2022 Top Story in Oncology: Immunotherapy for the First-Line Treatment of Metastatic/Recurrent NSCLC

Since the beginning of 2022, the experts of the PracticeUpdate Lung Cancer Center of Excellence have reviewed 191 articles published on thoracic tumors. The majority were selected to be posted on the PracticeUpdate Lung Cancer channel. The most significant papers addressed questions related to new therapeutic approaches, most often in the field of immunotherapy.

In patients with metastatic/recurrent non–small cell lung cancer (NSCLC), studies on the use of immune checkpoint inhibitors (ICIs) have confirmed with a longer follow-up that immunotherapy for the first-line treatment of advanced or recurrent disease is the new standard of care (SOC) as compared with conventional chemotherapy and should be now considered as the reference treatment to be challenged in clinical trial designs in the future. In most of the randomized trials published this year, overall survival (OS) is clearly improved, with a durable effect and an acceptable tolerance profile and no late side effects. Long-term (>5 years) follow-up provides such evidence for the combination of nivolumab–ipilimumab,¹ pembrolizumab,² and, to a lesser extent, durvalumab–tremelimumab.³ With the use of ICIs in the first-line setting, the 5-year survival rate in these trials reached 20% to 25%. Data generated in real-world practice, in addition, seem to confirm the important role of ICIs. The data published so far in 2022 showed a paradigm shift in the management of metastatic/recurrent NSCLC. Some questions, however, remain unanswered, including the duration of treatment and need for maintenance, rechallenge at progression, better patient selection, and mechanisms of resistance.

Similarly, in patients with locally advanced and potentially curable disease, immunotherapy with ICIs has shown promising and even established efficacy. In locally advanced unresectable NSCLC, the initial encouraging results of the PACIFIC trials are now confirmed after 5 years of follow-up,^4,5 and the use of durvalumab after concurrent chemotherapy/radiotherapy is the present SOC. Questions remain unanswered and should be addressed in further trials, such as the duration of consolidation treatment and the use of sequential rather than concurrent chemotherapy radiation for accessibility reasons. The use of immunotherapy in resectable stages is also paving its way. Nivolumab combined with chemotherapy for patients with stages IB to IIIA disease in CheckMate 816^6,7 showed an impressive pathologic complete response (pCR) rate that was 10 times higher than that with chemotherapy alone and a reduction in the risk of recurrence or death of 47%. A longer follow-up is needed to assess the benefit in terms of OS, but the present published results are quite encouraging.

In addition, data emerging from randomized trials monitoring patients undergoing treatment with the measurement of circulating tumor DNA (ctDNA) are promising. In CheckMate 816, preliminary data showed a good correlation between ctDNA clearance and event-free survival and pCR. Similarly, in the NADIM trial,⁸ the 3-year OS was associated with ctDNA levels and was more accurate than RECIST in predicting survival. The use of immunotherapy in the neo-adjuvant setting reopens the long-lasting debate on neoadjuvant therapy, and the use of circulating biomarkers such as circulating ctDNA might engage a new paradigm shift.