Editor’s Note: The 27th National Clinical Oncology Conference and 2024 CSCO Academic Conference, co-hosted by the Chinese Society of Clinical Oncology (CSCO) and the Beijing CISCO Clinical Oncology Research Foundation, took place in Xiamen from September 25 to 29, 2024. During this event, Dr. Tetsuya Mitsudomi, who has led several large-scale immunotherapy clinical trials, gave an academic report on the latest progress in immunotherapy for NSCLC. Oncology Frontier invited Dr. Baohui Han from Shanghai Chest Hospital to have an in-depth conversation with Dr. Tetsuya Mitsudomi from Kindai University School of Medicine in Japan. They shared insights on decision-making strategies for perioperative treatment, prognostic biomarkers, and managing adverse events in NSCLC immunotherapy.

1. The CheckMate-816 study has demonstrated that neoadjuvant nivolumab combined with chemotherapy significantly improves event-free survival (EFS) and pathological complete response (pCR) in resectable NSCLC patients compared to chemotherapy alone. Could you share your thoughts on these results?

Dr. Tetsuya Mitsudomi: The CheckMate-816 study is the first Phase III trial of preoperative chemotherapy combined with immunotherapy in patients with resectable lung cancer. In this trial, patients received three cycles of nivolumab combined with chemotherapy before surgery, with the option of postoperative adjuvant chemotherapy but no additional immunotherapy. When I first heard about the trial design, I was curious because three cycles seemed more than expected, and no adjuvant treatment was planned post-surgery. As one of the participants in this trial, we recruited a few patients who generally responded well, and the surgeries went smoothly, with good prognoses overall. The results showed that the treatment group had higher pCR and major pathological response (MPR, defined as less than 10% viable tumor cells) rates than the chemotherapy group, with prolonged EFS. Although overall survival (OS) has not been reached, there is a clear trend toward improved OS in the chemotherapy/immunotherapy group. I believe CheckMate-816 is a positive trial and could potentially change standard clinical practice.

Dr. Baohui Han: At this year’s World Conference on Lung Cancer (WCLC) in San Diego, the latest four-year follow-up data from the CheckMate-816 study was presented. The results are both encouraging and impressive. The CheckMate-816 model demonstrated significant improvements in EFS and four-year OS rates compared to chemotherapy alone. The data revealed that the four-year OS rate in the neoadjuvant nivolumab + chemotherapy group reached 71%, showing a clear advantage over chemotherapy. Particularly noteworthy is that 24% of patients achieved pCR in the CheckMate-816 study, and among those who did, the four-year OS rate was 95%, which is an exciting result. It indicates that for this group of patients, neoadjuvant immunotherapy combined with chemotherapy can achieve near-curative outcomes, reducing the need for further treatment.

For patients who do not achieve pCR, the CheckMate-77T model can serve as a reference, where four cycles of neoadjuvant immunotherapy combined with chemotherapy are followed by one year of postoperative immunotherapy maintenance. For those who did not achieve pCR, one year of postoperative immunotherapy maintenance reduced the risk of death by 38% compared to the control group. Therefore, this is a promising strategy for adjuvant therapy after surgery.

2. How should we choose between adjuvant therapy, neoadjuvant therapy, and perioperative treatment strategies for resectable NSCLC?

Dr. Tetsuya Mitsudomi: Before the CheckMate-816 study, the results of postoperative adjuvant immunotherapy were already available. First, we had the IMpower010 study, which used chemotherapy followed by immunotherapy as adjuvant treatment. In PD-L1-positive stage II-III patients, this approach extended disease-free survival (DFS), making it a positive trial. Next, the KEYNOTE-091 trial had a similar design, using pembrolizumab as the immunotherapy drug. The primary endpoints were DFS in the overall population and in those with PD-L1 TPS (tumor proportion score) ≥ 50%. While the overall DFS endpoint was positive, surprisingly, the PD-L1 TPS ≥ 50% population did not show a positive result, even though it is usually a good predictor of better outcomes. Additionally, at the recent ESMO meeting, results from the CCTG BR.31 trial, which used durvalumab as the immunotherapy drug, were presented, but the trial was negative. So, the results of adjuvant immunotherapy are mixed.

Then, we have the perioperative strategy of chemotherapy combined with immunotherapy before surgery, followed by postoperative immunotherapy maintenance. The perioperative trials reported so far have all shown positive results. In terms of choosing among these three strategies, animal studies and human melanoma clinical trials have clearly shown that preoperative immunotherapy is more effective than postoperative immunotherapy. In my opinion, preoperative immunotherapy should be the preferred approach for lung cancer patients.

However, the question of whether postoperative immunotherapy is necessary is difficult to answer. At the WCLC meeting three weeks ago, data comparing the perioperative CheckMate-816 (preoperative) and CheckMate-77T (perioperative) trials using propensity score matching (PSM) were presented. This was not a randomized trial, but since both trials were sponsored by Bristol-Myers Squibb, they could perform patient-level analyses with PSM to adjust for biases as much as possible. The results suggested that the perioperative regimen from the CheckMate-77T trial seemed to be more effective. I don’t believe all patients need postoperative immunotherapy, but some could benefit. However, we currently lack clear biomarkers to identify which patients would benefit from postoperative immunotherapy.

Dr. Baohui Han: This is a matter of personalized treatment. Several studies have explored neoadjuvant therapy or the CheckMate-816 model, as well as the IMpower010 model and the “sandwich” model (neoadjuvant immunotherapy/chemotherapy + surgery + adjuvant immunotherapy) in patients with localized NSCLC. Which treatment model is most appropriate for a given patient depends on the individual case. In clinical practice, there are many patients who undergo surgery only to find they are stage II or higher, and in such cases, postoperative adjuvant immunotherapy is undoubtedly necessary.

As neoadjuvant therapy becomes more common, more patients may receive the CheckMate-816 or CheckMate-77T models in the future. These two models should be selected based on the patient’s condition, starting with neoadjuvant therapy and assessing after three cycles. Of course, the final evaluation is the pathological assessment after surgery. As previously mentioned, the pCR rate in the CheckMate-816 study was as high as 24%, meaning nearly a quarter of patients could achieve pCR, and this group does not require further postoperative immunotherapy.

There are also other promising reference indicators, such as minimal residual disease (MRD). Although MRD is not yet a widely accepted testing method, it should become a valuable indicator in the future. Preliminary data analysis suggests that if a patient achieves pCR, the probability of MRD positivity is very low. Therefore, if a patient reaches pCR and has a negative MRD result, there is no need for further treatment.

For non-pCR patients who achieve stable disease (SD) or partial response (PR), effective postoperative interventions such as immunotherapy combined with chemotherapy may be necessary. If a patient achieves SD or shows minimal change in the tumor bed, clinical experience and preliminary study observations suggest that the treatment strategy should be adjusted. If the tumor has not shrunk or has shrunk inadequately after 3-4 cycles of immunochemotherapy, continuing the original regimen is unlikely to be beneficial. Of course, how to define this boundary is still up for discussion.

The question of whether switching to a new regimen is better than continuing with the original one is worth further exploration. We need to conduct randomized controlled trials in the future to answer this scientifically. The choice of perioperative treatment will likely depend on the postoperative pathological results and whether the patient should be observed, given immunotherapy maintenance, or switched to a new maintenance therapy.

3. Neoadjuvant immunotherapy may cause some patients to lose the opportunity for curative surgery due to adverse reactions or disease progression. What biomarkers can help identify suitable candidates for neoadjuvant immunotherapy?

Dr. Tetsuya Mitsudomi: So far, the most important predictor of response is PD-L1 expression level, but it’s an imperfect marker. Even some PD-L1-negative patients can achieve pCR, so we cannot exclude them solely based on that. Another predictor of efficacy is the patient’s stage—generally, stage III patients benefit more. Additionally, some studies have shown that smokers tend to benefit more. Regarding histological types like squamous cell carcinoma or adenocarcinoma, both positive and negative results have been observed, so we cannot definitively say that one histological type is better than the other. Overall, we have some markers to predict efficacy, but there is no clear or definitive biomarker yet, and we will certainly need more accurate predictive biomarkers in the future.

In addition, patient factors such as physical condition, age, and comorbidities are crucial. Older patients with comorbidities are more likely to experience adverse events, and some may not be fit for surgery. It’s important to consider the balance between these factors—clinically, patients often have both favorable (high PD-L1 expression, stage III disease) and unfavorable (age, comorbidities) factors. We need to balance these elements and make personalized decisions through multidisciplinary tumor boards, taking into account the patient’s preferences as well.

Dr. Baohui Han: We are now in the era of immunotherapy, which is generally safe and convenient for most patients. However, some patients, due to individual factors, pre-existing immune-related diseases, or long-term use of steroids, face higher risks and poorer outcomes when receiving immunotherapy. At present, finding a universally accepted biomarker to exclude such patients before treatment is still challenging.

For now, we rely on clinical experience to perform individualized assessments for each patient before deciding whether to use immunotherapy. For example, patients with severe diabetes requiring insulin treatment, those with interstitial lung disease, chronic obstructive pulmonary disease (COPD), systemic sclerosis, lupus, or other steroid-dependent conditions should be cautious when considering immunochemotherapy.

On the other hand, even among patients who receive immunochemotherapy, up to 15% may not respond to the treatment. Without effective methods for identifying these patients, they may lose the opportunity for surgery due to ineffective immunochemotherapy. Therefore, we need to find more effective biomarkers or parameters to prevent such patients from receiving immunotherapy, improving the overall efficiency of treatment and helping patients achieve the goal of surgery.

4. Managing adverse reactions is critical in the clinical application of immunotherapy. Could you discuss how to handle adverse events during immunotherapy?

Dr. Tetsuya Mitsudomi: Immune-related adverse events (irAEs) are a major issue because we cannot predict their timing or type, requiring us to approach immunotherapy cautiously. In the CheckMate-816 trial, about 15% of patients were unable to undergo surgery, and upon closer examination, 5-7% of these patients were unable to have surgery due to irAEs. For patients whose disease progressed during immunotherapy, even if they underwent initial surgery, their prognosis was poor. We aim to reduce the number of surgeries canceled due to irAEs, but it’s difficult to bring this number to zero.

Even in patients receiving adjuvant therapy after surgery, according to the IMpower010 data, around 75% of patients were randomized post-surgery, and two-thirds of these patients completed one year of adjuvant treatment. This means that from the surgical stage, only about 50% of enrolled patients were able to complete both surgery and one full year of adjuvant therapy. Thus, in my view, the 15% of patients who cancel surgery during neoadjuvant therapy represent an acceptable number.

Dr. Baohui Han: When immunotherapy was first introduced to China, there were many concerns about its use in clinical practice due to the emergence of severe adverse reactions like immune-related pneumonitis, hypophysitis, myocarditis, and others. This led to the perception that immunotherapy was risky. However, with years of experience and knowledge exchange at academic meetings, clinicians have gained rich experience in managing, grading, and monitoring these adverse reactions. Nowadays, for patients receiving immunotherapy, we routinely conduct comprehensive immune-related tests, including endocrine, myocardial enzyme profiles, liver and kidney function tests, liver enzyme profiles, and other kinases. This enables the early detection and timely management of irAEs. From experience, the earlier an adverse event is addressed, the better the outcome, helping prevent the progression of irAEs from grade 1-2 to more severe levels, significantly reducing the occurrence of fatal adverse events. In the early days, we saw deaths due to irAEs, but with large-scale clinical use, the proportion of severe adverse events leading to death has dropped to a very low level.

Dr. Tetsuya Mitsudomi Thoracic Surgery, Kindai University School of Medicine, Osaka, Japan Since April 2022, he has served as the Special Director of Izumi City General Hospital, Japan. From March 2012 to March 2022, he was a professor in the Department of Thoracic Surgery at Kindai University School of Medicine. He graduated from Kyushu University School of Medicine in 1980 and earned his PhD in 1986. From 1989 to 1991, he studied lung cancer molecular biology at the National Cancer Institute in the United States. From 1995 to 2012, he was the Chief of Thoracic Surgery at Aichi Cancer Center in Nagoya, Japan. From 2019 to 2021, he served as the President of the International Association for the Study of Lung Cancer (IASLC) and is an active member of AACR, ASCO, and ESMO. He served as the President of the Japanese Lung Cancer Society (JLCS) from 2014 to 2018 and is currently an honorary member of JLCS, JSMO, and JCA. His accolades include the Shinobi-Kawai Award (JLCS, 2001), the Mauvernay Award (JCA, 2005), the Mary Matthews Award (IASLC, 2013), and the Paul Bourdarie-Goto Scientific Award (Nagoya, 2014).

Dr. Baohui Han Shanghai Chest Hospital A leading talent in Shanghai and an outstanding academic leader, Professor Han is the Executive Dean of the Chinese Lung Cancer Academy. He serves as the Chair of the Oncology Precision Medicine Committee of the Initial Insurance Fund, the former Chair of the CSCO Tumor Vascular Targeting Committee, Vice Chair of the Precision Medicine Committee of the Chinese Anti-Cancer Association, and Chair of the Oncology Division of the Asia-Pacific Society for Biomedical Immunology. He is the Deputy Editor of Chinese Journal of Oncology and Vice Chair of the Molecular Targeting Committee of the Shanghai Medical Association, later serving as Chair. He is also Vice President of the Respiratory Society of the Shanghai Medical Doctor Association. Professor Han specializes in the diagnosis and multidisciplinary treatment of lung cancer, targeted immunotherapy, and clinical research on new anti-tumor drugs. He has received the second prize in Chinese Medical Science and Technology, the eighth China Respiratory Physician Award, and the first prize for innovation in the Chinese pharmaceutical industry. He has also received numerous awards from the Shanghai Medical Science and Technology Award. He has published over 300 papers in the field of lung cancer and has led and authored Chinese Lung Cancer Treatment Guidelines, Tumor Biologic Immunotargeted Therapy, and Endobronchial Ultrasound Techniques. He is the chief translator of Anti-Tumor Anti-Angiogenesis Therapy and has co-authored over ten other books.