Immunotherapy Also Showed Highly Effective Results in Early-Stage Lung Cancer

Very favorable results were recently reported in early-stage non-small-cell lung cancer (NSCLC), whose standard treatment is neoadjuvant (preoperative tumor-shrinking) chemotherapy, with the addition of immunotherapy to this standard approach. The Lancet Oncology published a phase-II clinical trial that predominantly enrolled patients with stage IIIA NSCLC and evaluated the combination of nab-paclitaxel plus carboplatin chemotherapy with atezolizumab immunotherapy, showing how much its addition improved disease outcomes.

This experimental immunotherapy-containing neoadjuvant regimen, followed by standard lung cancer surgery, was safe and feasible without treatment-related delays to surgery. R0 resection (complete tumor removal) was possible in 27 of the 30 enrolled patients, without a marked increase in serious postoperative complications (potential problems).

As the study's most striking result, efficacy was promising, with N2-to-N0 downstaging (disappearance in pathological lymph nodes) in 11 of 19 patients (58%), a major pathological response rate of 57%, and a complete pathological response in 33%.

After neoadjuvant chemotherapy, pathological response is a surrogate/intermediate endpoint for efficacy in early-stage NSCLC treatment. However, it has not been established whether pathological response after neoadjuvant immunotherapy can be used as a surrogate endpoint for improved survival after lung cancer surgery.

Immunotherapy for early-stage lung cancer

Numerous phase I to III clinical trials are investigating neoadjuvant and/or maintenance immunotherapy in early-stage NSCLC. Compared with adjuvant treatment, immune-based neoadjuvant therapy has several theoretical advantages for the immune system, potentially being more effective at eliminating occult metastatic disease: it can provide an abundant source of neoantigens in the primary tumor, suppression of tumor-infiltrating lymphocytes through the PD-1 checkpoint, and an intact regional immune environment including the primary tumor and lymph node drainage system. A preclinical experimental model showed that neoadjuvant administration was more effective than adjuvant immunotherapy.

Previous studies in early-stage NSCLC had shown that neoadjuvant immunotherapy with single agents—nivolumab, pembrolizumab or atezolizumab—was safe and feasible and produced a substantial number of major pathological responses after 2 treatment cycles. In addition, 5-8 cycles of combined neoadjuvant nivolumab and ipilimumab had been investigated in NEOSTAR. Interestingly, this new study suggests that adding immunotherapy to neoadjuvant chemotherapy may be more effective.

Understanding the tumor microenvironment

PD-1 checkpoint inhibitors have significantly improved 5-year survival in advanced NSCLC. Before immunotherapies, 5-year survival in "advanced" NSCLC was around 10%; it has now risen to around 25%. How can survival rates be increased further in advanced lung cancer and other solid / organ cancers? To achieve this, we need a comprehensive understanding of

• tumor biology,
• T cells,
• B cells,
• natural killer cells,
• regulatory T cells,
• myeloid-derived suppressor cells,
• the microbiome (gut flora),
• immune evasion, and
• the tumor microenvironment

and how they contribute to immunotherapy response.

The standard small biopsies taken for cancer diagnosis are not suitable/sufficient for analyzing neoantigens (new proteins produced by the tumor), the tumor microenvironment, and T cell and B cell populations. By contrast, neoadjuvant immunotherapy strategies in early-stage NSCLC offer unique opportunities to investigate resistance to immunotherapy and factors associated with response and resistance mechanisms by collecting sufficient tumor tissue, because post-treatment surgery removes the entire tumor. For example, this study investigated a mutation associated with resistance to PD-1 checkpoint therapy in advanced NSCLC: STK11 mutation in three tumors. It showed that PD-L1-positive and negative tumors did not differ significantly in pathological response rates, and that there were no major pathological responses. Thus, the association of the STK11 mutation with immunotherapy resistance was clarified once again.

Researchers should try to collect appropriate amounts of blood and particularly tumor samples in neoadjuvant immunotherapy trials for early-stage NSCLC. Analysis of the tumor microenvironment after PD-1 checkpoint treatment may lead us to the next, more effective treatments for both early- and advanced-stage NSCLC.

Why should we be optimistic?

This study adding atezolizumab to nab-paclitaxel plus carboplatin for neoadjuvant treatment of early-stage lung cancer, along with neoadjuvant studies combining chemotherapy and PD-1 checkpoint treatment, such as NADIM with nivolumab, reports impressive major pathological response rates. There are reasons to be optimistic that incorporating immunotherapy into standard surgery and chemotherapy regimens for early-stage NSCLC will improve survival outcomes. If the results of these early clinical studies are confirmed by large, randomized phase-III trials, immunotherapies will become standard in the neoadjuvant treatment of early-stage NSCLC in the near future.