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Immunotherapy and Targeted Treatments for mNSCLC: Some Updates from ESMO 2022

Presentation by Neal Ready, MD, PhD, Duke Health at ESMO22 Pennsylvania.

Treatment of patients with metastatic, non-small cell lung cancer (mNSCLC) was once limited to platinum-based chemotherapies with poor tolerability. Today we have, as an integral component of treatment, immunotherapies, which stimulate the body’s immune system to attack cancer cells, and targeted, or molecular therapies, which target a specific molecular alteration, or mutation, that drives cancer growth. At this year’s third ESMO US review session in Philadelphia, PA, Dr Neal Ready from Duke Health discussed relevant updates on these mNSCLC treatments from the ESMO 2022 Congress, with particular emphasis on those abstracts which spoke to areas of significant unmet need in mNSCLC.

IPSOS - Immunotherapy

Dr Ready noted that the most common types of patients who present with mNSCLC have been almost completely excluded from major clinical trials. These include patients 70 years or older (approximately 50% of presenting mNSCLC patients), and those with poor performance status (PS). As such, the IPSOS trial presented at ESMO 2022 was unique in that it sought to investigate the efficacy of the immunotherapy atezolizumab versus single-agent chemotherapy of the investigator’s choice (vinorelbine or gemcitabine), in a population of patients who would not otherwise be candidates for the standard platinum doublet chemotherapy regimen, specifically those who were either 70 or older or who had poor PS, defined as a PS of 2 or 3.

While patients with EGFR or ALK mutations were excluded from this trial (as they are known not to derive meaningful benefit from immunotherapy), the median age of patients in IPSOS was 75 years (approximately 10 years older than a typical mNSCLC trial), and over 80% of patients had a poor PS of 2 or 3. In addition, patients with treated brain metastases were permitted in the trial, and brain metastases are frequently observed in patients presenting with mNSCLC in a real-world setting. Results showed that the primary endpoint of overall survival (OS) was significantly better for patients receiving immunotherapy versus chemotherapy, and OS was better in nearly all relevant patient subgroups. While the improvement in survival was not as impressive as in other immunotherapy trials in mNSCLC (10.3 months versus 9.2 months), Dr Ready emphasized that by the landmark of 2 years, OS was nearly doubled (24.3 mo vs. 12.4 mo), overall response rate (ORR) was more than doubled with atezolizumab versus chemotherapy (16.9% vs 7.9%), and the duration of response was over one year (14.0 months) with atezolizumab, suggesting that immunotherapy is an attractive first line treatment option for this very frail population. In addition, treatment-related adverse events (AEs), serious AEs, and deaths were lower with atezolizumab, with no new safety signals observed. Dr Ready also noted that there was a worsening of quality-of-life (QoL) measures for patients on chemotherapy, while these measures remained stable with atezolizumab. Taken together, the results suggest that immunotherapy with atezolizumab can provide good disease control for this highly relevant, older, sicker, population of patients with mNSCLC, while sparing the harmful effects of chemotherapy.

CodeBreaK 200 – Targeted Therapy

Dr Ready also reviewed data from the CodeBreak 200 study of the targeted agent sotorasib (as compared with the chemotherapy docetaxel) for the treatment of mNSCLC patients with a specific mutation called KRAS G12C who had relapsed on a prior treatment for their disease. He noted that KRAS mutations are commonly seen in mNSCLC, about 30% of the time, and about 40% of these mutations are KRAS G12C. Thus, there are a large number of patients, between 10 and 12% of all lung adenocarcinomas, who have this mutation, a percentage that is similar to the incidence of EGFR mutations. Sotorasib is a “first-in-class” targeted agent for patients with KRAS G12C, and Dr Ready noted this mutation has been especially difficult to target with drug therapy, unlike other mutations like EGFR which are frequently seen in mNSCLC.

The patients in the trial were well-balanced for prior lines of therapy as well as immunotherapy parameters such as programmed death ligand 1 (PD-L1) expression. The 12-month progression free survival (PFS) rate was more than doubled with sotorasib as compared with standard dose docetaxel (24.8 mo vs. 10.1 mo), and a benefit was observed across all relevant patient subgroups. Other important endpoints, including ORR, disease control rate, and duration of responses were also better with sotorasib as compared with docetaxel. While the study was not sufficiently powered to detect a difference in OS, and no such difference was observed, Dr Ready noted that the drug was overall well tolerated, and there were fewer AEs of grade 3 or higher with sotorasib. In addition, several patient reported QoL measures including global health status, physical functioning, and symptoms like shortness of breath and cough remained stable for a significantly longer period with sotorasib relative to the chemotherapy. Taken together, the results from the trial identify sotorasib as an important new option for mNSCLC patients with this specific mutation, and suggest that patients who relapse on a prior therapy should be tested for KRAS G12C to see if they are a candidate for this therapy. Dr Ready also emphasized the potential benefits of an oral therapy which can be taken at home and does not require an infusion.

INSIGHT 2 – Targeted Therapy

Another significant unmet need in mNSCLC which Dr Ready highlighted was what to do for patients who progress on molecular therapies such as osimertinib. In this regard, results from a Phase II study of another targeted therapy, tepotinib plus osimertinib was reported at ESMO 2022. Dr Ready noted that tepotinib plus osimertinib is a promising combination for patients with an EGFR mutation (EGFRm) who progress after first line (1L) osimertinib and who also have a specific molecular alteration called MET amplification (METamp). He noted that METamp can occur in as many as 30% of patients with mNSCLC who develop resistance to 1L osimertinib, and is associated with poor prognosis for these patients. In this study (INSIGHT 2), most patients received tepotinib, a MET inhibitor, in combination with the EGFR inhibitor osimertinib; accrual was halted in another monotherapy arm with tepotinib only, due to a low response rate.

The results showed a confirmed ORR of 54.5% for patients with 9 or more months of follow up, and a majority of patients had shrinkage of their tumors. Responses occurred within 6 weeks and half of patients who responded had been treated for 6 months or more. Overall the safety profile was consistent with the known individual safety profiles for tepotinib and osimertinib, and AEs led to dose reduction in 18.2% and treatment discontinuation in 6.8% of patients. Taken together, the results show the combination therapy of tepotinib and osimertinib to be an active oral regimen for patients with EGFRm and METamp who progress after 1L osimertinib, potentially allowing these patients to be spared chemotherapy. Dr Ready noted the results are especially promising for younger mNSCLC patients on molecular therapies who progress, as combination therapy such as this can allow them to continue targeted treatment for a longer period of time, although tepotinib plus osimertinib in METamp lung cancer is not yet an FDA approved regimen.

See more from the 2022 ESMO Pennsylvania Conference here.

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