Wu Yilong/Zhong Wenzhao's team found that immuno+ chemotherapy neoadjuvant treatment regimens may also be suitable for patients with driver gene-positive lung cancer

PD-1/L1 inhibitors have been widely used in lung cancer, and their advantages in neoadjuvant therapy for resectable non-small cell lung cancer (NSCLC) are becoming increasingly prominent, especially the pivotal clinical phase III study CheckMate-816, which strongly confirms the clinical benefits of neoadjuvant immunotherapy [1].

However, most of the previous clinical studies of neoadjuvant immunotherapy have excluded patients with EGFR mutation or ALK fusion [1-2], and for resectable NSCLC with positive driver genes such as EGFR mutation, can neoadjuvant immunotherapy combined with chemotherapy achieve better efficacy than chemotherapy?

In order to clarify this problem, the team of Professor Wu Yilong and Professor Zhong Wenzhao of Guangdong Provincial People's Hospital conducted a multicenter retrospective study to evaluate the clinical results and safety of neoadjuvant immunotherapy combined with chemotherapy in driver gene-positive resectable NSCLC, and explored the potential mechanisms leading to differences in efficacy of neoadjuvant immunotherapy through dynamic multiomics sequencing, the results of which have been published in NPJ Precision Oncology [3].

The data showed that for 40 patients with resectable NSCLC positive for driver gene, the overall objective response rate of neoadjuvant immunotherapy combined with chemotherapy reached 62.
5%, the complete resection (R0 resection) rate of 39 patients undergoing surgery was as high as 97.
4%, while the main pathological response rate (MPR) was 37.
5%, and the pathological complete response rate (pCR) was 12.
5%, and the results of this study have a lot of guiding value for the future neoadjuvant treatment mode of patients with positive driver gene resectable NSCLC
。

Screenshot of the first page of the paper

Let's take a look at how this study was conducted
.

The researchers initially screened patients receiving neoadjuvant immunotherapy from 26 centers across the country, and finally included a total of 40 driver gene-positive patients from 8 centers, including EGFR mutation (19/40), KRAS mutation, RET/ALK/ROS1 fusion, BRAF V600E mutation, and HER2 insertion
.
All patients received 2-4 sessions of PD-1/L1 inhibitor neoadjuvant therapy, of which 3 received immune monotherapy neoadjuvant therapy and 37 received neoadjuvant immunotherapy in combination with chemotherapy
.

Clinicopathological features and clinical outcomes of the patient

In terms of clinical efficacy, 37.
5% (15/40) of patients achieved major pathological response (MPR) and 12.
5% (5/40) achieved complete pathological response (pCR), and whether MPR was achieved was not significantly correlated
with the expression level of PD-L1.
At a median follow-up of 15.
5 months, the median disease-free survival (DFS) was 28.
5 months for the whole population and those with EGFR mutations, and the median DFS was longer
in MPR patients.

In terms of safety, no patient interrupted treatment due to severe toxicity, only 2 patients developed grade 3 anemia, and the other patients only had grade 1-2 rash or diarrhea, which was
safer.

The investigators also performed subgroup analyses specifically for patients with EGFR mutations and compared
them with the EGFR mutation cohort of previous CTONG1103 studies.
The results showed that compared with erlotinib and chemotherapy alone, the MPR of neoadjuvant immunotherapy combined with chemotherapy had a significant advantage (42.
1% vs 12.
5% vs 0%), and no patients in the chemotherapy alone group and erlotinib group achieved pCR, but 10.
5% of patients in the IO+CT group achieved pCR.
However, for less common EGFR insertions or point mutations, neoadjuvant immunotherapy plus chemotherapy does not show advantages
.

Comparison of the efficacy of three different neoadjuvant treatment modalities

In order to further elucidate the reasons why driver gene positive resectable NSCLC responds to immunotherapy, the researchers performed genome and transcriptome analysis of lung primary lesions (PL) and drainage zone lymph nodes (DLN) in four patients to explore tumor heterogeneity and immune microenvironment
.
The results showed that the immune microenvironment of metastatic lymph nodes was similar to that of the lung primary, and even after neoadjuvant therapy, there was a similar immune microenvironment in lymph nodes up to pCR, while similar immune microenvironments
were not found in normal lymph nodes.

To determine the reason why patient 4 (PT4) did not respond to neoadjuvant immunotherapy at all, the researchers established a phylogenetic tree
.
The study found that CD274 amplification in this patient predicted a good response to immunotherapy, and MDM4 amplification, which predicted immune hyperprogression, possibly because of this contradictory relationship, which offset the effectiveness of
immunotherapy.

Phylogenetic tree of lymph nodes in the lung primary and drainage areas

To further evaluate the phenotype of the immune microenvironment, the researchers applied different functional genomes in PL and DLN to assess antigen-presenting cell (APC) abundance, T/NK cell abundance, IFN activity, and T cell exhaustion
.
Notably, these genomes are highly expressed in both PL and DLN in immunotherapy responders and relatively low
in nonresponders.

The researchers also found that the functional genome in patient 2 (PT2) was poorly expressed in PL, but there was high expression of APC abundance and IFN activity in DLN, and only 16% of tumor cells remained in the primary lesion after immunotherapy, which indicates that the inflammatory phenotype of DLN has a potential role
in promoting the efficacy of immunotherapy.

Expression of functional genomes in PL and DLN and pathological remission

In summary, neoadjuvant immunotherapy combined with chemotherapy improved MPR and pCR in patients with EGFR mutation-positive resectable NSCLC compared with chemotherapy alone or targeted therapy.
In the overall population of driver gene positivity, including rare driver genes, there are also considerable MPR and pCR, which have certain clinical application value, and the phenotype of the immune microenvironment in PL and DLN can predict the efficacy of
neoadjuvant immunotherapy.

However, the study still has certain limitations, such as small sample size, multiple driver genes, and inconsistent PD-1/L1 inhibitors or chemotherapy regimens received by enrolled patients
.
In addition, assessment of pathological remission is performed in individual centers and there is a lack of centralized assessment, which may lead to overestimation
of MPR data.
Prospective clinical studies are expected to further evaluate the value
of neoadjuvant immunotherapy in patients with driver positive resectable NSCLC.

References:

[1].
Forde PM, Spicer J, Lu S, et al.
Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer.
N Engl J Med.
2022; 386(21):1973-1985.
doi:10.
1056/NEJMoa2202170

[2].
Zhang F, Guo W, Zhou B, et al.
Three-Year Follow-Up of Neoadjuvant Programmed Cell Death Protein-1 Inhibitor (Sintilimab) in NSCLC.
J Thorac Oncol.
2022; 17(7):909-920.
doi:10.
1016/j.
jtho.
2022.
04.
012

[3].
Zhang C, Chen HF, Yan S, et al.
Induction immune-checkpoint inhibitors for resectable oncogene-mutant NSCLC: A multicenter pooled analysis.
NPJ Precis Oncol.
2022; 6:66.
Published 2022 Sep 19.
doi:10.
1038/s41698-022-00301-8