ESMO 2025 | Choosing the optimal immunotherapy approach in resectable NSCLC

Yeah, so at the current time, all three approaches, neoadjuvant, perioperative, and adjuvant, IO, are all acceptable standards of care and have received FDA approval in the U.S. and in many countries globally. So how do we decide in the absence of head-to-head trials? There are head-to-head trials that are currently underway. ETOP is running a study in Europe. In the US, Alliance and SWOG are running the Clear Insight trial, as well as an additional trial that is going to evaluate head-to-head comparisons. So in the absence of head-to-head trials, how do we decide on the most appropriate approach? Well, from a surgical perspective, our staging is not very accurate, so we tend to underutilize invasive mediastinal staging. So we upstage upwards of about 20% of patients, even in clinical stage 1 patients, where they’ve had negative PET-CT scans, go to resection, and prior to resection, they had invasive mediastinal lymph node staging. And despite that, despite having a negative PET-CT and invasive staging by EBUS or mediastinoscopy, we’re still seeing about 15% to 20% of patients being upstaged with either N1 or N2 disease, and that’s based upon almost 30,000 patients in the Society of Thoracic Surgeons database. So by default, these patients who have surprised N1 and N2 patients, N2 disease, are going to get adjuvant therapies by default. So everybody else, it’s now choosing between a neoadjuvant, perioperative, and adjuvant approach in the patients where we do know up front that they’re stage two or three. I think there’s several considerations. One is there’s going to be differences in terms of determining medical operability of the patient and surgical resectability of the tumor and lymph nodes. These are two entirely different concepts for the surgeon. Medical operability is performance status of the patient, and this is largely governed by cardiac and pulmonary function and comorbidities, whereas surgical resectability of tumor and lymph nodes are guided by imaging and invasive lymph node staging. And what goes into the factor of who should get upfront surgery versus who should go to a neoadjuvant or perioperative approach depends on what is our expected response rate to chemo IO. This is where the immune bond markers, PD-L1 is the most well-known one, but it’s imperfect. And then we also take into consideration the NGS testing results. So at the current time, classic EGFR mutations and ALK rearrangements are excluded any time patients are undergoing systemic therapy in the early stage setting. But in the metastatic disease setting, the first-line therapy for actionable genomic altered non-small cell lung cancer, there’s about nine different genetic alterations that receive first-line therapy as targeted therapy. So I think we need to have equipoise and say, if we know that in the metastatic setting, the first-line therapy is not chemo IO and it’s targeted therapy, but yet those targeted therapies are not approved in the early stage setting, it shouldn’t mean that we should give neoadjuvant chemo IO just because those drugs are not approved. And because the expectant response rates are poor or very low in those AGA lung cancer patients. So I think those patients should go to upfront surgery or get a neoadjuvant chemo and then go to surgery. And whatever expectant response you may get in the adjuvant setting, then give your IO if there’s no approved drugs. So I think the NGS testing is important. And the PD-1 marker is imperfect. There are PD-1 negative patients that respond to chemo IO. However, there are three trials that have read out with overall survival advantage. That’s Checkmate 816, which is a pure neoadjuvant chemo with nivolumab. Perioperative KEYNOTE-671, which is upfront chemo Pembrolizumab, and then surgery and then adjuvant Pembrolizumab for a year. And then you have RATIONALE-315, which is a China-only study with chemo IO and then adjuvant IO as well. And all three of those studies have shown an OS survival benefit. So when you look at the subset analyses, the PD-1 negative cohort had hazard ratios of about 0.9 in all three trials. So still we’re having a deficiency in terms of impacting survival and especially overall survival in the PD-1 negative cohorts. So if I have a PD-L1 negative patient, even though the indications say they can receive neoadjuvant or perioperative chemo IO, I think about in the absence of an AGA lung cancer and their PD-L1 negative, I think about how will three to four cycles of chemo IO impact disease progression. If it takes the cancer from a lobectomy to a bilobectomy or pneumonectomy, and it’s a larger amount of lung that has to come out, and my expected response rate is low because the PD-L1 is negative or in the absence of an AGA cancer, then I think a patient like that, we should consider going to upfront surgery because there’s a low expectant response rate, and it’s going to impact the conduct of my surgery in terms of how much lung I take out. Also, if it’s an AGA lung cancer without an approved targeted therapy, giving chemo IO where the response rates are very low and it’s gonna result in more lung to come out. I also think that in scenarios like that, patients just go to upfront surgery. So we really need to think about immune bond markers and NGS testing results similar to the way medical oncologists use them and say, should this patient get IO at all? Or if their response rates are low, then these patients should go to upfront surgery. But overall, I favor a perioperative approach, but at the current time, all three approaches are FDA approved and acceptable standards of care.

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