The Biggest Advance of 2023: Immunotherapy for Operable Lung Cancer

The year 2023 marked a major turning point in treating operable lung cancer. This year, several important clinical trials were reported in operable non–small-cell lung cancer (NSCLC) involving immunotherapies from the immune checkpoint inhibitor class as part of treatment.

These immunotherapy approaches, started before surgery, serve two important purposes in previously untreated patients:

1. Further shrinking the main tumor so that it can be removed more easily and effectively through surgery;
2. Enabling the immune system to recognize the tumor and triggering a systemic antitumor immune response.

In this way, immunotherapies aim to reduce the risk of cancer recurrence after surgery.

Recent clinical trials testing immunotherapies in operable NSCLC include:

• IMpower010 (atezolizumab),
• AEGEAN (durvalumab),
• CheckMate 77T (nivolumab),
• CheckMate 816 (nivolumab),
• KEYNOTE-671 (pembrolizumab), and
• Neotorch (toripalimab).

We already knew that immunotherapies were effective in advanced lung cancer, but these studies demonstrated their efficacy in treating early-stage lung cancer.

Most of these trials have short follow-up periods, and their current focus was event-free survival (EFS). They also examined the potential predictive value of major pathologic response (mPR) or pathologic complete response (pCR).

In most of these studies, immunotherapies were added to chemotherapy in the neoadjuvant (before surgery) or perioperative (before and after surgery) setting.

Summary of Study Results

IMpower010 is the only trial combining atezolizumab with chemotherapy versus chemotherapy alone in the adjuvant (after surgery) setting. The recently published first interim overall survival analysis showed no overall survival benefit in the entire trial population after a median follow-up of 45.3 months. A 57% reduction in the death rate was seen only in the subgroup with PD-L1 of 50% or higher. Following this study, atezolizumab became the first immunotherapy approved by the FDA, on October 15, 2021, for adjuvant treatment of stage 2 – 3A NSCLC with tumor-cell PD-L1 expression ≥ 1%.

AEGEAN is a perioperative trial using durvalumab combined with chemotherapy in the neoadjuvant setting. The primary endpoints were EFS and pCR. Adding durvalumab to chemotherapy yielded an EFS hazard ratio of 0.68.

The term "EFS hazard ratio of 0.68" here means that adding durvalumab reduced the risk of undesirable events, such as deterioration in health due to cancer, cancer recurrence, or death, by 32% compared with the control group without durvalumab.

The pCR rate was 17.2% with durvalumab versus 4.3% with placebo, and mPR was 33.3% in patients treated with durvalumab versus 12.3% in those treated with placebo.

CheckMate 816 is the only trial adding nivolumab to chemotherapy in the neoadjuvant setting. Additional postoperative chemotherapy or radiotherapy was allowed but not required. There were two coprimary endpoints: EFS and mPR. With at least 21 months of follow-up, the EFS hazard ratio was 0.63, a statistically significant result. The pCR rate was 24% versus 2.2% in favor of adding nivolumab to chemotherapy, with this benefit observed across all subgroups. Interestingly, the EFS hazard ratio in patients with pCR was 0.13.

CheckMate 77T has a design similar to CheckMate 816, but adds nivolumab in the adjuvant setting as part of a perioperative approach. With a median follow-up of 25.4 months, the EFS hazard ratio was 0.58—a 5-point improvement over CheckMate 816, possibly attributable to adjuvant nivolumab, although cross-trial comparisons have inherent limitations. The pCR rate was 25.3%, quite similar to that seen in CheckMate 816, and the EFS hazard ratio in the subgroup achieving pCR was 0.33.

KEYNOTE-671 tested pembrolizumab plus chemotherapy in a perioperative design similar to CheckMate 77T. With a median follow-up of 25.2 months, the EFS hazard ratio was 0.58. mPR was observed in 30.2% of patients in the pembrolizumab plus chemotherapy group versus 11% in the placebo group. pCR rates were 18.1% versus 4%, favoring pembrolizumab. At the time of publication, overall survival did not show a statistically significant difference; the overall survival data were immature and required longer follow-up, with the survival curves tending to separate at approximately month 24.

Neotorch is a Chinese trial involving Chinese patients with operable NSCLC. Toripalimab is an anti–PD-1 monoclonal antibody. In the phase III perioperative Neotorch trial, toripalimab combined with platinum-based chemotherapy followed by toripalimab maintenance was compared with chemotherapy. EFS and mPR were coprimary endpoints. In an interim analysis with a median follow-up of 18.3 months, the EFS hazard ratio was 0.40, mPR was 48.5% versus 8.4%, and pCR was 24.8% versus 1%, showing superiority in favor of toripalimab across all subgroups.

An indirect comparison of the study results can be seen below:

Conclusion

In 2023, numerous important studies were published on the efficacy of immunotherapies in early-stage, operable non–small-cell lung cancer (NSCLC). These consistently demonstrated the benefits and safety of immunotherapy, including in relation to surgery. Noticeable improvements were observed in EFS (event-free survival). mPR (major pathologic response) and pCR (pathologic complete response) were considered important measures of success. Longer follow-up will help us better understand the effects on overall survival. Detailed pathological analysis of tumors, advanced bioinformatics studies, and the discovery of new biomarkers are critical for predicting treatment success.

In conclusion, adding immunotherapies to the treatment of operable non–small-cell lung cancer is now becoming the new standard of care.