Surgical considerations in non-small cell lung cancer patients following neoadjuvant immunotherapy or targeted therapy: a narrative review

Introduction

Background

Treatment of non-small cell lung cancer (NSCLC) is rapidly evolving. Historically, early-stage and locoregionally-advanced NSCLC was treated with complete surgical resection. However, high rates of recurrence prompted the investigation of adjuvant therapies (1,2). Adjuvant chemotherapy was shown in multiple large randomized controlled trials, including the International Adjuvant Lung Cancer Trial, the National Cancer Institute of Canada and Intergroup Study, and the Adjuvant Navelbine International Trialist Association (ANITA) Trial, to provide a significant survival advantage compared to surgery alone, consequently shifting the standard of care for NSCLC to a multi-modal approach (3-5) when appropriate.

A greater understanding of the molecular and translational underpinnings of NSCLC has ushered in the era of immunotherapy and targeted agents. Immune checkpoint inhibitors (ICIs) have rapidly been incorporated into treatment paradigms for NSCLC after being found to provide survival benefits in both the metastatic and locoregionally-advanced settings (6-11). In the IMpower010 trial, atezolizumab after adjuvant chemotherapy was shown to improve disease-free survival (18.1 vs. 10.1 months) and decrease the risk of distant metastasis (9% vs. 26%) for patients with resected stage II–IIIA NSCLC and high PD-L1 expression (12). Additionally, adjuvant pembrolizumab was shown to improve disease-free survival in resected stage IB–IIIA NSCLC patients, regardless of PD-L1 expression, in KEYNOTE-091 with subsequent FDA approval (13).

As a logical extension of these treatments, interest in neoadjuvant therapy has culminated in several published trials. Neoadjuvant therapy has several potential advantages over adjuvant therapy including exposure of the in-situ tumor and its antigens to host immune cells with a more robust immune response compared to those treated in the adjuvant setting (14). Such priming of the immune system may have long-term recurrence and survival benefits, though randomized data comparing these approaches are lacking. Additional benefits of neoadjuvant therapy including the potential for a more parenchymal sparing resection in select cases due to reductions in tumor size. Moreover, providing systemic therapy upfront followed by re-staging allows for observation of how the tumor responds to therapy and thus, tests the biology of the disease prior to committing to surgery. Finally, due to the potential for complications postoperatively, there may be increased tolerance of pre-operative rather than post-operative systemic therapy (15-17).

The safety and feasibility of neoadjuvant immunotherapy for early-stage NSCLC has been shown in multiple phase I trials. Forde and colleagues administered two pre-operative doses of nivolumab to 22 patients with stage I–IIIA NSCLC (18). They found no treatment-related surgical delays and acceptable treatment-related adverse events. Additionally, the major pathologic response (MPR) rate for these patients was 45% with a pathologic complete response (pCR) rate of 15% (18). The safety and efficacy of pembrolizumab has also been demonstrated in the neoadjuvant setting in both the MK3475-223 and NEOMUN studies (19,20). In MK3475-223, 26 patients with stage I–II NSCLC received two cycles of neoadjuvant pembrolizumab with no dose limiting toxicities observed and an MPR and pCR rate of 27% and 12%, respectively (19). Similar rates of pathologic response (MPR 27% and pCR 13%) were seen in the phase II NEOMUN trial, which enrolled 15 patients with stage II–IIIA NSCLC (20). The pathologic response rates in these trials generated a great deal of excitement about the potential for significantly improved long-term outcomes after neoadjuvant immunotherapy and surgical resection. Larger landmark phase II and III trials will be further discussed in the body of this review.

Rationale and knowledge gap

Many excellent reviews have detailed the roles of immunotherapy and neoadjuvant therapy for early-stage NSCLC (21-24). However, a review of surgical outcomes in patients who received neoadjuvant chemoimmunotherapy or targeted therapy has not been performed. Due to the robust immune response and resulting fibrosis seen at the time of resection in patients treated with neoadjuvant immunotherapy or targeted therapy, concerns exist regarding the challenges associated with operating on this population.

Objective

In this review, we will briefly discuss several landmark neoadjuvant chemoimmunotherapy and targeted therapy trials as well as surgical considerations and outcomes in this population. We present this article in accordance with the Narrative Review reporting checklist (available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-38/rc).

Methods

The MEDLINE (PubMed) database was queried to identify original research and review articles describing neoadjuvant therapy for early-stage NSCLC patients and surgical outcomes with no restrictions on publication date. This search strategy was conducted using the following terms: “neoadjuvant therapy” or “neoadjuvant chemoimmunotherapy” or “neoadjuvant targeted therapy” combined with “non-small cell lung cancer” and “surgical outcomes” or “surgical complications”. This search was conducted in September 2024. Abstracts were reviewed to identify references meeting the objectives of this review. Studies were excluded if they were not published in the English language or if the full manuscript text was not available. The search strategy summary is available in Table 1.

Key neoadjuvant chemoimmunotherapy trials

Phase II trials

Multiple phase II trials showed potential benefit of neoadjuvant immunotherapy, laying the groundwork for subsequent practice changing phase III trials. Briefly, the LCMC3 (Lung Cancer Mutation Consortium 3) trial studied patients with untreated, resectable stage IB to IIIB NSCLC who received two doses of neoadjuvant atezolizumab monotherapy and found that 20% had a MPR with no unexpected safety signals (25). The NADIM trial, performed at 18 institutions across Spain, administered perioperative nivolumab in addition to neoadjuvant carboplatin and paclitaxel to patients with resectable stage IIIA NSCLC and found an impressive 77% progression-free survival rate at 24 months (26). The NEOSTAR trial, in two sequential single arm phase II studies, studied patients with stage IB to IIIA NSCLC treated with neoadjuvant nivolumab in addition to chemotherapy or neoadjuvant nivolumab plus ipilimumab in addition to chemotherapy (27). MPR rates were 41.2% in the nivolumab plus chemotherapy group and 62.5% in the nivolumab, ipilimumab, and chemotherapy group with no new safety signals observed in either arm (27). Finally, the SAKK 16/14 trial gave patients with stage IIIA NSCLC with proven N2 disease neoadjuvant chemotherapy followed by durvalumab prior to surgical resection (28). The authors reported an MPR rate of 62%, with 7% of patients experiencing a pCR, and a one-year event-free survival of 73% (28).

NADIM II was the first randomized phase II trial to investigate neoadjuvant immunotherapy for resectable NSCLC. The authors randomized 87 patients with stage IIIA NSCLC to receive either neoadjuvant nivolumab, carboplatin, and paclitaxel, or neoadjuvant chemotherapy alone (29,30). The primary endpoint of pCR occurred significantly more often in patients who received nivolumab in addition to chemotherapy compared to chemotherapy alone (36.2% vs. 6.8%, P=0.007). Similar rates of adverse events were seen in both groups. Serious adverse events occurred in 18% of the chemoimmunotherapy group and 10% of the chemotherapy group. The most common adverse events in the chemoimmunotherapy group were fatigue, diarrhea, and febrile neutropenia, while peripheral sensory and motor neuropathies were most common in the chemotherapy group (29,30).

Checkmate 816

In the landmark phase III Checkmate 816 trial, Forde and colleagues randomized 358 patients with stage IB to IIIA disease [according to American Joint Committee on Cancer (AJCC) 7^th edition staging] to receive three cycles of either neoadjuvant nivolumab in combination with chemotherapy or chemotherapy alone followed by surgical resection (31). The majority of patients in both groups completed the prescribed neoadjuvant treatment (94% chemoimmunotherapy and 85% chemotherapy alone) and 83% of patients in the chemoimmunotherapy and 75% in the chemotherapy alone group underwent definitive surgical resection. Surgery was not attempted due to disease progression in 6.7% of patients in the chemoimmunotherapy group and 9.5% of patients in the chemotherapy alone group. Notably, adverse events associated with induction treatment which rendered the patient not a surgical candidate was similar between both cohorts (1.1% of the chemoimmunotherapy group and 0.6% of the chemotherapy alone group).

The primary outcome of median event-free survival, defined as disease progression, disease recurrence, or death, was significantly higher in the chemoimmunotherapy group (31.6 vs. 20.8 months in the chemotherapy alone group). Notably, event-free survival was most pronounced in patients with more advanced (IIIA) disease, those with PD-1 expression greater than 1%, and those with non-squamous cell histologies. A pCR was reported in 24% of patients in the chemoimmunotherapy group, compared to 2.2% of the chemotherapy alone group. Importantly, safety outcomes were similar between groups: grade 3 or 4 treatment-related adverse events (most commonly neutropenia) occurred in 33.5% of patients in the chemoimmunotherapy group and 36.9% of the chemotherapy alone group (31).

Checkmate 816 was the first phase III trial to demonstrate a benefit in event-free survival and higher pCR rate for patients with resectable NSCLC who received neoadjuvant chemoimmunotherapy compared to chemotherapy alone. The publication of these results marked a turning point in the treatment of early-stage NSCLC, while also demonstrating an acceptable safety profile, with no increases in perioperative complications or mortality in the chemoimmunotherapy group.

AEGEAN

The AEGEAN trial was a double-blind phase III trial that randomized 802 patients with stage II or III NSCLC (according to AJCC 8^th edition staging) to receive either perioperative durvalumab or placebo in addition to neoadjuvant platinum-based chemotherapy (32). A similar proportion of patients from both groups completed neoadjuvant therapy (86.9% of the durvalumab group compared to 88.5% of the placebo group) and underwent definitive surgical resection (77.6% of the durvalumab group and 76.7% of the placebo group). At one year, patients in the durvalumab group had improved event-free survival, again defined as disease progression, disease recurrence, or death, compared to the placebo group (73.4% vs. 64.5%). Patients in the durvalumab group were also found to have higher rates of pCR compared to the placebo group (17.2% vs. 4.3%). The frequency of grade 3 or 4 adverse events was similar between the two groups (32.2% in the durvalumab group and 36.2% in the placebo group in the neoadjuvant period) (32).

The AEGEAN trial was the first randomized controlled trial to report results of perioperative immunotherapy in combination with neoadjuvant chemotherapy, building on the results of Checkmate 816 and Impower010, which demonstrated benefit to immunotherapy in the neoadjuvant and adjuvant settings, respectively.

KEYNOTE-671

In a similar study design, Wakelee and colleagues randomized 797 patients with stage II to IIIB (N2 nodal stage) NSCLC in a double-blinded trial to receive neoadjuvant chemotherapy with or without perioperative pembrolizumab (33). Eighty-two percent of patients in the pembrolizumab group and 73% in the placebo group underwent definitive surgical resection. Event-free survival was superior in the pembrolizumab group: 62.4% of people who receive immunotherapy were event-free at 24 months compared to 40.6% in the placebo group. The pCR rate was 18.1% in the pembrolizumab group and 4.0% in the placebo group. Grade 3 and higher adverse events were similar between the groups, seen in 17.7% of patients in the pembrolizumab group and 14.3% of patients in the placebo group. Treatment-related adverse events leading to patient death occurred in 1% of patients in the pembrolizumab group and 0.8% of patients in the placebo group, and treatment-related adverse events necessitating cessation of treatment occurred in 12.6% of patients in the pembrolizumab group and in 5.3% of patients in the placebo group (33).

KEYNOTE-671 is the first randomized controlled trial to demonstrate an overall survival benefit in addition to event-free survival benefit to perioperative immunotherapy in combination with neoadjuvant chemotherapy in early-stage NSCLC.

Neotorch

In the Neotorch trial, Lu and colleagues randomized 501 patients with stage II to IIIB NSCLC to receive perioperative toripalimab, a monoclonal antibody for PD-1, in combination with platinum-based chemotherapy compared to chemotherapy alone (34). Patients with stage II NSCLC were ultimately excluded from interim analysis. Overall, 82.2% of patients in the toripalimab group and 73.3% of patients in the placebo group underwent surgical resection. The one-year event-free survival rate was 84.4% for patients in the toripalimab group compared to 57.0% in the placebo group. Rates of pCR were also greater in the toripalimab group (24.8% vs. 1%). Similar rates of grade 3 and higher adverse events were seen between groups; 63.4% vs. 54.0% in the toripalimab and placebo groups, respectively. The toripalimab and placebo groups were also similar in rates of treatment-related adverse events necessitating discontinuation of treatment (9.4% vs. 7.4%) and fatal adverse events (3.0% vs. 2.0%) (34).

Neotorch confirmed the benefit of perioperative immunotherapy in combination with neoadjuvant chemotherapy to event-free survival, MPR, and pCR seen in the AEGEAN trial, but analyzed only patients with stage III disease.

Checkmate 77T

Checkmate 77T randomized 461 patients with resectable stage II–IIIB NSCLC to receive perioperative nivolumab + chemotherapy or chemotherapy alone with the primary outcome of event-free survival (35). Surgical resection was performed in 77.7% of the chemoimmunotherapy group and 76.7% of the chemotherapy alone group. Eighteen-month event-free survival was 70.2% in the chemoimmunotherapy group and 50.0% in the chemotherapy alone group. In the chemoimmunotherapy group, 25.3% of patients achieved pCR compared to 4.7% in the chemotherapy alone group. Grade 3 or 4 adverse events occurred in 32.5% of the chemoimmunotherapy group and 25.2% of patients in the chemotherapy alone group (35).

Checkmate 77T built on the results of Checkmate 816 and confirmed the results of AEGEAN, KEYNOTE-671, and Neotorch showing the benefit of perioperative chemoimmunotherapy over chemotherapy alone for event-free survival and pCR. Though cross-trial comparisons are limited due to heterogeneous populations, pCR rates from Checkmate 77T were very similar to those seen in Checkmate 816 and higher than the range of values seen in AEGEAN, KEYNOTE-671, and Neotorch, introducing questions regarding the optimal immunotherapy regimen. Checkmate 77T led to FDA approval of the use of nivolumab in the perioperative setting for early-stage NSCLC. A summary of the five key phase III trials can be found in Table 2.

While questions remain regarding the optimal number of cycles of preoperative immunotherapy and which patients benefit most from adjuvant treatment, the improvement in outcomes seen by combining immunotherapy to standard of care chemotherapy in the neoadjuvant setting seems clear based on the available evidence and has been practice changing in the care of patients with NSCLC.

Surgical outcomes and considerations

The addition of immunotherapy in the preoperative setting does not appear to increase the likelihood of serious adverse events or safety concerns in phase III trials. However, a robust immune response to tumor antigens may increase the inflammatory response, potentially affecting tissue planes and increasing the difficulty of surgical resection.

That said, surgical outcomes did not differ between groups in the phase III neoadjuvant immunotherapy trials. In Checkmate 816, the R0 resection rates were higher in the chemoimmunotherapy group compared to the chemotherapy alone group (83.2% vs. 77.8%). Additionally, chemoimmunotherapy treated patients had a higher percentage of lobectomies (77.2% vs. 60.7%), while the chemotherapy only group underwent more pneumonectomies (25.2% vs. 16.8%) (31), suggesting a robust response to induction treatment affected the extent of resection required. Duration of surgery was a median of 185 minutes in the chemoimmunotherapy group and 213.5 minutes in the chemotherapy only group. Fifty-nine percent of patients in the chemoimmunotherapy group underwent thoracotomy, compared to 63% in the chemotherapy alone group. The authors also report equivalent median length of stay; 10 days in each group (31).

Similarly, in the AEGEAN trial, 94.7% of patients in the durvalumab group had an R0 resection compared to 91.3% of patients in the placebo group. Patients in the durvalumab group were less likely to undergo thoracotomy compared to those in the placebo group (30.6% vs. 40.9%, respectively) (32). A summary of outcomes in the five key phase III trials can be found in Table 3.

Because neoadjuvant chemoimmunotherapy can result in dense adhesions and fibrosis, especially in patients with a significant treatment response, multiple groups have investigated surgical outcomes on a more granular level. Zhang and colleagues retrospectively evaluated 131 patients with stage IB to IIIB NSCLC treated with neoadjuvant chemoimmunotherapy (36). Overall, 40.5% of patients underwent resection via video-assisted thoracoscopic surgery (VATS) and the remainder (59.5%) via open thoracotomy or conversion to thoracotomy. Of those patients with a planned VATS resection, the conversion rate was 44.2%. Reasons for conversion included primary tumor invasion (45.2%), dense adhesions/fibrosis (26.2%), fibrocalcified lymph nodes (14.3%), intraoperative vascular injury (9.5%), and pleural adhesions (4.8%) (36). Patients who ultimately underwent a minimally-invasive operation had lower staged tumors with 34% of patients in the VATS group having stage IB–IIB disease vs. 16.7% in the thoracotomy group. Conversely, 13.2% of patients in the VATS group had stage IIIB disease compared to 34.6% in the thoracotomy group (P=0.008). After propensity score matching for tumor characteristics including location, size, stage, and radiographic tumor response, the VATS group had fewer post-operative intensive care unit stays (2.3% vs. 20.5%, P=0.007) but there were no significant differences in operative time, blood loss, chest tube duration, or overall hospital stay (36).

Hong and colleagues similarly described dense adhesions necessitating a high rate of open operations after neoadjuvant therapy (37). In this study, 44% of patients underwent planned thoracotomy, and an additional 12% were converted to thoracotomy from an initial minimally-invasive approach due to dense adhesions of hilar lymph nodes to underlying vasculature. When comparing surgical outcomes in patients who had a MPR with those who did not, the authors found no difference in thoracotomy rates, extent of resection, operative time, blood loss, chest tube duration, hospital length of stay, postoperative complications, or R0 resection rates (37).

Based on these data, there appears to be relatively high rates of primary thoracotomy or conversion, which is an important consideration that merits discussion with patients pre-operatively. Herrera and colleagues retrospectively evaluated 7,216 patients from the Pulmonary Open, Robotic and Thoracoscopic Lobectomy study consortium, which included patients who did and did not receive neoadjuvant chemotherapy (38). The authors found conversion rates of 3.6% after robotic lobectomy and 12.9% after VATS lobectomy (P<0.001). On multivariable analysis, the most important predictors of conversion were tumor size [odds ratio (OR) =1.21 for each millimeter increase in size, P<0.001] and induction treatment (chemotherapy and/or radiation, OR =2.64, P<0.001) (38).

Additional studies comparing operative approaches and associated conversion rates have yielded mixed results. Zeng and colleagues examined 220 patients who underwent either VATS or robotic resection after neoadjuvant chemoimmunotherapy (39). The authors found a significantly lower rate of conversion to thoracotomy in the robotic group (7.5% vs. 28.2%, P<0.001) as well as higher number of lymph node stations harvested (8.09±5.73 vs. 5.63±1.75, P<0.001). Dense adhesions/fibrosis and intraoperative bleeding were the most common reasons for conversion. The overall complication rates were similar between groups: 31.7% of patients in the robotic group experienced a complication compared to 33.2% of patients in the VATS group (P=0.803). There were no differences in length of stay (39).

Yao and colleagues also compared surgical outcomes in 119 patients who received neoadjuvant chemoimmunotherapy followed by resection via VATS or robotic resection over a two-year period (40). VATS resection was performed in 72.3% of patients and 27.7% underwent robotic resection. The authors found low conversion rates in both groups (4.7% in the VATS group and 0% in the robotic group), similar operative times, and blood loss (40).

Finally, though more investigation will be necessary to determine the optimal regimen, the number of cycles of neoadjuvant chemoimmunotherapy does not appear to be associated with surgical outcomes. Chen and colleagues investigated 176 patients who received two or greater cycles of neoadjuvant chemoimmunotherapy (41). They found no difference in objective response rates in patients who received two, three, four, or five cycles as well as no association between the number of cycles and major or complete pathologic response rates. The authors also reported no differences in operating time, post-operative chest tube drainage, and length of hospital stay among patients receiving different numbers of chemoimmunotherapy cycles (41).

Overall, the data does not suggest that receipt of neoadjuvant chemoimmunotherapy is associated with increased adverse surgical outcomes. Though surgeons should anticipate an increased likelihood of a potentially challenging dissection, with some studies reported higher conversion rates from minimally-invasive surgery to an open thoracotomy, resection after chemoimmunotherapy is increasingly being performed and can be done safely with careful operative planning and adherence to safe surgical principles.

Timing of surgery after neoadjuvant chemoimmunotherapy

In review of the major phase III trials evaluating neoadjuvant chemoimmunotherapy, there is some heterogeneity present regarding timing of resection in relation to completing induction treatment. In the Checkmate 816 trial, patients underwent surgery 6 weeks after completion of neoadjuvant therapy. Similarly, in the AEGEAN trial patients underwent resection no later than 40 days after administration of the last dose of neoadjuvant treatment. In the KEYNOTE-671 trial, surgery was required no later than 20 weeks after the receipt of the first dose of neoadjuvant therapy (4 cycles given once every 3 weeks, so if the study schedule was maintained, no more than 8 weeks after the final cycle) (31-33). Ideal timing of surgical resection after neoadjuvant therapy, and as a corollary, potential detrimental impacts of delaying surgery related to toxicity-associated adverse events, will need to be investigated moving forward to optimize patient outcomes.

Toxicities associated with immunotherapy

Similar to chemotherapy, immunotherapy is associated with specific toxicities that surgeons should be aware of. Cathcart-Rake and colleagues summarized these nicely in a population-level analysis of a large administration claims database (42). Data from 3,164 patients with NSCLC who received an ICI were evaluated. The authors found that the cumulative risk of experiencing an adverse event related to immunotherapy increased over time; 31% experienced an adverse event at 3 months and 52.5% experienced an adverse event at 12 months. The most common immunotherapy-related adverse event across all time points (1, 3, 6, and 9 months), and particularly relevant to surgeons, was pneumonitis. The risk of pneumonitis was progressive with 2.5% of patients developing pneumonitis after 1 month of therapy, 5.9% after 3 months, and 10.5% after 6 months. Anemia was the next most common adverse event with 1.8% of patients experiencing this complication after 1 month of immunotherapy (3 months: 4.4%, 6 months: 7.8%), closely followed by arrhythmia (1 month: 1.5%, 3 months: 3.2%, 6 months: 6%), and acute kidney injury (1 month: 1.1%, 3 months: 3.1%, 6 months: 5.2%). Other less common but important toxicities to be aware of include hypothyroidism (0.8% at 1 month but up to 6.8% after 6 months of therapy), hepatitis (up to 3.1% after 6 months), colitis (up to 2.5% at 6 months), pericarditis (up to 1.6% after 6 months), and type 1 diabetes (up to 1.1% after 6 months) (42). Awareness of the mounting risks of toxicity with immunotherapy is an important consideration for surgeons during their preoperative evaluation and when discussing the relative benefits of increasing treatment cycles with medical oncologists.

Targeted therapy

Transition of targeted therapies into the neoadjuvant space is still under investigation. Several phase II trials have been performed with EGFR tyrosine kinase inhibitors (TKIs) in the neoadjuvant setting. In the ESTERN study, Xiong and colleagues administered neoadjuvant erlotinib to 19 patients with stage IIIA (N2) EGFR-mutated NSCLC (43). Fourteen patients (74%) underwent surgical resection. Twenty-one percent of patients were found to have a pathologic downstaging after neoadjuvant treatment and the objective response rate was 42%. Median progression-free and overall survival were 11.2 and 51.6 months, respectively. Thirty-seven percent of patients experienced an adverse event, the most common being rash (43). In the EMERGING-CTONG 1103 study, Zhong and colleagues randomized 72 patients with stage IIIA EGFR-mutated NSCLC to receive peri-operative erlotinib or peri-operative chemotherapy (44). The objective response rate after neoadjuvant therapy was not significant but trended toward improvement in the erlotinib arm (54.1% vs. 34.3%, P=0.092). The MPR rate was 9.7% in the erlotinib group and 0% in the chemotherapy group. Median progression-free survival was significantly longer in patients who had received erlotinib (21.5 vs. 11.4 months, P<0.001) (44).

Several trials evaluating targeted therapy in the neoadjuvant setting are ongoing with the results eagerly anticipated (Table 4). The NeoADAURA (NCT04351555) trial is a phase III study evaluating the efficacy and safety of neoadjuvant osimertinib alone or in combination with chemotherapy compared to chemotherapy alone in patients with stage II to IIIB (N2) EGFR-mutated NSCLC (45). The primary endpoint will be MPR at time of resection. Secondary endpoints will include event-free survival, disease-free survival, and overall survival. Patients will be recruited from 184 sites in 23 countries (45). For patients with ALK-mutated tumors, the ALNEO (NCT05015010) trial is a phase II single arm study which will include patients with locally-advanced stage III ALK-mutated NSCLC (anyTN2 and T4N0-1) and administer alectinib for two cycles in the neoadjuvant setting and 24 cycles in the adjuvant setting (46). The primary endpoint will be MPR. Secondary endpoints will include pCR, objective response, event-free survival, disease-free survival, and overall survival (46).

As new driver mutations are identified, the use of neoadjuvant targeted therapies is expanding rapidly. Currently, neoadjuvant sotorasib is being investigated in a single arm, open-label study at MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center for patients with KRAS p.G12C mutations (47). Additionally, NAUTIKA1 (NCT04302025) is a multicenter, non-randomized, open-label trial with cohorts consisting of patients with ALK, ROS1, NTRK, BRAF, RET, PD-L1, and KRAS mutations that is currently recruiting. All groups will receive specific, mutation-based targeted therapy in the neoadjuvant setting with the primary endpoint of MPR (48). We anticipate the investigation of targeted therapies in the neoadjuvant space to grow exponentially as new driver mutations are identified.

Because receipt of neoadjuvant targeted therapy is in its infancy and these therapies are only approved in the context of ongoing clinical trials, no published data exists regarding surgical outcomes. These data will be important as the standard of care for NSCLC continues to evolve with the incorporation of novel agents for induction treatment in patients with locoregional disease.

When considering toxicities of targeted therapy, the FLAURA study provided robust safety data for the available EGFR TKI agents (49). The most common adverse event noted in the study population was a rash in 54% of patients who received osimertinib and 74% of patients who received erlotinib or gefitinib. Diarrhea was the next most common adverse event, seen in 49% of the osimertinib group and 51% in the older generation TKI group, followed by dry skin in 33% of both groups (49). Potential treatment-related safety signals noted in the ALUR trial for alectinib included constipation (18.6%), dyspnea (8.6%), fatigue (5.7%), elevated bilirubin (5.7%), neutropenia (2.9%), and diarrhea (2.9%) (50).

Strengths and limitations

This review is, to our knowledge, the first to include both neoadjuvant chemoimmunotherapy and targeted therapies with a focus on toxicities and surgical outcomes in early-stage NSCLC. This review is limited by the heterogeneity of data available regarding surgical outcomes including variable time to surgery after neoadjuvant therapy and lack granular details regarding postoperative complications. Additionally, published data regarding surgical outcomes after targeted therapies is quite limited with several trials ongoing in this space.

Conclusions

The evolution of treatment options for early-stage and locoregionally advanced NSCLC is occurring rapidly and generating a great deal of excitement in the field. With the advent of new treatment paradigms and improved long-term outcomes with neoadjuvant therapy, there is the potential for increased technical difficulty at the time of surgical resection. Thankfully, despite often reported increased fibrosis after the receipt of neoadjuvant immunotherapy, the available evidence suggests surgical outcomes are similar to those receiving chemotherapy alone. Postoperative complications rates after induction immunotherapy appear similar to those receiving chemotherapy alone with the potential benefit of downstaging and parenchymal preservation in those treated with ICIs. Additional studies are needed to determine the optimal immunotherapy regimen and timing of surgery after receipt of neoadjuvant therapy. Much is unknown regarding the role of targeted therapy in the neoadjuvant setting, though early signals suggest excellent tolerance of these agents with phase III investigations ongoing.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-38/rc

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-38/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-38/coif). R.R. served as an unpaid editorial board member of Current Challenges in Thoracic Surgery from January 2023 to December 2026. 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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