Advancing neoadjuvant immunotherapy in non-small cell lung cancer (NSCLC): commentary on the Lung Cancer Mutation Consortium 3 trial (LCMC3)

Introduction

The perioperative management of resectable non-small cell lung cancer (NSCLC) has evolved from adjuvant systemic therapy to an added focus on neoadjuvant therapy, which is thought to have increased efficacy due to the presence of intact tumor and ability to induce tumor shrinkage prior to surgery (1). Findings from the Lung Cancer Mutation Consortium 3 (LCMC3) trial, the largest neoadjuvant immunotherapy trial, established a benefit with checkpoint inhibitor monotherapy and set the stage for subsequent trials studying neoadjuvant and perioperative chemoimmunotherapy (2). The landmark Checkmate 816 and KEYNOTE-671 trials, for instance, led to recent Food and Drug Administration (FDA) approvals for neoadjuvant and perioperative immunotherapy in combination with chemotherapy, respectively (3,4). However, several questions remain regarding the optimal perioperative management in this diverse patient population, including the role of biomarkers in treatment selection, the identification of patients who may benefit from immunotherapy alone rather than combined chemoimmunotherapy, and the impact of perioperative therapies on surgical approach and outcomes (5,6).

A recent report on pathologic and surgical outcomes in patients enrolled in LCMC3, which confirmed the benefit of neoadjuvant immunotherapy, provides important contributions to ongoing discussion regarding patient selection and multidisciplinary care within this rapidly changing therapeutic context (7). Here, we review the findings reported from LCMC3 and interpret them in the context of more recently published randomized chemoimmunotherapy trials. We reflect on how the results of LCMC3 provide a foundation upon which to further discuss patient selection for perioperative treatments and optimization of the multidisciplinary treatment approach for resectable NSCLC.

LCMC3 overview and summary: pathologic and surgical outcomes

LCMC3 was a multicenter, single-arm phase II study that investigated the programmed death ligand 1 (PD-L1) checkpoint inhibitor atezolizumab as neoadjuvant treatment for patients with untreated, resectable stage IB–IIIB NSCLC (7). A total of 181 patients were enrolled and treated with 2 cycles of atezolizumab prior to surgical resection, followed by up to 12 months of adjuvant atezolizumab in patients with evidence of pathologic response or lack of radiographic progression. The primary endpoint of the study was major pathological response (MPR), defined as 10% or less viable tumor tissue at the time of surgical resection. Secondary endpoints included pathologic complete response (pCR) and radiographic response (7).

Most (81%) patients had stage IIB–IIIB tumors: 18 (10%) had stage IB disease, 16 (9%) had IIA disease, 55 (30%) had IIB disease, 70 (39%) had IIIA disease, and 22 (12%) had IIIB disease. Most patients (90%) were current or former smokers, and 38% of tumors had squamous histology. The trial population was unselected for PD-L1; 27% of tumors had a tumor proportion score (TPS) for PD-L1 of ≥50% and 15% had a TPS of 1–49% (7). All 181 patients received at least 1 cycle of neoadjuvant atezolizumab, and 88% (n=159) proceeded to surgery. Of the 22 patients (12%) who did not undergo surgery, 10 (6%) had evidence of radiographic progression, 6 (3%) did not proceed with surgery due to physician decision, 3 (2%) withdrew consent, and 3 (2%) were noted to have “other” reasons: 1 patient was noted to have congestive heart failure, 1 declined surgery, and 1 was lost to follow-up.

The primary efficacy population (n=143) that was used for analysis included all patients who underwent surgery, but excluded 16 patients with EGFR mutations or ALK translocations due to emerging evidence that the benefit of immunotherapy is limited in this patient population (8,9). Within the primary efficacy population, an MPR was observed in 20% (n=29 of 143) of patients, and pCR was observed in 6% (n=8 of 143), as noted in Table 1 (3,7,10-17). Of note, while evaluation of pCR is generally thought to be more reliable, interobserver reproducibility has been demonstrated for MPR assessment (18). In line with findings from other neoadjuvant trials, there was a lack of association between radiographic response and final pathological stage in LCMC3. This highlights the importance of the latter in accurately assessing response to neoadjuvant immunotherapy.

Surgical outcomes are summarized in Table 2 (3,7,10-17). Of the 159 patients who underwent surgery, only 4 patients experienced a treatment-related surgical delay. Over half (54%, n=86) underwent a minimally invasive surgery by video-assisted thoracoscopic surgery (VATS) or robotic VATS, and the rate of conversion from minimally invasive surgery to thoracotomy was 15% (n=15) (7). Most patients (79%, n=125) underwent a lobectomy, and pneumonectomy was uncommon (9%, n=14) (7). Complete resection (R0) was achieved in 91% of patients (n=145). Intraoperative complications were rare (n=5) but successfully managed, and the rate of grade 4–5 adverse events (AEs) was higher in patients who received pneumonectomy (28.5%) compared to patients without a pneumonectomy (10%). Pre- and postoperative treatment-related and immune-related AEs (irAEs) were consistent with known immunotherapy-related toxicities.

The encouraging results of LCMC3, the largest single-arm phase II trial of neoadjuvant immunotherapy, provided rationale to conduct subsequent randomized chemoimmunotherapy trials. In addition to size, strengths of the trial include its multicenter design and review of institutional MPR assessments by a central pathology committee (2,7). However, the study has several limitations. First, it is a single-arm study, which limits our ability to draw definitive conclusions regarding the immediate and long-term benefit of neoadjuvant atezolizumab. Second, documentation of lymph node involvement by endobronchial ultrasound or mediastinoscopy for patients with clinical II–IIIA disease was not required, which may lead to inaccurate staging and interfere with the interpretability of results. Third, although surgical candidacy was determined jointly by the treating thoracic surgeon and medical oncologist, criteria for surgical candidacy were not standardized or assessed centrally, which increases the likelihood of selection bias. Fourth, pathologic response was only assessed on primary tumors. Excluding lymph node responses limits the pathologic evaluation and our ability to assess treatment effectiveness (2). Fifth, while MPR is now commonly used as an endpoint for neoadjuvant trials and has been shown to correlate with both overall survival and disease-free survival (19,20), assessing for MPR can be subjective, despite efforts to standardize pathologic calculations (21-23). Finally, most of the patients on the study were white (81%), current or former smokers (90%), and had stage IIB or higher disease (81%), thus limiting the generalizability of results.

Context and implications of pathologic outcomes in LCMC3

The favorable pathologic outcomes observed in LCMC3 provided the basis for administering neoadjuvant immunotherapy to patients with resectable NSCLC. Similar findings were reported in the smaller phase II NEOSTAR trial, which randomized patients to receive neoadjuvant nivolumab or nivolumab plus ipilimumab (Table 1) (10,11). In the wake of LCMC3 and NEOSTAR, several phase III neoadjuvant and perioperative chemoimmunotherapy trials have been conducted and have demonstrated consistently higher levels of pathologic response with the addition of immunotherapy. The control arm across these trials is neoadjuvant chemotherapy alone, which has an established benefit in locally advanced disease but was variably adopted (24-26).

Five large randomized phase III chemoimmunotherapy trials—KEYNOTE-671, Checkmate-816, AEGEAN, Checkmate-77T, and Neotorch—all recently reached their primary endpoints (3,12-14,16). A comparison of pathologic outcomes is summarized in Table 1. Compared to patients treated with neoadjuvant chemoimmunotherapy in the phase III trials, a lower rate of both MPR and pCR was observed in patients in LCMC3. On the other hand, the pathologic response rates observed in LCMC3 appeared to be superior to pathologic response rates in patients treated with chemotherapy only in the phase III trials and to historical rates of pCR after induction chemotherapy (27). There have been no large head-to-head comparisons of immunotherapy alone to either chemoimmunotherapy or chemotherapy alone in the neoadjuvant setting. However, as demonstrated by LCMC3, there may be a subset of patients who benefit from neoadjuvant immunotherapy alone and would not require escalation to chemoimmunotherapy. Although the rate of MPR in LCMC3 was higher in patients with high PD-L1 TPS, no informative biomarkers have been established in the neoadjuvant setting (2). Further investigation is needed to better characterize these subpopulations of patients.

Context and implications of surgical outcomes in LCMC3

Surgical outcomes are a crucial marker of clinical benefit in patients who are treated with curative intent and can have significant impact on quality of life. A comparison of surgical outcomes across trials is summarized in Table 2. At 88%, the rate of surgical resection in LCMC3 was similar to the surgical rate seen with neoadjuvant nivolumab in NEOSTAR and higher than surgical rates observed in the chemoimmunotherapy arms of subsequent phase III trials (11,28). Although there is no clear explanation, this might be due in part to fewer cycles of neoadjuvant treatment and/or the absence of chemotherapy-related AEs in LCMC3. In LCMC3, AEs with neoadjuvant therapy precluded 0.5% of patients (n=1) from proceeding with surgery. The rate of cancelled surgery due to AEs from neoadjuvant chemoimmunotherapy varies between trials from 1.1% in Checkmate-816 and 1.8% in AEGEAN to 3.0% in NEOTORCH and 6.3% in KEYNOTE-671 (3,13,16,28). Although AEs from neoadjuvant therapy appears to be more problematic with chemoimmunotherapy, it is difficult to draw conclusions based on cross-trial comparisons. However, immunotherapy alone inherently carries less toxicity risk than chemoimmunotherapy. For this reason, it may be a reasonable option for patients who are unable to tolerate chemotherapy prior to surgery. Still, further investigation is needed to improve patient selection in this context.

The rate of complete (R0) resection, an important predictor of long-term outcomes, was over 90% in LCMC3 and comparable to chemoimmunotherapy-treated arms of the subsequent phase III trials (Table 2). The rate of minimally invasive surgery, which has implications for patient function and quality of life, was higher in LCMC3 compared to Checkmate-816 and AEGEAN. The high rate of a minimally invasive approach in LCMC3 supports surgical feasibility after immunotherapy, but the discrepancy with the phase III chemoimmunotherapy trials is difficult to interpret. The differences in rate of minimally invasive surgery may be attributed to the increased variability in surgical technique and experience that is seen when conducting larger trials and/or to a larger proportion of patients with stage III disease in Checkmate-816 and AEGEAN. Fifty one percent of patients in LCMC3 had stage IIIA or IIIB disease, compared to 63% of patients in Checkmate-816 with stage IIIA disease, and 71% of patients in AEGEAN with stage IIIA–IIIB disease (7,12,13).

An important consideration when evaluating surgical results is that surgical planning often depends on radiographic assessments, which may not accurately reflect tumor response to immunotherapy. As the authors of LCMC3 note, there was a lack of association between radiologic response and final pathological stage; of the 29 patients with MPR, 25 had stable disease and only 4 had a partial response by RECIST criteria (7). Inaccurate interpretation of tumor response based on imaging studies may affect surgical approach and outcomes across clinical trials that involve neoadjuvant immunotherapy. This highlights the need for better radiographic assessment tools in this setting.

Where we are now? Barriers to adopting neoadjuvant immunotherapy and chemoimmunotherapy

Considering the success of LCMC3 and the recent FDA approvals of neoadjuvant and perioperative chemoimmunotherapy, neoadjuvant and perioperative therapy have become widely, though not universally, adopted. Even though KEYNOTE-671 recently demonstrated a significant improvement in overall survival, some remain hesitant to implement neoadjuvant or perioperative therapy due to a lack of long-term survival benefit thus far (29). Overall survival data from the other randomized studies will be valuable.

While the focus of this commentary is on the neoadjuvant and perioperative approach, adjuvant systemic therapy remains a valid approach especially for patients who proceed to surgery immediately after diagnosis or who are not diagnosed with primary lung malignancy until after surgery. In our opinion, however, neoadjuvant and perioperative approaches are preferred over adjuvant-only treatment for a number of reasons, including the ability to target an intact tumor, assess pathologic response to treatment, and potentially improve surgical resectability (1,30). Adherence to systemic therapy is also likely superior with a neoadjuvant approach, as was previously demonstrated for chemotherapy in the NATCH trial (31). There are no randomized data directly comparing neoadjuvant immunotherapy to adjuvant immunotherapy in patients with lung cancer, but clinical trials in melanoma have demonstrated that moving immunotherapy treatments into the neoadjuvant setting improves outcomes compared to an adjuvant-only approach (32).

Although it is difficult to draw definitive conclusions from cross-trial comparisons, the magnitude of survival benefit observed in neoadjuvant and perioperative trials like KEYNOTE-671 and CheckMate 816 has been consistently greater than what was seen in adjuvant trials such as IMpower010 and KEYNOTE-091 (33,34). Ultimately, we believe the broad spectrum of clinical presentations within resectable NSCLC warrants an equally broad range of treatment options. Investigative efforts aimed at improving patient selection, such as the use of pathologic response to tailor adjuvant treatment, will promote truly personalized medicine in this space.

Surgical risk after neoadjuvant immunotherapy

Additional barriers to implementing neoadjuvant therapy include concerns regarding the consequences of delaying curative resection and the possibility that exposure to systemic therapy increases the risk of surgical complications. The high rates of surgical resection, complete resection, and pathologic response across neoadjuvant trials provide reassurance that delaying surgery for neoadjuvant therapy does not negatively impact clinical outcomes. Furthermore, no new or unexpected surgery-related AEs were reported in either LCMC3 or subsequent phase III chemoimmunotherapy trials. The concern that neoadjuvant immunotherapy increases surgical difficulty and complications has so far not been corroborated in large clinical trials. However, a more detailed report of specific surgical complications may help address these concerns.

Some small early studies of surgical morbidity following neoadjuvant immunotherapy cautioned that dense mediastinal and hilar fibrosis may result after treatment with immunotherapy and lead to more challenging surgical resections (35-37). In a phase I study where 20 patients underwent resection after neoadjuvant nivolumab, 54% of VATS and robotic cases required conversion to thoracotomy, often as a result of hilar inflammation and fibrosis (36). Although concerning, this finding has not been reproduced in larger trials. In NEOSTAR, 40% of operations performed after neoadjuvant nivolumab or nivolumab and ipilimumab were graded by surgeons to be “more complex” than a typical resection, but only one patient required conversion to thoracotomy due to hilar fibrosis (11). The overall perioperative morbidity and mortality in NEOSTAR was thought to be comparable to what has previously been seen with neoadjuvant chemotherapy or upfront resection (11).

Although perihilar fibrosis was not assessed directly in LCMC3, the authors note that the low frequency of intraoperative AEs suggests that fibrosis was not a significant problem (7). Fifteen patients (15%) required conversion to thoracotomy for unclear reasons that may or may not have been related to fibrosis. The rate of conversion to thoracotomy in Checkmate-816 was 11.4% in the nivolumab plus chemotherapy arm and 15.6% in the chemotherapy treated arm, though the exact circumstances are not reported (12). Overall, the current data regarding surgical morbidity and mortality from LCMC3 and phase III chemoimmunotherapy trials are reassuring and do not point towards perihilar fibrosis or other treatment-related surgical complications to be a major concern.

The unique toxicity profile of immune checkpoint inhibitors is important to bear in mind, as surgeons must be aware of potential complications in the perioperative setting. In LCMC3, the overall rate of irAEs was low, and irAEs did not significantly impact surgery (7). Only one patient experienced low-grade pneumonitis prior to surgery, and pulmonary function tests (PFTs), which were performed for all patients before and after neoadjuvant therapy, showed no changes in lung function after immunotherapy (7). In the post-operative setting, 5% of patients (n=8) had pneumonitis (including 3 patients with a grade ≥3 event and one patient who died 2.5 months post-operatively), 3% (n=5) had grade ≥3 colitis, and 4% (n=7) had hypothyroidism.

Long-term toxicities in LCMC3 are not reported, but it is well-known that some irAEs, including many endocrinopathies, can be permanent (38). Patient-reported outcomes (PROs) were not included in LCMC3, though PROs reported from Checkmate-816 and KEYNOTE-671 suggested that adding immunotherapy to chemotherapy does not adversely affect quality of life (39,40). Nevertheless, physicians and patients must acknowledge both the immediate and long-term risk of immunotherapy-related toxicities.

Conclusion

The pathologic and surgical outcomes observed in LCMC3 confirm the benefits of neoadjuvant immunotherapy and mitigate concerns over surgical delay or increased surgical complications. While LCMC3 provides rationale for neoadjuvant immunotherapy and set the stage for subsequent chemoimmunotherapy trials, in this rapidly changing field, studies have demonstrated that neoadjuvant chemoimmunotherapy is the superior approach. Chemoimmunotherapy regimens have achieved the highest pathologic response rates and should be considered over both immunotherapy alone and chemotherapy alone for most patients with locally advanced resectable NSCLC, particularly for high-risk patients (such as those with high tumor burden or with PD-L1 negative tumors) (5).

That being said, LCMC3 remains relevant to clinical practice and to ongoing discussion surrounding patient selection. Twenty percent of patients achieved MPR and 6% of patients pCR with just 2 cycles of neoadjuvant atezolizumab, suggesting that immunotherapy alone likely remains a viable alternative for a select few patients. These patients may derive adequate benefit from immunotherapy alone without being subjected to the added toxicities of chemotherapy. Ongoing efforts should focus on recognizing when de-escalation of care in the neoadjuvant setting is appropriate. This need is even more compelling when considering that chemotherapy-related AEs can preclude a subset of patients from undergoing curative resection. Informative biomarkers are needed to identify those who are vulnerable to chemoimmunotherapy-related AEs and who might still achieve pathologic response with immunotherapy alone.

Finally, although no significant perioperative or intraoperative safety concerns have been reported in LCMC3 or subsequent phase III chemoimmunotherapy trials, a more granular review of intraoperative findings and surgical complications after immunotherapy in these trials is needed. Standardized assessments of perihilar fibrosis and surgical difficulty, for instance, would improve our understanding of the impact of neoadjuvant therapy on curative resection and be informative for patients and multidisciplinary cares teams in the decision-making process.

Future directions

As perioperative management of resectable NSCLC continues to evolve at a rapid pace, many questions remain unanswered but are subject to ongoing investigation. As noted above, informative biomarkers are needed to improve patient selection and decide, for instance, when neoadjuvant immunotherapy alone may be used in place of chemoimmunotherapy. One small previous phase II study, which included 52 patients, found that MPR was higher with chemoimmunotherapy compared to immunotherapy alone among patients with ≥50% PD-L1 expression (41). SKYSCRAPER-05, an ongoing study of neoadjuvant tiragolumab in combination with atezolizumab, with or without chemotherapy in patients with resectable stage II-IIIB disease, includes both a PD-L1 high (≥50%) and all-comer PD-L1 cohort (42). Results of this trial, among other ongoing trials (such as NCT04040361), may provide additional insight on the role of PD-L1 as a biomarker in the neoadjuvant setting.

Whether a neoadjuvant or perioperative approach is superior remains the subject of ongoing debate (43). Although a recent meta-analysis suggests against clinical benefit of adding adjuvant immunotherapy to neoadjuvant chemoimmunotherapy, randomized data are needed (43). It is not clear whether adding adjuvant therapy should depend on pathologic response to neoadjuvant therapy. Does pCR permit the omission of adjuvant therapy, or should the same treatment be continued after surgery given that the disease appears responsive? Should patients without a pathologic response be recommended to undergo additional treatment or further intensified therapy in the adjuvant setting? Circulating tumor DNA to assess minimal residual disease (MRD) may be the key to unlocking the answers. There are several ongoing trials assessing its role in guiding treatment for early-stage NSCLC after definitive therapy (NCT04585477; NCT04585490; NCT04966663) (44,45).

The potential for added benefit to chemoimmunotherapy with additional agents is also under scrutiny. Ongoing trials such as NeoCOAST-2 (NCT05061550), which is investigating the addition of novel agents to a chemoimmunotherapy backbone, and SKYSCRAPER-05 as mentioned above, will continue to push the field forward (46). Targeted therapies are also being increasingly tested in the neoadjuvant setting, as evidenced by studies like NeoADAURA (NCT04351555) and NAUTIKA1 (NCT04302025).

From a global perspective, as neoadjuvant treatment paradigms continue to be revised, regional differences in clinical practice and access to care may become increasingly apparent. A recent report, for instance, discusses regulatory differences between the FDA and European Medicines Agency (EMA) and highlights disparities in patient access and patient care across European countries in the context of novel treatments for resectable early-stage NSCLC (47,48). In addition to differences in regulatory practices, differences in insurance reimbursement structure, other cost considerations, patient population, and clinician preferences may lead to geographic variation in treatment practice. The National Institute for Health and Care Excellence, for instance, recently recommended neoadjuvant nivolumab plus chemotherapy as a cost-effective treatment approach for patients in the United Kingdom (49), Furthermore, since surgical resections are complicated procedures that require trained thoracic surgeons, differences in access to experienced surgical teams also have an impact on outcomes of perioperative therapies. This should all be taken in to consideration when evaluating the global impact of novel therapies in this heterogeneous patient population (48).

Finally, as new treatment approaches emerge for resectable NSCLC, additional information will be needed to guide treatment selection. Real-world studies on treatment effectiveness and incorporation of patient-reported outcomes to ongoing and future clinical trials may provide useful guidance for both patients and practitioners when facing treatment decisions.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-13/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-13/coif). B.P.S. participated in educational talks for Merck. J.R.S. reports consulting fees from Medtronic and served as an advisory board of Genentech. C.A.S. reports personal fees from Arcus Biosciences, AstraZeneca, Daiichi-Sankyo, Genentech, Janssen, Takeda. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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