC) who are ineligible for platinum-based therapies. These findings were presented by Prof. Siow Ming Lee (University College London Hospitals, UK) as a Presidential Address at the European Society of Medical Oncology (ESMO) 2022 Congress, held in Paris, France 9-13 Sept [1]. Physician’s Weekly interviewed Prof. Lee.

“IPSOS is the first randomized study to show that first-line treatment with atezolizumab improves overall survival in this poor-prognosis NSCLC population unfit for standard platinum chemotherapy with no EGFR or ALK alterations, regardless of histology, PD-L1 status, and ECOG performance status,” said Prof. Lee during his presentation.

The trial included stage IIIB/IV NSCLC patients (n=453) not eligible for platinum-based treatments who were randomized to receive atezolizumab (n=302) or single-agent chemotherapy with vinorelbine or gemcitabine (n=151). With a median follow-up of 41.0 months, there was a significant improvement in OS favoring the atezolizumab arm (10.3 months versus 9.2 months; HR 0.78; 95% CI 0.63-0.97; P=0.028). The 12-month OS rate was 43.7% for patients receiving atezolizumab, and 38.6% for those receiving chemotherapy. The 24-month OS rates were 24.3% and 12.4%, respectively. However, there was no difference in progression-free survival (PFS) between the treatment arms (4.2 months for atezolizumab versus 4.0 months; HR 0.87; 95% CI 0.70-1.07; not significant).

The overall response rate was 16.9% in the atezolizumab arm and 7.9% in the chemotherapy arm. The median duration of response was 14.0 months and 7.8 months, respectively.

Safety favored atezolizumab as well, with grade 3-4 adverse events (AEs) related to study treatment were reported in 16.3% of patients in the atezolizumab arm and 33.3% of patients in the chemotherapy arm. Serious treatment-related AEs occurred in 11.7% and 15.6%, respectively. Grade 5 fatal AEs occurred in 3 patients in the atezolizumab arm and 4 patients in the chemotherapy arm.

We interviewed Prof. Lee to position these results in context:

There is a notable unmet need in poor-prognosis NSCLC patients; how did IPSOS try to address that?

“As background, cancer immunotherapy treatment has transformed the landscape for metastatic NSCLC populations since 2016, but these treatments are mainly recommended for fit patients as per ASCO guidelines and others. I must emphasize that it is important to remember that all these first-line pivotal NSCLC trials comparing immunotherapy alone or in combination with chemotherapy against standard platinum chemotherapy were all conducted on relatively fit patients (ECOG PS 0 or 1) able to tolerate standard platinum chemotherapy with median age ranging from 62-65 years old.

In the real world, in contrast to these selected study cohorts above, we have a large population of NSCLC patients who are predominantly elderly with poor performance status, with a lot of comorbidities including renal impairment and perhaps also taking multiple comorbid medications for their underlying heart, diabetes, lung or rheumatological disorder which we see regularly in our clinics for which we would not treat with standard platinum chemotherapy because of poor tolerance and increased toxicity. They are not your typical patient you select for clinical trials. In the UK, when we did our last UK Lung Cancer audit last year [2], we discovered only 47% of our patients had a good performance status (PS) of 0 or 1, whereas most of them have poor performance status of 2 or greater. Even among our good performance status NSCLC patients, only 55% receive formal systemic treatment because of significant comorbidities contraindication.

IPSOS trial was designed to examine the role of first-line immunotherapy treatment with atezolizumab comparing against the less effective single chemotherapy as recommended by several treatment guidelines to treat these poor prognosis NSCLC patients with a median survival less than 6 months. We also included PS 3 patients and elderly patients with significant contraindications for platinum chemotherapy. With IPSOS trial, we met the primary endpoint of overall survival in patients that had a poor prognosis considered unfit for standard platinum chemotherapy. Our result is as impressive or better when compared to other studies examining the role of first line platinum chemotherapy regimens to treat good performance PS 0 and 1 patient including the classic ECOG 1594 study examining four new 3rd generation platinum doublet chemotherapies where they had to stop recruiting PS2 patients due to excessive toxicity and deaths. One in four patients in IPSOS is still alive at two years, with a response rate which has moved from single number to double number, which is impressive with just immunotherapy monotherapy alone. We also see a doubling of the disease response rate and duration of disease response from this single agent immunotherapy treatment alone

I would also like to point out that in the quality-of-life data, which was a secondary endpoint of IPSOS, we observed stabilization over the long term of many functional domains of the patient’s life including role function, social function and cognitive function when treated with atezoluzumab. We also saw improvement in patient-reported outcomes of cough, chest pain and appetite loss when compared against single agent chemotherapy.

No new or unexpected safety concerns were noted for this poor prognosis population when treated with atezolizumab. One unique aspect of IPSOS is that we included PDL1-negative patients, and we discovered it still works regardless of their tumour PD-L1 expression level. These results will probably change the treatment landscape for this poor prognosis population considered unfit for standard platinum chemotherapy treatment currently treated with the less effective single agent chemotherapy or offered best supportive care.”

What are some of the upcoming studies that are going to be following up on this data?

“We are trying to work out why atezolizumab works for some of our patients so that we can personalize IO treatment similar to personalized TKI treatment for oncogenic NSCLC.

We are planning to conduct exploratory biomarker analyses on the tumour and blood samples collected from our IPSOS trial patients to attempt to identify predictive biomarker of response and toxicity for our poor prognosis NSCLC patients.

We also need to work out whether we can further boost immune response for patients where IO does not work well from our study so that we can design newer drugs combination trial with atezolizumab for this unfit NSCLC population.”