The risk of postoperative recurrence of lung cancer is expected to be greatly reduced. The use of O-drug combined with chemotherapy for neoadjuvant significantly improves the rate of complete tumor pathology

Lung cancer is a leading cause of cancer deaths worldwide, but as many as half of non-small cell lung cancer (NSCLC) patients have not yet metastasized at the time of diagnosis and can still undergo surgery.

In order to improve the effect of radical surgery and eliminate micrometastases, treatments such as chemotherapy can be used for "pretreatment" before surgery.
This strategy is called neoadjuvant therapy.

However, for non-small cell lung cancer, the effect of neoadjuvant chemotherapy is not good, and the five-year overall survival rate is only about 5% higher than that of patients without chemotherapy.

Among lung cancer patients undergoing surgical treatment, about half of the patients will relapse.
Clinically, it is urgent to explore better neoadjuvant treatment options to improve the long-term survival of patients.

Chemotherapy alone is not effective, but how about a combination of immunotherapy and chemotherapy? The latest clinical trial data show that nivolumab (Drug O) combined with chemotherapy as a preoperative neoadjuvant treatment for lung cancer can significantly improve the pathological remission of the tumor and is safe and feasible.

01 The world's first non-small cell lung cancer immune neoadjuvant phase III clinical study CheckMate-816 is one of the world's oldest and largest tumor research academic conferences.
The 2021 American Association for Cancer Research (AACR) annual meeting will be held on April 10 At the opening, CheckMate-816 clinical research data on non-small cell lung cancer was released at the conference: Compared with chemotherapy alone, operable patients in stage IB~IIIA receive 3 cycles of O-drug combined with chemotherapy before surgery , Can significantly improve tumor pathological complete remission (pCR).

CheckMate 816 is a randomized, open-label, multi-center phase III clinical trial for resectable stage IB~IIIA non-small cell lung cancer.
It evaluates the feasibility of drug O combined with chemotherapy as a neoadjuvant treatment strategy.
The control group is chemotherapy alone.

The primary research endpoints are pathological complete remission (pCR) and event-free survival (EFS) assessed by the Independent Blind Evaluation Committee (BIPR); key secondary research endpoints include BIPR-assessed overall survival (OS) and primary pathological response (MPR) ), etc.
, and the time to death or distant metastasis (Figure 1).

Figure 1 The research design of combined therapy allows 24% of patients to achieve complete pathological remission.
02 What is the impact of the three cycles before surgery on the tumor? The results found that chemotherapy alone is not effective, and the pathological complete remission rate is very limited (only 2.
2%).
However, after the combination of O drug, 24% of patients can achieve pathological complete remission, that is, every four preoperative combined therapy Among the patients, there was one patient whose surgical resection specimens did not find cancer cells.

For patients who ultimately undergo surgery, about 1/3 of them have achieved complete pathological remission after receiving the combined treatment (Figure 2).

This shows that there is a good synergistic effect between O drug and chemotherapy, and the effect is significant when used in the neoadjuvant phase.

Figure 2 Pathological complete remission rate statistics (left) Intent-to-treat (ITT) population; (upper right) surgical population; (bottom right) ITT population with primary tumors.
Next, the investigator conducted a detailed subgroup analysis.
It was found that even if the clinical characteristics (clinical stage, histological subtype, PD-L1 expression level) of patients are different, they can all benefit from O-drug combination chemotherapy (Figure 3).

Figure 3 Pathological complete remission rate subgroup analysis 03 The main pathological remission of the combination therapy group is also better than that of chemotherapy alone.
The main pathological remission standard is slightly broader, referring to the lack of residual tumor cells in the primary tumor and the biopsy lymph node 10 %, this is also one of the important criteria for evaluating the efficacy of neoadjuvant therapy.

Similar to the trend of pathological complete remission, compared with chemotherapy alone, the main pathological remission rate of drug O combined with chemotherapy is significantly higher (36.
9% vs 8.
9%); especially for patients undergoing surgery, nearly half (46.
8%) of patients have reduced residual tumor cells More than 90%, reaching the major pathological remission criteria (Figure 4).

This further confirms the feasibility of O drug combined with chemotherapy for the neoadjuvant stage.

Figure 4 Main pathological remission statistics (left) ITT population; (top right) operation population; (bottom right) ITT population compared with chemotherapy alone, in the combined treatment group, not only the number of major pathological remission cases increased significantly, but also the pathology The degree of relief is deep (Figure 5).

This fully demonstrates the killing and inhibiting effect of immunotherapy on tumor cells.

Figure 5 Depth of remission (left) O drug combined with chemotherapy; (right) More than half of the patients with chemotherapy alone achieved imaging remission, and 30% of patients achieved downgrade.
04 In addition to pathological evaluation, imaging examinations can also better reflect the overall tumor shrinkage.

More than half (54%) of patients receiving O drug combined with adjuvant chemotherapy achieved radiological remission, while only 37% of the chemotherapy group alone (Figure 6 left); 30% (31%) of the patients' tumors reached downgrade (the chemotherapy group was 24%) (Figure 6 right).

This shows that O drug combined with chemotherapy can significantly inhibit tumor growth and improve the staging after treatment.

Figure 6: Imaging efficacy evaluation (left) and proportion of down-stage cases (right) 05ctDNA clearance is significantly improved.
As an exploratory research endpoint, the ctDNA level can reflect the clearance of circulating tumor cells in the blood by treatment.

Compared with chemotherapy alone, the combination of O drugs can significantly increase the ctDNA clearance rate (from 34% to 56%) (Figure 7 left).

Moreover, for patients whose ctDNA was cleared, the pathological complete remission rate was significantly improved in the combined treatment group (Figure 7 right).

This shows from another angle that O drug combined with chemotherapy has a better effect on tumor clearance.

Figure 7 ctDNA clearance rate (left) and its relationship with complete pathological remission (right).
The overall safety and tolerance are good.
06 Up to the present statistical data, O drug combined with chemotherapy is generally safe and tolerable, and does not significantly affect subsequent surgery.

In terms of common treatment-related adverse events, the incidence of drug O combined with chemotherapy is not more common than that of chemotherapy alone (Figure 8).

These data further demonstrate the feasibility of this treatment strategy from a safety perspective.

Figure 8 Postscript of common treatment-related adverse events (≥15% of the population) Based on the encouraging results of CheckMate-816, O drug is expected to become a neoadjuvant treatment option for patients with non-small cell lung cancer that can be excised, and immunotherapy is expected to advance to the forefront.
Patients benefit earlier.

The follow-up of this study will continue, and it is hoped that the improvement of pathology can prolong the event-free survival period of patients and ultimately extend the overall survival period.

We will continue to follow up and report the follow-up results.

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References: Forde P, Spicer J, Lu S, et al.
Nivolumab + platinum-doublet chemotherapy vs chemotherapy as neoadjuvant treatment for resectable (IB–IIIA) non-small cell lung cancer in the phase 3 CheckMate 816 trial.
AACR 2021.
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