Neoadjuvant singular immunotherapy versus perioperative chemoimmunotherapy for early-stage lung cancer

Dr. Mariano Provencio, Hospital Universitario Puerta de Hierro, Spain, explained that options to improve poor lung cancer survival include adjuvant treatment for stage I and II and neoadjuvant treatment for stage III disease. Where both neoadjuvant and adjuvant treatments provide a clinically significant improvement of 5% in overall survival, neoadjuvant treatment also provides several theoretical advantages such as attacking micrometastasis from the beginning, better compliance, increased resectability, and better response assessment that enables the study of tumor biology and its treatment effects.

Dr. Provencio asserted, “I strongly believe that the question nowadays is no longer whether immunotherapy will play a role in the adjuvant setting, but whether it will be monotherapy or combined with chemotherapy.” For studies of monotherapy treatment, the sample size is usually less than 40 patients with approximately 33% of lung cancer patients in stage IIIA. Where major pathological response (MPR) to neoadjuvant treatment, defined as less than 10% residual tumor after neoadjuvant therapy, is a potential surrogate endpoint for survival, only 14% to 45% of patients have achieved MPR and 5% to 38% of them have achieved complete pathological response (CR).1 Dr. Provencio pointed out, “I think it is important to emphasize that despite being very early stages, there have been progression of the disease in these treatments with monotherapy in different percentages”. As for trials of chemotherapy in combination with immunotherapy, more than 90% of patients were in stage IIIA. MPR or CR was achieved by around 60% of patients with 70% to 90% of patients underwent downstaging.

Despite having 3 times more patients in stage IIIA disease, more than 3 times lung cancer patients in the combination trials achieved CR and MPR than in the monotherapy trials, indicating that combination chemoimmunotherapy is superior to monotherapy. However, a low proportion of patients have achieved CR and the association with survival outcomes has not been validated in NSCLC.2 Thus, a study was designed to investigate the effects of nivolumab plus paclitaxel-carboplatin in treatment-naïve patients with potentially resectable stage IIIA NSCLC.2

The addition of neoadjuvant nivolumab to chemotherapy was welltolerated and was not associated with surgical delays.2 Compared to adjuvant therapy, neoadjuvant therapy was shown to induce a stronger and more prolonged T-cell immune response that might confer long-term protection.1 Finally, all patients who achieved MPR or CR were alive at 24 months, and the progression-free survival among patients with CR was significantly higher when compared to those with MPR or incomplete pathological response.2 Although studies of longer duration would be needed to validate the association between MPR and the survival of NSCLC patients treated with neoadjuvant immunotherapies, this study suggested that MPR could be a surrogate endpoint for survival and may lower the duration and cost of drug trials in resectable NSCLC.2

Lastly, Dr. Provencio pointed out the utility of biomarkers in identifying patients who would most likely benefit from immunotherapy. While programmed death ligand-1 (PD-L1) expression and tumor mutational burden (TMB) are suggested to be predictive biomarkers, the current study found that both of them were not associated with survival.1,3 A meta-analysis of 6 randomized controlled trials found PD-L1 to be a predictor of objective response rate (ORR), but not overall survival or progression-free survival.4 However, significantly higher ORR was observed in the high PD-L1 expression group when compared to those with low PD-L1 expression.4 Nevertheless, the meta-analysis was limited by small sample size in the low PD-L1 expression group and more randomized controlled trials should be analyzed to corroborate the results.4 On the contrary, high TMB patients treated with ipilimumab immunotherapy were found to have better prognosis than the low TMB patients.3 Moreover, a significantly higher mean mutational burden but no significant difference in PD-L1 expression was observed in tumors with MPR than those without.3

Dr. Provencio concluded, “[Neoadjuvant chemoimmunotherapy] provides more responses, more downstaging and greater survival when compared with historical data. This treatment is a window of opportunity after 20 years without progress.”

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