Selecting a treatment for operable non-small cell lung cancer from the many options available involves consideration of tumor stage and biomarkers.
At the 2023 Congress of the European Society for Medical Oncology, Heather Wakelee, MD, delivered a presentation on the current standard of care in adjuvant/neoadjuvant therapy for operable non-small cell lung cancer (NSCLC). The presentation took place during the session Adjuvant/Neoadjuvant Therapy of Operable NSCLC in 2023.
PW spoke with Dr. Wakelee to learn more about her presentation.
PW: What are the primary adjuvant and neoadjuvant options for operable NSCLC?
Heather Wakelee, MD: When we think about optimal treatment for early-stage NSCLC, we need to think about tumor stage and biomarkers, in particular the PD-L1 protein level on the tumor and whether an EGFR mutation or ALK translocation of another biomarker is present.
If an EGFR mutation or ALK positivity is identified, the standard approach is to go to surgery. We then use adjuvant targeted therapy with osimertinib for EGFR-mutated disease for up to 3 years, with debate ongoing about longer use; the agent is approved now in many parts of the world.
Alectinib is used for ALK-positive disease for up to 2 years, with debate also ongoing about longer use, though it does not have the same current approvals.
If no driver mutation is found, immune therapy and chemotherapy can be added to surgery. In the US and many parts of the world, nivolumab added to chemotherapy for three cycles is an approved option; that’s the CheckMate 816 regimen. This is likely more active in patients with some PD-L1 expression on tumors.
If a patient has already had surgery, we have adjuvant atezolizumab if there is PD-L1 expression, especially if it is greater than 50%. This was assessed in the IMpower010 trial. Pembrolizumab was examined in the KEYNOTE-091 trial and likely also works better with PD-L1 expression but has approval regardless of PD-L1 expression in some regions. In either case, the immune drug is given for 1 year after completion of surgery and chemotherapy.
We now also have results from five trials of perioperative immune therapy, where the drug is given with chemotherapy for four cycles prior to surgery; the patient has surgery and then receives up to 1 year of additional immune therapy. The trials were with pembrolizumab (KEYNOTE-671), durvalumab (AEGEAN), and nivolumab (CheckMate77T). Two trials were done exclusively in China with toripalimab or tislelizumab (RATIONALE-315).
In all trials, the complete pathologic response was better with the addition of the immune therapy. Further, in the four trials where we have data, the event-free survival—disease-free survival plus events that prevented surgery—was strongly positive; this includes all but the RATIONALE-315 trial. In KEYNOTE-671, there was also a proven overall survival (OS) benefit and FDA approval. The other regimens do not yet have approval, but there are a lot of options.
PW: What factors influence therapeutic decisions in this patient population?
Heather Wakelee, MD: For patients who do not appear to have lymph nodes involved, but then go to surgery and are found to have more extensive disease, an adjuvant approach will be used when there are no driver mutations. However, our enthusiasm for the adjuvant therapy is lower if there is no PD-L1 expression. For stage 2 disease, many patients will have neoadjuvant or perioperative therapy, but some may go to surgery first if there is known high PD-L1 expression and therefore a likely benefit with adjuvant therapy and a reason to consider an earlier surgery, such as if the patient does not want to delay. We do not yet know about the additional benefit of the adjuvant part of a perioperative regimen, but with the FDA approval and OS benefit, the perioperative approach will be utilized extensively.
PW: What are the primary take-home messages you aimed to convey?
Heather Wakelee, MD: I wanted to emphasize the importance of comprehensive tumor testing for EGFR, ALK, and PD-L1 levels to make sure that patients with driver mutations do not get the wrong therapy and that patients with low PD-L1 expression are prioritized for a neoadjuvant or perioperative approach. Those seem to be more effective than adjuvant in that setting. We have a lot of options now, which is very exciting, and all patients should be discussed at a tumor board or with a multidisciplinary team before any treatment is started to make sure the best choice is offered to them.
PW: How can this inform real-world treatment decisions in NSCLC?
Heather Wakelee, MD: This is a rapidly expending area where we still have questions about the optimal strategy for each patient. In the session, we tried to capture all the emerging data and decide how to interpret this in the context of each patient. It is critical to have full testing and a multidisciplinary discussion for each patient as often as possible, as the best approach can be personalized based on the biomarkers. We still have to figure out how much the extra adjuvant therapy helps in the perioperative trials and which patients are the best candidates to go straight to surgery, but we have many fabulous options for patients now with proven OS benefit in the perioperative KEYNOTE-671 trial and strong indications in subsets with PD-L1 expression in two of the other trials, including the adjuvant IMpower010 trial for PD-L1 expression of much higher than 50% and neoadjuvant CheckMate816 with any PD-L1 expression of greater than 1%.
