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There were 19 recommendations for the perioperative treatment of NSCLC
Written by | Su Xuhan
In recent years, a number of phase III trials of early-stage resectable non-small cell lung cancer (rNSCLC) have achieved positive results, which not only provide more evidence for clinical diagnosis and treatment, but also show the increasing demand for multidisciplinary collaborative care for rNSCLC patients. To this end, the International Association for the Study of Lung Cancer (IASLC) commissioned a multidisciplinary international panel of experts to develop an expert consensus for rNSCLC with a view to providing recommendations on diagnosis, staging, and treatment. The medical community has compiled the essence of consensus to provide reference for clinicians.
A total of 19 recommendations were made in the consensus, including general recommendations, recommendations for neoadjuvant therapy and adjuvant therapy, and all but 15 recommendations were agreed upon (>85%). Recommendation 6 of the general recommendation, consensus recommendations 7, 8, and 13 of the neoadjuvant therapy, and recommendation 16 of the adjuvant therapy are compiled and interpreted here, and the recommendations are detailed in Table 1.
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Table 1 General and special recommendations for neoadjuvant and adjuvant therapy for early-stage rNSCLC
Suggested interpretation: Do I need adjuvant chemotherapy before adjuvant immunotherapy?
- Recommendation 6: At a minimum, EGFR, ALK mutation status, and PD-L1 expression levels should be measured in patients who are being considered for neoadjuvant or adjuvant system therapy
Targeting and immunization are the two main treatment modalities for NSCLC today. Previous studies, including the randomized trial of immune checkpoint inhibitor (ICI) monotherapy versus docetaxel[1], have not found a significant improvement in survival in patients with EGFR mutations or ALK rearrangements. As a result, most trials evaluating ICIs as advanced first-line treatment excluded people with EGFR or ALK mutations.
Recently, CheckMate-722 and KEYNOTE-789 specifically evaluated chemotherapy plus ICI versus chemotherapy alone after tyrosine kinase inhibitor (TKI) failure in patients with advanced/metastatic EGFR mutant tumors, but failed to meet their primary progression-free survival (PFS) and overall survival (OS) endpoints. The latest analysis results of the ORIENT-31 study in China showed that chemotherapy combined with sintilimab achieved a statistically significant PFS benefit compared with chemotherapy alone in patients with EGFR-mutant NSCLC, but there was no difference in OS between treatment groups. Overall, there is a large body of evidence that does not support the role of ICIs in patients with EGFR and ALK-mutated tumors.
In addition, the panel concluded that PD-L1 was not an important factor in deciding whether a patient should be considered for neoadjuvant or perioperative immunotherapy in combination with chemotherapy. Therefore, for patients who are considering neoadjuvant or adjuvant system therapy, it is necessary to measure the mutation status of EGFR and ALK, as well as the level of PD-L1 expression.
- Recommendation 7: Neoadjuvant immunotherapy plus chemotherapy is a superior option to upfront surgery in treatment-naïve patients with resectable stage IIIA or IIIB NSCLC, regardless of PD-L1 expression levels.
- Recommendation 8: Adjuvant immunotherapy may be considered postoperatively for patients receiving neoadjuvant immunotherapy in combination with chemotherapy.
In light of the reported robust and consistent event-free survival (EFS) benefits in Phase III clinical trials, as well as significant OS benefits, the panel made it clear that neoadjuvant immunotherapy plus chemotherapy is preferred for eligible Phase III patients.
The benefits of postoperative adjuvant ICI therapy appear to be limited to patients receiving platinum-doublet chemotherapy. Results from the VIOLET trial showed that no more than 50% of patients eligible for postoperative indications would receive adjuvant chemotherapy, whereas only 50% of patients with PD-L1 appeared to benefit from OS from adjuvant ICI therapy ≥ IMpower 010 trial. As a result, only a small number of patients with stage III rNSCLC have a survival benefit from adjuvant ICI.
In summary, the expert group said that although there are no studies comparing neoadjuvant immunotherapy with chemotherapy and adjuvant chemotherapy after immunotherapy, it is important to recommend the preferred regimen based on the available data, so recommendations 7 and 8 have been formed.
- Recommendation 13: It is recommended that the surgical pathology report of patients who have undergone neoadjuvant therapy should include at least complete pathological response, the proportion of residual viable tumor cells, and the yp-TNM stage.
Due to the lack of practical recommendations, pathology reports of lung cancer resection after neoadjuvant chemotherapy vary. In 2020, the IASLC published a multidisciplinary recommendation on the general standardized management and microscopic evaluation of NSCLC after neoadjuvant therapy, which clearly stated that the clinical report must include a section on the pathological response of the primary tumor site and lymph nodes, and should also evaluate the pathological response of metastatic lymph nodes. Patients with major pathological response (MPR)-positive lymph nodes have been shown to survive longer than patients with MPR-negative lymph nodes [2-3].
A retrospective study of a single-center cohort of rNSCLC after neoadjuvant immunotherapy showed that the proportion of residual viable tumor cells (%RVT), MPR, and pCR percentage were at least 90% accurate when submitting all residual primary tumors or at least 20 tumor sections. In addition, pathologists in the United States require that pathology reports must include ypTNM staging.
- Recommendation 16: Adjuvant chemotherapy is recommended prior to adjuvant immunotherapy.
Adjuvant platinum-based chemotherapy is currently the standard of care for completely resected IB (≥4 cm)-stage IIIA NSCLC (AJCC-UICC 7th edition). The panel concluded that adjuvant chemotherapy should continue to be recommended where feasible. In the case of adjuvant immunotherapy, chemotherapy is a necessary component of the benefit regimen.
Urgent issues to be solved and future directions
Finally, the panel discussed several issues of clinical value that were not addressed in the recommendations and provided brief answers.
- What is the best time to undergo surgery after neoadjuvant therapy?
The panelists agreed that the typical timing of surgery ranged from 3 weeks (to allow for recovery of bone marrow function after platinum-doublet chemotherapy) to 6 weeks. At this time, there is no additional data to support the optimal time window for a particular surgery beyond the data recommended by existing phase III studies. In any case, as many patients as possible should be treated with surgery, as overall data from large trials suggest that patients who receive surgery benefit more. How the timing of surgery after neoadjuvant therapy affects the complexity and outcome of surgery requires specialized research. In addition, the timing of surgery may have an important impact on the depth of pathological remission.
- How can neoadjuvant and adjuvant trials of NSCLC be improved in the future?
In response to this question, the expert group made 11 answers, including the standardization of clinical trial endpoints, subgroup populations, the optimal number of cycles of neoadjuvant therapy, etc., representing the expert group's expectations for future perioperative clinical studies of NSCLC, as follows:
- Neoadjuvant, adjuvant, or both?
1. There are no direct data comparing neoadjuvant immunotherapy with chemotherapy and adjuvant immunotherapy.
2. Several studies evaluating neoadjuvant immunotherapy in combination with chemotherapy followed by surgery have shown long-term EFS benefits in patients who achieve pathologic complete response (pCR), suggesting that these patients may not require further adjuvant immunotherapy. In contrast, patients who received neoadjuvant immunotherapy plus chemotherapy followed by reoperation had a shorter EFS benefit if MPR was achieved or stable disease (SD) was achieved. However, further long-term follow-up is needed to confirm these results.
Finally, it is important to note that most of the available trial data testing novel targeted or immunotherapies are still relatively immature. Further long-term follow-up is needed to determine the durability of these interventions in terms of OS, which is the clear goal of a patient's cure.
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Bibliography:
[1] Yang J.C.H, Lee D.H, Lee J.S.et al. Pemetrexed and platinum with or without pembrolizumab for tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutant, metastatic nonsquamous NSCLC: phase 3 KEYNOTE-789 study. J Clin Oncol. 2023; 41
[2] Liu X, Sun W, Wu J, et al. Major pathologic response assessment and clinical significance of metastatic lymph nodes after neoadjuvant therapy for non-small cell lung cancer. Mod Pathol. 2021; 34(11):1990-1998. doi:10.1038/s41379-021-00871-1
[3] Pataer A, Weissferdt A, Vaporciyan AA, et al. Evaluation of Pathologic Response in Lymph Nodes of Patients With Lung Cancer Receiving Neoadjuvant Chemotherapy. J Thorac Oncol. 2021; 16(8):1289-1297. doi:10.1016/j.jtho.2021.03.029
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