The world's first phase III study of neoadjuvant therapy for lung cancer was successful!

In the development of immunotherapy, the two-year period seems to be only a short period of time.

In the eyes of Singularity Cake, it used to be like a seedling.
The neoadjuvant treatment of lung cancer immunotherapy, which is in the exploratory stage, has now grown into a big tree.

At the recent American Association for Cancer Research (AACR) annual meeting, the world's first phase III neoadjuvant treatment of lung cancer immunotherapy, the first positive endpoint result of CheckMate-816 was announced: Nivolumab + chemotherapy neoadjuvant treatment plan , The tumor pathological complete remission (pCR) rate is significantly better than standard platinum-containing dual-drug chemotherapy! This victory of nivolumab is the first time that neoadjuvant immunotherapy has succeeded in non-small cell lung cancer (NSCLC).
For many early patients who are at high risk of recurrence, this new treatment model is undoubtedly of far-reaching significance.

Following advanced NSCLC, the treatment pattern of early lung cancer will also begin to be rewritten.

Knowing the near and far, neoadjuvant therapy is expected to bring patients with multidisciplinary treatment that may be cured by surgery, and is expected to cure NSCLC patients with stage I-IIIA, but the recurrence rate of patients within 5 years after surgery is still as high as 30-55% [1], perioperative neoadjuvant/adjuvant chemotherapy can only increase the 5-year survival rate of patients by 5%, and the efficacy is relatively limited [2].

Therefore, after the successful treatment of advanced lung cancer, immune checkpoint inhibitors began to march towards neoadjuvant/adjuvant therapy for early NSCLC.
Compared with traditional chemotherapy, immunotherapy also has advantages in the mechanism of action.

Take neoadjuvant therapy as an example.
Before surgery, patients have large tumors, many new antigens, and relatively complete immune system functions.
Neoadjuvant immune therapy can fully activate immune response, shrink tumors before surgery, and hopefully clear them before surgery.
Of micrometastases [3].

Immune neoadjuvant therapy activates the mechanism of systemic immune response (picture source: "Science") The current clinical research on immunotherapy uses very diverse treatment models.
The successful CheckMate-816 study is preoperative immunization + chemotherapy In addition, there are multiple models of preoperative immunization with single-drug neoadjuvant, postoperative immunization with single-drug adjuvant, and perioperative neoadjuvant + adjuvant therapy.

It is worth mentioning that in clinical studies of immune neoadjuvant therapy, the index to measure the efficacy is generally pathological complete remission (pCR) or major pathological remission (MPR, that is, residual cancer cells in the tumor after neoadjuvant therapy ≤ 10%).
Rather than the overall survival (OS) or progression-free survival (PFS) commonly used in the treatment of advanced NSCLC.

Effective neoadjuvant immunotherapy can achieve MPR and even pCR, and improve the long-term prognosis (picture source: "Science") The prognosis of early NSCLC patients is relatively good, so if clinical research wants to collect PFS, OS and other efficacy data, long-term follow-up is necessary Like a study of neoadjuvant chemotherapy, it took 12 years from the beginning of the enrollment to the publication of the results [4].
Such a long period of time is long enough for a new generation of immune checkpoint inhibitors to come out.
I can’t wait.

And if it performs well on indicators such as pCR and MPR, it means that neoadjuvant therapy has fully achieved the goal of killing cancer cells before surgery and is expected to improve the prognosis of patients.

In 2014, an expert opinion in The Lancet Oncology cited multiple chemotherapy studies and proposed MPR as a surrogate endpoint for neoadjuvant studies of NSCLC [5].

At the 2020 European Society of Medical Oncology (ESMO) annual meeting, the results of the first meta-analysis CA209-8Y9 related to pathological response and OS after neoadjuvant chemotherapy in NSCLC were announced, suggesting that neoadjuvant therapy achieves pCR or MPR, which is better for patients The results of OS and EFS are related [6].

The main data analyzed by CA209-8Y9 (picture source: ESMO 2020) If the immune neoadjuvant treatment of NSCLC is more effective than chemotherapy, it is expected to help more patients achieve long-term cure.
This is also the significance of a large-scale clinical phase III study such as CheckMate-816 Where.

The road to early lung cancer cure.
From this point on, from the perspective of neoadjuvant treatment, each group of CheckMate-816 study is a bit like an early study group.
The 358 patients in this analysis received platinum-containing dual-drug chemotherapy, or navolidol.
Anti-platinum-containing dual-drug chemotherapy (based on early research results, the nivolumab+Ipilimumab group was discontinued).

There are two primary endpoints of the study.
The first is the pCR data reported in this report, and the second is the event-free survival of patients after receiving standard adjuvant therapy (chemotherapy ± radiotherapy, whether to receive radiotherapy is determined by the investigator) Phase (EFS), secondary endpoints include MPR, OS, and the time from treatment to the patient's distant metastasis or death.

CheckMate-816 study design The pCR data of this report shows that the pCR rate of nivolumab + chemotherapy group reached 24.
0%, while that of chemotherapy alone group was only 2.
2%.
The pCR rate of nivolumab + chemotherapy group was higher.
More than ten times (OR=13.
94, P<0.
0001), the MPR rate is also 36.
9% to 8.
9% (OR=5.
70), which is also a win.

Further analysis of the pCR data of the primary endpoint of the study showed that only 10% of cancer cells remained in the tumors of patients in the nivolumab + chemotherapy group, while the average residual cancer cells in the chemotherapy group alone was as high as 74%; imaging judgement In terms of the objective remission rate, the nivolumab + chemotherapy group was 54%, which was also higher than the 37% of the chemotherapy alone group.

Comparison of tumor shrinkage effects between the two treatment groups in the study.
From the perspective of multiple indicators such as pCR, MPR, and tumor shrinkage effects, the neoadjuvant treatment plan of nivolumab plus chemotherapy has achieved a complete victory in efficacy.

In terms of treatment safety, the incidence of adverse events and serious adverse events in the nivolumab+chemotherapy group and the chemotherapy alone group are basically the same, and there is basically no impact on surgery.

The study also carried out an exploratory analysis of 90 patients.
The data showed that 24 patients in the nivolumab + chemotherapy group who achieved ctDNA clearance after the end of neoadjuvant treatment had a pCR rate of 46%, but did not achieve ctDNA clearance.
None of the 19 patients achieved pCR.

Exploratory subgroup analysis of the correlation between ctDNA clearance rate and pCR rate This AACR annual meeting also announced a follow-up analysis of the NADIM study: detection of patients with ctDNA mutation allele frequency (MAF) <1% at baseline, and immunity Better PFS (HR=0.
24) and OS (HR=0.
04) after neoadjuvant treatment.

Combining these two data, it may be promising to use liquid biopsy to guide immune neoadjuvant therapy in the future [7].

The CheckMate-816 study is the fourth successful phase III study of nivolumab in the treatment of early cancer after urothelial cancer, esophageal cancer/gastroesophageal junction cancer, and melanoma.
Although the long-term efficacy data such as EFS and OS are still Further follow-up is needed, but nivolumab has become the leader in neoadjuvant treatment of lung cancer.

In many early clinical explorations carried out before, the MPR and pCR rates of the nivolumab-containing regimen were relatively better, and the CheckMate-816 study reached the primary endpoint of pCR also confirmed these data.

However, neoadjuvant immunotherapy must completely rewrite the pattern of perioperative immunotherapy for early NSCLC, and there is still a lot of work to be done.

After the CA209-159 study introduced by Singularity Cake two years ago, the clinical studies of various PD-1/L1 inhibitors have reported a lot of results, such as Navuli in the table below.
In the study of Eumab, the MPR and pCR rates of different schemes are quite good, suggesting the effectiveness of neoadjuvant therapy [8-11].

Summary of early studies on neoadjuvant therapy of nivolumab Take the NADIM study, which has excellent MPR and pCR rates, for patients with stage IIIA who received neoadjuvant immune plus adjuvant full-course treatment, the 24-month PFS rate reached 77.
1%, which is better than the study design The estimated 55% in China is much better, which is almost double the level of about 40% in the chemotherapy era, and the patient’s OS data is expected to increase significantly.

The preliminary recurrence-free survival (RFS) data of the NEOSTAR and CA209-159 studies also show that neoadjuvant immunotherapy has good mid-term benefits, and further confirm that MPR and pCR can be used as surrogate endpoints for evaluating the long-term efficacy of neoadjuvant therapy.

And these early studies can solve another clinical practical problem.

The multidisciplinary treatment of lung cancer, which includes neoadjuvant therapy, is surgical resection.
However, many surgeons have some concerns about neoadjuvant therapy, worrying about whether the side effects of immune neoadjuvant therapy will delay the timing of surgery.
Or affect the surgical resection rate, resection scope, risk of complications, and so on.

However, judging from the existing clinical data, the surgeon’s concerns are not a big problem: First of all, in various studies of nivolumab, more than 90% of patients can complete neoadjuvant treatment, and these patients will be surgically removed thereafter.
The proportion is also close to 90%, and only a very small number of patients are unable to operate or delay the operation due to side effects of treatment.

The surgical perspective analysis of the NADIM study also showed that although most of the patients enrolled were IIIA-N2 patients with complicated conditions and difficult surgical procedures, the neoadjuvant treatment of nivolumab had an effect on the surgical method, the scope of resection, and intraoperative complications.
Neither postoperative mortality nor postoperative mortality has a significant impact, and the overall treatment is quite safe and controllable [12].

NADIM studies the scope of resection, surgical procedures, and complications (picture source: European Journal of Cardio-Thoracic Surgery) to clear up surgical concerns, which is very important to improve the acceptance of neoadjuvant immunotherapy.

As the world's first successful Phase III study of neoadjuvant immunotherapy for lung cancer, the success of CheckMate-816 is expected to enable neoadjuvant immunotherapy to truly enter the clinic and begin to make strides forward.

Continue to explore and keep moving forward CheckMate-816 is the first to initiate and report the positive results of the primary endpoint in the current phase III study of immune neoadjuvant therapy.
In addition, there are a number of phase III studies with different schemes that are worthy of attention.

For example, using the NADIM research model, that is, the CheckMate-77T study of nivolumab + neoadjuvant chemotherapy before surgery and adjuvant treatment of nivolumab after surgery.

There are excellent MPR, pCR and PFS data from NADIM research first, and the data from CheckMate-77T research is also very worth looking forward to.

Further screening of patients according to Biomarker and finding the most suitable group for immune neoadjuvant therapy in advance is another important direction for exploration.

From the exploratory analysis of the NADIM study, although the expression level of PD-L1 in patients is related to the pCR and MPR rates of neoadjuvant therapy, the relationship with PFS and OS in patients is still unclear.

For sensitive mutations such as EGFR and ALK that are common in Chinese patients, the value of immune neoadjuvant therapy has yet to be determined.

Various gene mutations may also have an impact on immune neoadjuvant therapy (Image source: Pixabay) Of course, it is more worth looking forward to, or the long-term efficacy data of key studies such as CheckMate-816.
If immunotherapy can not affect surgery and patients' lives On the premise of quality, it can effectively reduce the risk of recurrence of patients and improve the long-term survival rate.
The Singularity Cake believes that the treatment pattern of early lung cancer will definitely be rewritten.

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Head image source: NIH Author of this article | Tan Shuo