ESMO 2023 | Dr. Spicer explains controversies in perioperative immunotherapy for patients with early-stage NSCLC

Editor's note: For operable EGFR/ALK-negative non-small cell lung cancer (NSCLC), the administration of immunotherapy has gradually become the new standard of care. Yet there is still much controversy about immunotherapy modalities, treatment cycles, and which patients benefit from adjuvant therapy. Jonathan Spicer, McGill University Health Centre, Montreal, reported data from the KEYNOTE-671 study of perioperative immunotherapy at the 2023 ESMO meeting (Abstract No. LBA56). Oncology Frontier invited Jonathan Spicer to share insights on controversial issues in perioperative immunotherapy at the 2023 ESMO.

Oncology Frontier:  Please introduce yourself, including your name, profession and where are you from?

Dr Spicer: My name is Jonathan Spicer. I am a thoracic surgeon in Montreal at McGill University Health Center. I am also the Medical Director of our thoracic oncology network, working in a multidisciplinary group there.

Oncology Frontier: 2023 ESMO released the data of overall survival in the KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (LBA56). Please share your views on the efficacy and safety of this strategy.

Dr Spicer: In terms of my thoughts on KEYNOTE-671, the results of which were released just a couple of days ago, I think it is an important moment in time that we are able to show that the neoadjuvant strategy, and one involving perioperative pembrolizumab, can improve overall survival. Still to this day, overall survival is our gold standard of efficacy. This is the first of the perioperative approaches, whether as neoadjuvant, adjuvant, or perioperative strategies, to show an overall survival benefit in the intent-to-treat population. I think that is extraordinarily important, setting KEYNOTE-671 apart in that regard for the time being. I think it is also interesting that it was able to achieve this result in such a short period of time. It has been about 5 1/2 years since the first patient was recruited, further demonstrating that this neoadjuvant strategy is a rapid way to get meaningful endpoints. To get overall survival in that period of time makes for a very efficient trial design. Those are my thoughts. I think we have made a lot of headway.

Oncology Frontier: For patients with early-stage non-small cell lung cancer who receive neoadjuvant immunotherapy, do patients who achieve pCR require further adjuvant therapy?

Dr Spicer: One of the big questions around the perioperative strategy is whether patients who have developed a pathological complete response (pCR) need further treatment. We don’t have the answer to the question - we haven’t conducted the correct trial to determine whether there is added value to the adjuvant component. What we have established is a platform of treatment that we think could be beneficial. Certainly, when these trials were designed, there was no way to know whether the neoadjuvant was going to be sufficient or what the benefit of adjuvant was, so this is why these trials were designed with a perioperative strategy. It is clear that although patients who develop pCR have the best prognosis, some do develop events down the road. I have to say that having been using the CHECKMATE-816 regimen for a little while now, it is very nice to be able to tell a patient that they have had a pCR and that their prognosis is excellent, and that they are finished with their treatment course. At least the patients I treat are very happy to know that they no longer need to take more treatment. I think now that this new option is becoming available, the conversation changes a little bit. It becomes one about risk benefit, and does it feel valuable to that patient to continue on with that year of infusions, understanding that we don’t quite know who will and won’t benefit from that sizable extra treatment course. A lot more work needs to be done in that domain to understand who needs it and who doesn’t so we don’t overtreat or undertreat the wrong patients.

Oncology Frontier: Are all early-stage NSCLC patients eligible for neoadjuvant plus adjuvant immunotherapy?

Dr Spicer: I often get asked who is or is not eligible for a perioperative strategy. I think it is the same patients who are eligible for a neoadjuvant strategy. It is more about figuring out who will benefit from preoperative systemic therapy and who we want to take directly to the operating room. This remains a very difficult question. In my practice, when I have clear indications that the patient would benefit from systemic therapy (which is stage IIA or higher), I generally favor giving the treatment beforehand, because I know they are more likely to get it. In my center, they will almost, with very rare exceptions, all go to the operating room, so I think it is important to develop experience and know what your data is. I would say 95-98% of our patients will go to the operating room once they are induced with chemoimmunotherapy. Upfront surgery is reserved for those who are ineligible for immunotherapy, ineligible for chemotherapy, or who might have tumor-related complications that force us to go to the operating room earlier and make systemic cytotoxic therapy not possible (patients with post-obstructive pneumonias, with renal issues and not able to get cisplatin-based regimens, and things like that). So it is really the contraindications to systemic therapy like autoimmune disorders that might preclude chemoimmunotherapy that might push us towards an upfront surgery type of strategy.

Oncology Frontier: The optimal number of courses of perioperative immunotherapy is still controversial, what do you think is the optimal duration of treatment?

Dr. Spicer: Now that we have established these platforms of treatment with a lot of cycles that are programmed in both before and after, we have to start the difficult work of figuring out how much is actually needed and for which patients. It will probably be an increasingly individualized approach. We don’t know how many neoadjuvant cycles are needed. It does seem that three is just as good as four, so there may not be much upside to giving that fourth neoadjuvant cycle, especially if you look at pCR as a metric of response to the extra treatment. In the adjuvant setting, we have no idea how much is required. I think there are going to be a whole bunch of studies that need to be done, probably led by the academic groups, to sort this out.