The latest progress of neoadjuvant therapy for lung cancer!

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The latest progress of neoadjuvant therapy for lung cancer!

The latest progress of neoadjuvant therapy for lung cancer! New adjuvant chemoradiation therapy, targeted therapy, immunotherapy, a large inventory of the progress of neoadjuvant therapy for lung cancer!

Lung cancer is the malignant tumor with the highest morbidity and mortality in the world. Neoadjuvant therapy refers to patients who are potentially eligible for surgical resection, given preoperative anti-tumor therapy and then surgical treatment.

Neoadjuvant therapy can reduce tumor volume and tumor stage through preoperative treatment; it can also kill circulating tumor cells and micrometastasis in the patient’s body, which will benefit the patient’s long-term survival. Neoadjuvant chemotherapy has been used in the neoadjuvant treatment of lung cancer, but it has not significantly improved the overall survival rate.

In recent years, as the first-line application of targeted therapy and immunotherapy in advanced lung cancer has achieved good results, more and more targeted neoadjuvant and immune neoadjuvant therapies have been applied in potentially resectable lung cancer.

This article elaborates on the related progress of neoadjuvant therapy for lung cancer based on literature and related clinical trials.

Neoadjuvant chemotherapy

The results of Faber et al. showed that neoadjuvant chemotherapy can completely remove tumors in most patients, and the long-term survival results seem to be better than surgery alone. Rosell et al., Roth et al., Pisters et al., Felip et al., and Scagliotti et al. compared the effects of neoadjuvant chemotherapy and surgery alone, and the results showed that the former has better survival benefits. From the clinical data, neoadjuvant chemotherapy has the following advantages:

It can reduce the stage of lung cancer in patients with lung cancer, inactivate the micrometastasis that may exist in the body, and reduce the recurrence rate of the disease.

It can reduce or eliminate the metastatic lymph node cells and cancer foci, enhance the effect of surgical resection, reduce the possibility of bacterial planting in the chest cavity, thereby reducing the incidence of postoperative complications.

It can reduce the original lesions, increase the rate of surgical resection, preserve intact blood vessels, reduce the suffering of patients, and improve the survival rate and quality of life of patients. However, the meta-analysis confirmed that although neoadjuvant chemotherapy can significantly improve survival compared to surgery alone, with an OS HR of 0.8, the 5-year survival rate increased by only 5%.

Neoadjuvant radiotherapy

Simple neoadjuvant radiotherapy, even if it can lead to pathological remission of the excised specimen, cannot improve the resection rate or overall survival. The purpose of preoperative radiotherapy is to improve OS by reducing local tumor recurrence.

For example, in patients with Pancoast syndrome, local pulmonary dysfunction affects their quality of life, and reducing local tumor recurrence is the original intention. According to the literature, in the early treatment experience of patients with Pancoast syndrome, after neoadjuvant radiotherapy and chemotherapy, the proportion of incomplete tumor resection is reduced.

The MPR or pCR rate of traditional chemotherapy and radiotherapy for NSCLC neoadjuvant treatment is only less than 10%, and the 5-year overall survival rate has increased by only 5%, indicating that its efficacy is very limited. At present, as targeted and immunotherapy have achieved amazing results in advanced lung cancer, more and more clinical studies are exploring whether targeted therapy or immunotherapy can be used as a preoperative neoadjuvant for patients with potentially resectable or early resectable lung cancer. treatment.

Targeted neoadjuvant therapy

Some case reports suggest that neoadjuvant EGFR or ALK TKI is feasible without increasing toxicity and perioperative complications. But the problem is that for early-stage lung cancer, genetic testing is not routinely performed, and it takes several days to wait for the results of genetic testing. There are relatively few clinical studies on targeted neoadjuvant therapy for lung cancer.

CTONG 1103 study

The CTONG 1103 study is a phase II randomized controlled study designed to compare the efficacy of erlotinib and traditional chemotherapy regimens (gemcitabine + cisplatin) as neoadjuvant therapy in patients with NSCLC.

The results showed that the ORR of the chemotherapy group and the erlotinib group were 34.3% and 54.1%, the MPR rate was 0 and 9.7%, the mPFS was 11.4 months and 21.5 months, and no patients in the two groups achieved pCR. During neoadjuvant therapy, there were no grade 3 to 4 adverse reactions in the erlotinib group, while 29.4% of patients in the chemotherapy group had grade 3 to 4 adverse reactions.

NCT01217619 Research

The NCT01217619 study is a prospective single phase II clinical study involving 19 NSCLC patients with stage IIIA-N2 with EGFR mutations, aiming to evaluate the efficacy of erlotinib in neoadjuvant therapy.

The results showed that 14 patients underwent surgical treatment 8 weeks after taking the drug, and 13 of them achieved radical resection. The postoperative pathological downgrade rate was 21.1%, the objective remission rate was 42.1%, and the disease control rate was 89.5%. The median disease-free survival of surgical patients was 10.3 months; for the 19 patients who received neoadjuvant therapy, the median progression-free survival and median overall survival were 11.2 months and 51.6 months, respectively.

Ascent Research

The Ascent study is a prospective phase II clinical study that included patients with phase III EGFR mutation-positive NSCLC to explore the efficacy of afatinib combined with standard neoadjuvant therapy. The subjects first received afatinib treatment for 2 months, and then received concurrent chemoradiation. After treatment, 7 patients received surgical treatment, and the remaining patients continued to receive afatinib maintenance treatment.

The results showed that the MPR rate of patients undergoing surgery was 57.1%, and 1 patient (14.3%) achieved pCR. The overall ORR of the 13 patients was 69%, the mPFS was 34.6 months, and the 2-year OS was 85%.

NEOS Research

The NEOS study is a prospective, multi-center, single-group study to evaluate the efficacy and safety of osimertinib as a neoadjuvant treatment for resectable EGFR mutation (19del/L858R) lung adenocarcinoma.

The latest research results have just been announced at the 2021 ASCO annual meeting. Among all 15 patients who completed the efficacy evaluation after neoadjuvant osimertinib, the response rate (RR) was 73.3% (11/15), and the disease control rate (DCR) was 100% (15/15). 93.3% of patients underwent R0 surgical resection. 53.3% of patients experienced pathological downgrade. 42.9% of patients diagnosed with N2 fell to N0 stage after receiving osimertinib neoadjuvant therapy. The trial is ongoing and the final results will be provided in the future.

Unlike traditional neoadjuvant (radio) therapy, which seeks to reduce tumor foci and achieve preoperative downgrading, neoadjuvant immunotherapy focuses more on inducing the body’s immune effect on tumors to achieve long-term benefits. Some research suggests that immune new Adjuvant therapy should be used in patients with early and mid-stage lung cancer.

The theoretical basis for immune neoadjuvant therapy is:

There are a large number of tumor neoantigens in patients with early untreated NSCLC. PD-1/PD-L1 inhibitors can activate anti-tumor immunity to establish early immune memory, eliminate potential metastases, and prolong patient survival.

The benefits of neoadjuvant immunotherapy may continue to exist.

Neoadjuvant immunotherapy

LCMC-3 research

The LCMC-3 study is a multicenter single phase II clinical study. 101 patients with stage IB-IIIB NSCLC were treated with the PD-L1 inhibitor atilizumab.

The results showed that 90 patients underwent surgery, the ORR after surgery was 7%, the MPR rate was 18% (95% CI: 11%-28%), and the pCR rate was 5%. Two patients had grade 5 adverse reactions that were not related to treatment, and 29 patients had grade 3 to 4 adverse reactions.

CheckMate-159 research

The CheckMate-159 study is a single-arm phase II clinical study to evaluate the efficacy of the preoperative PD-1 inhibitor nivolumab.

The results showed that 22 patients with stage I-III resectable NSCLC were included in the study, and 20 of them received immunotherapy as originally planned. The ORR of the 20 surgical patients was 10%, the MPR rate was 45% (95% CI: 23% to 68%), and the pCR rate was 15%. The median follow-up time was 12 months (0.8 to 19.7 months), and 3 patients had disease progression.

During the neoadjuvant treatment process, there was no delay in surgery caused by immunotherapy, 23% of patients had treatment-related adverse reactions, and 5% of patients had grade 3 to 4 adverse events.

NADIM research

The NADIM study is a multi-center, single-arm, phase II clinical trial. The study included 46 patients with resectable stage IIIA NSCLC. All patients received neoadjuvant treatment with nivolumab, paclitaxel, and carboplatin. Some patients experienced disease progression or terminated the trial due to adverse reactions, and the remaining patients completed the complete treatment plan.

The results showed that 41 patients underwent surgical treatment, all of which were R0 (no residue under the microscope) resection. The ORR of postoperative patients was 78%, the MPR rate was 83% (95% CI: 71% to 95%), and the pCR rate was 71%.

Checkmate-816 research

The Checkmate-816 study is a randomized, open-label, multi-center phase III clinical study designed to evaluate the efficacy of nivolumab combined with chemotherapy for neoadjuvant therapy in patients with resectable NSCLC compared with chemotherapy alone.

The results showed that 24% of patients who received nivolumab combined with chemotherapy before surgery achieved pCR, compared with 2.2% of patients who received chemotherapy alone. The MPR of patients who received nivolumab combined with chemotherapy before surgery was 4 times that of patients with chemotherapy alone (36.9% vs 8.9%; OR = 5.70, 99%CI: 3.16-10.26). The safety of 3 cycles of nivolumab combined with chemotherapy is good, and no new safety signals have been observed.

In the nivolumab combined chemotherapy group and chemotherapy alone group, the incidence of all adverse events of grade 3-4 was 41% and 44%, respectively, and the incidence of treatment-related adverse reactions was 34% and 37%, respectively.

NEOSTAR research

The NEOSTAR study is open to follow-up phase II clinical studies to evaluate the efficacy of PD-1 inhibitor nivolumab combined with CTLA-4 inhibitor ipilimumab versus nivolumab as a single agent. Forty-four patients with stage I-IIA NSCLC were randomly assigned to the nivolumab group (N group, n = 23) or the nivolumab combined with ipilimumab group (NI group, n = 21) for treatment.

The results showed that the postoperative ORR of the N group was 22%, the MPR rate was 17%, and the pCR rate was 9%; the postoperative ORR of the NI group was 19%, the MPR rate was 33%, and the pCR rate was 29%. The incidence of treatment-related grade 3 to 4 adverse reactions in the N group and NI group were 13% and 5%, respectively. In terms of surgical complications, 2 patients in the N group developed bronchopleural fistula, 5 patients developed pneumothorax symptoms, and 3 patients in the NI group developed pneumothorax.

Recently, a meta-analysis of neoadjuvant immunotherapy before resection of non-small cell lung cancer was published in Lung Cancer. A total of 252 patients from 7 studies were included in the article. The primary pathological response (MPR) and pathological complete response (pCR) were used to evaluate the efficacy of neoadjuvant immunotherapy. Compared with neoadjuvant chemotherapy with MPR<25% and pCR of about 2% to 15%, the MPR value of neoadjuvant immunotherapy was significantly higher than that of neoadjuvant chemotherapy (MPR: OR = 0.59; 95% CI, 0.36 to 0.98; pCR : OR = 0.16; 95% CI, 0.09～0.27).

The safety evaluation indicators are the incidence of treatment-related adverse events (TRAE), the rate of surgical resection, the rate of surgical complications, and the rate of surgical delay. The combined OR values ​​of the incidence of TRAE, the incidence of surgical complications, and the incidence of surgical delay were 0.19, 0.41, and 0.03, respectively, which were significantly better than those of the neoadjuvant chemotherapy group (95% CI 0.04～0.90; 0.22～0.75; 0.01～0.10, respectively) . The average surgical resection rate was 88.70%, which was similar to the reported 75-90% neoadjuvant chemotherapy resection rate (OR = 7.61; 95% CI, 4.90-11.81). Therefore, it is concluded that the efficacy of neoadjuvant immunotherapy is better than chemotherapy; the safety of neoadjuvant immunotherapy is better than chemotherapy; no immune checkpoint inhibitor with absolute advantage has been found in neoadjuvant immunotherapy.

The Phase III clinical trials of neoadjuvant immunotherapy currently being carried out worldwide also include IMpower 030, KEYNOTE-671, AEGEAN, CheckMate 77T and other studies, all exploring the efficacy of PD-1/PD-L1 inhibitors in neoadjuvant treatment of NSCLC And safety.

Sum up

Compared with traditional radiotherapy and chemotherapy, preoperative neoadjuvant targeting and immunotherapy do bring a higher disease remission rate for NSCLC patients, but postoperative DFS and OS still require further observation.

In addition, the surgical-related risks (such as surgical delay and disease progression) and perioperative complications brought by neoadjuvant targeting and immunotherapy also require surgeons to pay attention. As with advanced lung cancer, how to find effective biomarkers, stratify patients, screen the people who benefit the most, and reduce toxic side effects requires further research and discussion.

In any case, neoadjuvant targeting and immunotherapy provide hope for the long-term survival of patients with early and mid-term resectable or potentially resectable NSCLC. In the future, more translational research and clinical trials are still needed for in-depth exploration.

(source:internet, reference only)

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