[Interview]‘Opdivo adds long-term survival as upfront adjuvant therapy for lung cancer’

When detected early, non-small cell lunger cancer (NSCLC) can be cured with surgery but many patients experience recurrence even after surgery. The five-year recurrence rate is as high as 45 percent for stage 1B, 62 percent for stage 2, and 76 percent for stage 3, indicating the need for effective systemic treatments for non-metastatic stages of resectable NSCLC.

In March 2022, the anti-PD-1 immuno-oncology drug Opdivo (nivolumab) won approval from the U.S. Food and Drug Administration for treating adult patients with resectable NSCLC as a neoadjuvant in combination with platinum-based chemotherapy.

Four-year follow-up data from the Opdivo clinical trial (CheckMate-816), presented in June at the American Society of Clinical Oncology Annual Meeting (ASCO 2024), showed that the combination of Opdivo and chemotherapy improved event-free survival (EFS) and overall survival (OS). Pathologic complete response rates were also high, confirming the long-term survival benefit.

In October 2022, the combination of Opdivo and chemotherapy was approved by the Ministry of Food and Drug Safety (MFDS), making the treatment available to Korean physicians. That opened the possibility of improving treatment outcomes by providing new treatment options for NSCLC patients.

Korea Biomedical Review spoke with Dr. Lee Jeong-eun, a professor in the Department of Respiratory and Allergy Medicine at Chungnam National University Hospital, to learn about the clinical value of Opdivo as a first-line adjuvant therapy for NSCLC, its applicability in the real world, the role of immuno-oncology in the future of lung cancer treatment, and actual prescribing practices.

Question: In early-stage lung cancer, upfront adjuvant therapy is gaining traction to prevent recurrence after surgery. What are the clinical benefits of these therapies?

Answer: While the recent introduction of immuno-oncology and targeted agents has significantly extended the survival of lung cancer patients, there have been few advances in perioperative care over the past 15 years. Some stage 1 lung cancer patients, as well as some stage 2 and 3 patients, receive adjuvant anticancer therapy with cytotoxic agents after surgery due to the possibility of microscopic residual cancer. In some cases, adjuvant therapy is given to inoperable patients in an attempt to increase the likelihood of surgery.

However, in most cases, it is recommended to proceed with surgery as soon as possible because the effectiveness of upfront therapy is uncertain, and disease progression after this therapy may result in a lost opportunity for surgery.

In general, the primary goal of adjuvant therapy is to reduce the size of the tumor through preoperative chemotherapy to increase the likelihood of resection and complete resection and to remove the tumor safely. Therefore, patients who do not have a good chance of a cure with surgery alone have been the primary candidates for this therapy.

However, upfront adjuvant therapy with immuno-oncology agents, such as Opdivo, limits the target population to surgically resectable patients. This has redefined the purpose of upfront adjuvant therapy by showing that it prolongs survival by enhancing anti-tumor immunity after surgical resection.

Q: In the CheckMate-816 study, the Opdivo plus chemotherapy arm had a pathologic complete response (pCR) rate more than 10 times higher than the chemotherapy alone. What does this mean?

A: The CheckMate-816 study sheds new light on the pathologic metric of pCR. It has been used as a marker of effectiveness in studies of adjuvant therapies, including chemoradiotherapy, but its use has been limited. However, CheckMate-816 demonstrated in a large cohort of patients that pCR is a marker of adjuvant therapy effectiveness and can predict recurrence and survival in treated NSCLC patients.

The four-year survival rate for patients who achieve a pathologic complete response to upfront neoadjuvant therapy with Opdivo plus chemotherapy is about 95 percent, similar to the five-year survival rate for patients with stage 1 NSCLC (70-90 percent). The significant improvement in event-free survival (EFS), especially in lymph node-positive stage 2 and 3 patients, suggests that even patients with higher-stage disease can achieve a high cure rate if they achieve a pathologic complete response.

In the CheckMate-816 study, pCR in the Opdivo plus chemotherapy arm was 24 percent, particularly frequent in patients with high PD-L1 expression. Based on these results alone, I would not hesitate to choose an upfront regimen with Opdivo if you have high PD-L1 expression. Patients with low or negative PD-L1 expression are unlikely to achieve a pathologic complete response, and the combination of Opdivo and chemotherapy may not be affordable for them, considering the patient's financial situation and expected benefit.

In the CheckMate-816 study, patients who did not achieve a pathologic complete response were not significantly different from the control group. This is why achieving a pathologic complete response is so important. That can be seen as a weakness, but it can also be seen as a strength because these biomarkers can predict pathologic response. In the future, there will be more research into new agents and therapies aimed at pathologic response.

In addition, the results of various clinical studies that include patients who do not achieve pathologic complete response are expected to be published soon. For these patients, there is a growing expectation that adjuvant therapy with immuno-oncology agents after surgery will be beneficial. Long-term follow-up results from trials comparing the effectiveness of adjuvant immuno-oncology therapy before and after surgery will soon be available to answer this question.

Q: Opdivo upfront is administered in three cycles spaced three weeks apart. How effective and convenient are three cycles every three weeks for patients in practice?

A: Three three-week cycles as upfront adjuvant therapy is generally considered tolerable by patients. There are no studies on the appropriateness of fewer cycles, so direct comparisons are difficult. However, based on other studies that have chosen to treat with four cycles, it is rare for patients to complete more than 75 percent of the four cycles as planned.

I had a patient who received upfront adjuvant therapy with four cycles of immuno-oncology before major surgery and planned maintenance therapy with immuno-oncology after surgery. However, she became too unwell by cycle four and her treatment was delayed, which delayed the timing of her surgery. Four treatment cycles are common in advanced NSCLC, and clinicians may be familiar with them. However, for patients who are scheduled for surgery, four cycles can result in a decreased ability to function in the days leading up to surgery.

Q: Four-year follow-up data from the CheckMate-816 study, presented at the American Society of Clinical Oncology in June, showed that the EFS in the Opdivo plus chemotherapy arm was 43.8 months, significantly higher than the 18.4 months in the chemotherapy alone group. The four-year EFS rate was 49 percent in the Opdivo plus chemotherapy arm, compared to 38 percent in the chemotherapy alone. Based on these four-year data, how can we assess the long-term treatment effectiveness of Opdivo upfront?

A: As expected, EFS in the CheckMate-816 study was more than twice as long as in the control arm, and the difference in event-free survival was about 10 percent. Considering the effectiveness of three cycles of preoperative treatment, this is a remarkable result. Median overall survival (mOS) was not reached, and EFS was found to differ by about 30 months. These results demonstrate that pre-adjuvant chemotherapy with Opdivo delays postoperative recurrence and contributes significantly to patients' long-term survival.

Q: What is the share of patients with lung cancer who may be considered for upfront neoadjuvant therapy, and what patient characteristics, if any, may benefit from Opdivo upfront neoadjuvant therapy?

A: The premise of upfront adjuvant therapy is “surgically resectable patients” and because it involves an immuno-oncology agent, it is not used in patients with EGFR mutations or ALK or ROS1 mutations. According to the Health Insurance Review and Assessment Service (HIRA), about 50 percent of all lung cancer patients undergo surgery, and about 30 percent have an EGFR mutation. Considering this, about 35 percent of all lung cancer patients could be eligible for immuno-oncology upfront.

However, the CheckMate-816 study showed a clear clinical benefit compared to controls in stage 2, 3, and especially stage 3 patients with lymph node metastases, suggesting that this percentage may be less than 35 percent. Stage 3 patients are particularly likely to be eligible, and stage 3 patients without significant lymph node metastases and who are operable are the best candidates for Opdivo upfront. Patients with stage 3A or stage 3B who have multiple lymph nodes or many lymph nodes are still considered for maintenance immuno-oncology after chemoradiotherapy.

In addition, because Opdivo is expected to be effective in patients with high PD-L1 expression, we are cautious about using it in all patients. The share of patients with high PD-L1 expression is approximately 30-40 percent, and these patients are more likely to benefit from upfront therapy with Opdivo to prolong EFS and OS.

Q: What is the process for surgery after Opdivo upfront?

A: Before deciding on upfront therapy, a thorough discussion of resectability with a cardiothoracic surgeon is conducted, and upfront adjuvant therapy with Opdivo is performed. Afterward, we discuss resectability again with imaging response assessment. Before this discussion, PET-CT may be used to assess metabolic response (SUV change on PET-CT) further. If new metastases are detected during treatment or if chest CT shows no reduction in tumor size and there is a suspicion that upfront adjuvant therapy is not effective, surgery is performed immediately after confirming the metabolic response. Because we consult with a professor of thoracic surgery from the beginning of treatment, surgery is rarely delayed as long as the patient remains sufficiently active.

For patients undergoing surgery after neoadjuvant therapy, it is often difficult for the multidisciplinary team to communicate sufficiently, so the medical staff in charge of treatment frequently communicate separately.

Q: Are the side effects of neoadjuvant immuno-oncology therapy manageable and how are they managed?

A: The side effects of adjuvant immuno-oncology are not significantly different from those seen in stage 3 or 4 patients. I think clinicians have a lot of experience with managing various immune-related side effects, including hypothyroidism. However, hormone-related side effects can present with vague symptoms, which can lead to a delay in diagnosis if the possibility of immune-related side effects is not considered in advance. In addition, immune-related side effects can occur during neoadjuvant therapy, before surgery, and during postoperative follow-up. In this case, immune-related side effects may be more easily overlooked than when immuno-oncology drugs are used as maintenance therapy in advanced stages, so always be alert to vague symptoms in patients.

This is especially true for older patients. While younger patients may be able to clearly describe their symptoms, older patients often don't talk about them unless asked. Therefore, doctors should carefully observe the patient's gait, eye color, and skin condition and actively question them.

Hormone screening before starting adjuvant therapy, before and after surgery, and at three-month intervals after surgery can also be helpful. It may also help to discuss these results with your endocrinologist in advance, as patients often have abnormalities in their tests even if they do not have symptoms.

Q: What research do you think needs to be done to improve the prognosis or treatment experience for lung cancer patients, and in what direction do you think it should go?

A: My research motto is to do research that directly benefits patients. I think clinicians should get ideas from the patients they see in the clinic. New ideas should be generated based on information gained through close observation and analysis of patients and their test results.

To do this, you need to follow the clues you find in the patient and try to solve the problem whether it is caused by patient factors or treatment. I think that research will naturally come out of this process. However, I am concerned that the short time frame of the current system of care may make it difficult for us to think deeply.

Q: Finally, what would you like to emphasize to improve the lung cancer treatment environment in Korea?

A: You must care about your patients. As with any relationship, you must feel comfortable with the person. The doctor-patient relationship is also a relationship between people, so it is important to have a comfortable relationship first so that the treatment can be done correctly. It's important that patients feel comfortable enough to tell their doctors what's bothering them, otherwise, they'll just put up with the discomfort and pain, which can become a big problem later on. Cancer patients, in particular, have a lot of different problems. So, doctors need to work with them and be persistent.

This requires an environment where doctors have plenty of time to see patients. That’s because humanizing the patient, observing them closely, and questioning them thoroughly can uncover problems that may be occurring. And even if a patient's symptoms or problems don't seem to be related to lung cancer or lung cancer treatment, it's important to consider the underlying cause. This is especially true if the problem occurred during lung cancer treatment.

Dismissing the problem as "unrelated to lung cancer" and referring the patient to another specialty can lead to difficult-to-diagnose or rare conditions related to lung cancer, causing the patient to endure discomfort and ultimately not receive treatment. As physicians treating the serious disease of lung cancer, it is important to remember that we are the ones our patients trust and rely on the most.