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Religious scholar once said, "The art of simplicity is a puzzle of complexity." Nowhere does that seem more apparent than in the realm of immunotherapy in the context of resectable non-small cell lung cancer (NSCLC).

Why? Because the "incorporation of immunotherapy brings potential to improve outcomes of patients with resectable NSCLC, but these advances have also increased the complexity of the treatment landscape and created important knowledge gaps," explained Bernardo Haddock Lobo Goulart, MD, MS, of the FDA Office of Oncologic Diseases in Silver Spring, Maryland, and colleagues.

As they noted in a , current evidence supports the use of three perioperative strategies: neoadjuvant chemoimmunotherapy, adjuvant chemotherapy followed by immunotherapy, or neoadjuvant chemoimmunotherapy followed by adjuvant immunotherapy.

Some of the immunotherapy agents and their corresponding trials that the authors pointed to were atezolizumab (Tecentriq) in the IMPower studies, nivolumab (Opdivo) in the CheckMate trials, and pembrolizumab (Keytruda) in the KEYNOTE trials. The team noted that preoperative chemoimmunotherapy studies have shown boosts in pathologic complete response (PCR) in patients with stage IB/III disease, and that event-free survival is also improved in stage II and III disease, based on perioperative studies.

Goulart and co-authors cautioned, however, that interpreting "PCR as a surrogate endpoint when the postoperative treatment is not uniform (as in all the perioperative studies)" is difficult.

The team highlighted three "evidence gaps" for perioperative immune checkpoint inhibitors (ICIs) in NSCLC:

• No trials have isolated the treatment effects of ICIs given in the neoadjuvant phase from ICIs given in the adjuvant phase, which may put lung cancer specialists in a tough position: Should they refer patients to surgery upfront, followed by adjuvant chemotherapy and ICI or go for neoadjuvant chemoimmunotherapy pre-surgery? And if the treatment path is neoadjuvant therapy before surgery, what's the value of adjuvant immunotherapy versus postsurgery observation?

• What is the best control regimen for future trials -- adjuvant chemo and then immunotherapy; neoadjuvant chemoimmunotherapy; or neoadjuvant chemoimmunotherapy and then adjuvant immunotherapy? Goulart and co-authors noted that "regional differences in ICI approvals compound the uncertainty regarding the choice of comparator regimens for future global trials."

• PCR can shorten the timeline for evaluating the efficacy of neoadjuvant therapies, along with helping to stratify which patients would benefit from further adjuvant therapies versus those who might get to cure without adjuvant treatment. Still, "the oncology community needs to develop a deeper understanding of the role of PCR and technical assessment of this marker as an intermediate end point and tool to guide treatment decisions for resectable NSCLC."

At ASCO's 2024 annual meeting, one of the co-authors, Jamie E. Chaft, MD, of Memorial Sloan Kettering Cancer Center in New York City, gave an update on immunotherapy in resectable, early-stage NSCLC. Below are excerpts from her comments.

How has stage I NSCLC figured in immunotherapy trials?

Chaft: We've had many game-changing studies in the last few years. However, they were all inclusive of stage III. We're many years from data specific to stage I, so we'll be focusing on some subsets. We have to think about our patient in the clinic based on the size of their tumor and whether or not lymph nodes are involved. We're really talking about tumors that are less than 4 cm or 4 cm or greater.

If the lymph nodes are involved, it's a different story. For tumors that are less than 4 cm, to date there is no adequate data to prescribe preoperative chemotherapy and immunotherapy. But we must remember that pathologic stage often is higher than the clinical stage preoperatively. For tumors that are 4 cm or larger, or if there are involved lymph nodes, trials across the board show benefit inclusive of this stage. However, the subsets are all underpowered to give your patient in the clinic an exact benefit ratio.

What are some risk-benefit considerations for immunotherapy in stage I NSCLC?

Chaft: Preoperative chemoimmunotherapy looks better than adjuvant immunotherapy. However, we must think about the risk-benefit on an individualized patient level. There is no role for immunotherapy without chemotherapy. And there's no role for immunotherapy in tumors driven by EGFR and ALK alterations.

So what are we talking about in terms of prognosis? We do pretty well with surgery alone in resected stage IA. However, when you're getting towards that 3-cm tumor, 5-year survivals are still pretty poor: 75% to 80%. Once lymph nodes are involved, stage really plummets. And that's where our systemic therapies improve survival.

So what are our considerations for the patient with stage I and II? Recurrence rates are high, but some of these patients were cured with surgery only. We believe that without randomized data in the NSCLC setting, preoperative immunotherapy is likely more effective than postoperative immunotherapy.

Neoadjuvant chemoimmunotherapy is certainly favored over adjuvant immunotherapy in my mind. And this is particularly called out by the squamous cell carcinoma subsets that don't appear to derive a dramatic benefit from adjuvant therapy. And finally, while the PCR data are truly intriguing in all of the perioperative studies, postoperative treatment was uneven, really limiting interpretability of that endpoint as a circuit.

What are some take-home messages?

Chaft: I hope the medical oncologists are seeing these patients preoperatively. If their tumors are even close to 4 cm, we really have to look for high-risk features and consider offering them preoperative chemotherapy and immunotherapy, but only if their biomarkers are known. These tumors must be EGFR- and ALK-negative. Currently, there's no role for adjuvant or neoadjuvant immunotherapy in the absence of chemotherapy. There's no role for these drugs if these tumors have EGFR or ALK alterations.

We have to keep in our minds that clinical stage is often lower than pathologic stage. At least 20% of the time, our patients are upstaged at the time of surgery.

Read the review here.