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Abstract

The advent of immune checkpoint inhibition has pushed the treatment paradigm for resectable non-small-cell lung cancer (NSCLC) toward neoadjuvant therapy. A growing number of promising trials have examined the utility of neoadjuvant immunotherapy, both alone and in combination with other modalities such as radiation therapy (RT) and chemotherapy. The phase II LCMC3 and NEOSTAR trials demonstrated a role for neoadjuvant immunotherapy in inducing meaningful pathologic responses, and another phase II trial established the feasibility of combining neoadjuvant durvalumab with RT. Significant interest in neoadjuvant chemoimmunotherapy resulted in the conduct of multiple successful phase II trials including the Columbia trial, NADIM, SAKK 16/14, and NADIM II. Across these trials, neoadjuvant chemoimmunotherapy led to high rates of pathologic response and improved surgical outcomes without compromising surgical timing or feasibility. CheckMate-816, which was a randomized phase III trial studying neoadjuvant nivolumab in addition to chemotherapy, definitively established a benefit for neoadjuvant chemoimmunotherapy compared to chemotherapy alone for resectable NSCLC. Despite the growing literature and success of these trials, several outstanding questions remain, including the relationship between pathologic response and patient survival, the role of biomarkers such as programmed death ligand 1 and circulating tumor DNA in determining patient selection and treatment course, and the utility of additional adjuvant therapies. Longer follow-up of CheckMate-816 and other ongoing phase III trials may help address these questions. Ultimately, the complexity of managing resectable NSCLC highlights the importance of a multidisciplinary approach to patient care.

Keywords

chemotherapy immunotherapy lung cancer neoadjuvant therapy non-small-cell lung cancer

Introduction

Although adjuvant therapy has traditionally been a key component of resectable non-small-cell lung cancer (NSCLC),¹ the advent and efficacy of immunotherapy has provided an inevitable push to move treatment into the neoadjuvant setting.

Resectable NSCLC is generally defined as stage I–IIIA disease, utilizing American Joint Committee on Cancer (AJCC) 8th edition guidelines, but ultimately determined by the surgeon.² Stage IA patients are not typically recommended to receive adjuvant (or neoadjuvant) systemic treatment as the risks of therapy have been observed to outweigh any survival benefit in meta-analyses.¹ Adjuvant therapy was first adopted by some practices in the 1980s in the form of postoperative RT (PORT) after some studies showed a potential benefit in local recurrence rates.³ This was quickly followed by multiple negative studies showing both a lack of overall survival (OS) benefit and potential harm,^4–6 which led to adjuvant PORT falling out of clinical favor. In the interim, multiple large clinical trials had opened investigating adjuvant chemotherapy with systemic cisplatin-based regimens in resectable NSCLC.^7–11 While the lack of standardization between patient selection and regimens initially led to both positive and negative results, the OS benefit of adjuvant cisplatin was later confirmed in the 1995 LACE meta-analysis, paving the way for widespread clinical use.¹

Following the adoption of adjuvant cisplatin-based chemotherapy for NSCLC, several neoadjuvant studies closed due to accrual difficulties.¹² This ultimately led to a paucity of treatment recommendations in the neoadjuvant space, despite arguments that patients may have better performance status preoperatively and demonstrate increased compliance to treatment.^13,14 However, the NSCLC Meta-analysis Collaborative Group published a meta-analysis in the Lancet in 2014 demonstrating similar improvement in OS with neoadjuvant chemotherapy to adjuvant therapy,¹⁵ and up until recently, physicians were using the two interchangeably. In the modern era, immunotherapy with immune checkpoint inhibitors (ICIs) has shifted the treatment paradigm of NSCLC in both the metastatic and resectable setting.^16,17 The theoretical benefits of administering immunotherapy in the neoadjuvant setting include increased efficacy of antitumor immune activity in the setting of an intact (rather than resected) primary tumor that is capable of shedding neoantigens from dying tumor cells, thereby increasing T-cell priming and redirection and facilitating a stronger immune response.^18,19 These agents include humanized IgG antibodies against programmed death 1/programmed death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).²⁰ Antagonistic agents against the PD-1/PD-L1 crosstalk such as pembrolizumab, nivolumab, atezolizumab, cemiplimab, and durvalumab have significantly altered practice habits alongside ipilimumab (anti-CTLA-4) in NSCLC. In addition to utilizing immunotherapy alone, there is a persuasive rationale for combining it with the immunomodulatory effects of chemotherapy.²¹ Chemotherapy induces immunogenic cell death and a subsequent release of tumor antigens and danger-associated molecular patterns into the tumor microenvironment, making it an optimal candidate for synergy alongside immunotherapy.²² The positive follow-up phase III trials comparing pembrolizumab or other biosimilars alone, dual ICI with anti-PD-1/anti-CTLA-4 therapies, or in combination with chemotherapy in NSCLC, ultimately led to approval by the Food and Drug Administration for use in the metastatic setting and consideration by clinical investigators for even earlier use.^16,23–28 Within this article, we review the role of ICI monotherapy, ICI in combination with RT, and ICI with chemotherapy in resectable NSCLC and discuss appropriate endpoints in neoadjuvant therapy and potential future directions in this disease space.

Neoadjuvant immunotherapy

Following the success of ICI in the metastatic setting, investigations into the utility of immunotherapy prior to resection gained traction. The preclinical rationale for neoadjuvant immunotherapy was based on the idea of efficient antigen presentation by tumor cells to immune cells. Therefore, delivering immunotherapy prior to resection might elicit a stronger antitumor T-cell response given the increased tumor burden and ensuing increased antigen presentation.²⁹ This hypothesis was supported by several preclinical studies that showed improved OS among mice treated with neoadjuvant checkpoint inhibition compared with mice who received adjuvant checkpoint inhibition.^19,30 In one study, neoadjuvant anti-PD-1 therapy was reported to increase tumor-specific CD8+ T cells in peripheral blood and organs of treated mice, demonstrating the immunologic benefit of neoadjuvant treatment.¹⁹ In humans, a pilot study of two cycles of preoperative nivolumab in a cohort of 21 patients with stage I, II, and IIIA NSCLC led to a major pathological response (MPR), defined as ⩽10% viable malignant cells noted in the resected primary tumor sample after neoadjuvant therapy, in 45% of patients without delay in surgery and with few side effects.³¹ Interestingly, the authors also found that treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in the blood. This important trial led to larger investigations of neoadjuvant ICI.

LCMC3 is a phase II clinical trial evaluating two doses of neoadjuvant atezolizumab in previously untreated stage IB–IIIB (AJCC 8th edition) resectable NSCLC without detectable EGFR or ALK mutations.³² Activated in April 2017, the primary endpoint in this study was MPR. In all, 181 patients were enrolled into the study with 159 patients undergoing resection 30–50 days after the first cycle. In total, 143 patients were evaluable in the primary endpoint analysis with an MPR of 20% (95% CI: 14–28%) with a 6% rate of pathologic complete response (pCR), defined as 0% viable tumor cells in the resected surgical specimen after neoadjuvant therapy. Median disease-free survival (DFS) and OS have not been reached. Of note, of 22 patients who did not undergo resection after at least one cycle of atezolizumab, 10 patients (6%) experienced radiographic progression of disease (PD) and 3 patients experienced clinical PD. The most common observed adverse events (AEs) were fatigue (39%) and procedural pain (29%). Immune-related AEs (IRAEs) were noted in 41% of patients. 9% and 8% of patients experienced elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT), respectively. Maculopapular rash (8%, n = 15) and infusion reaction (8%, n = 15) were the next most common IRAEs. In all, 20 patients (11%) had grade 3 or above AEs, including pneumonitis (2%, n = 4) and pneumonia (2%, n = 3). Three patients died during the neoadjuvant phase with one death attributed to treatment (pneumonitis).

Almost in parallel, the phase II clinical trial NEOSTAR was activated in June 2017, which explored neoadjuvant nivolumab versus nivolumab plus ipilimumab in resectable stage IA–IIIA (AJCC 7th edition) NSCLC.³³ The combination of anti-PD-1 and anti-CTLA-4 was proposed as a study arm after CheckMate-067 showed tolerability and efficacy in metastatic melanoma.³⁴ The primary endpoint of the trial was also MPR. The prespecified boundary for effect was ⩾6 MPRs in each treatment arm based on historical neoadjuvant platinum-based chemotherapy response rates of 15%.³⁵ In all, 44 patients were randomized to receive either neoadjuvant nivolumab (Arm A) or nivolumab plus ipilimumab (Arm B) with both study arms running in conjunction to each other. Arm A included 23 patients who were scheduled to receive nivolumab 3 mg/kg on Days 1, 15, and 29 prior to surgery. The 19 patients in Arm B were also treated with ipilimumab 1 mg/kg on Day 1. 93% of patients (n = 41) completed neoadjuvant treatment with one patient in Arm A developing grade 3 hypoxia after the first dose of nivolumab and two patients removed from Arm B due to intolerable IRAEs. In the intention to treat population of 44 patients, an MPR rate of 38% was achieved in the nivolumab + ipilimumab arm while 22% of patients reached MPR in the nivolumab monotherapy arm. Furthermore, among the 37 patients who underwent resection on trial, the MPR rate was 50% after nivolumab + ipilimumab and 24% after nivolumab monotherapy. pCR rates for these patients were also notably higher in the combination arm compared to nivolumab alone (38% versus 10%). Of note, a subset of patients experienced growth of nodal disease after neoadjuvant ICI; however, pathologic review of these lymph nodes showed only immune cell infiltration without the presence of tumor. This phenomenon, which had not been previously observed in patients treated with preoperative chemotherapy, was called nodal immune flare (NIF). It highlighted the importance of both tissue examination and radiologic correlation before diagnosing disease progression, treatment failure, and loss of surgical candidacy.

Neoadjuvant immunotherapy with RT

The basis for radiation-induced tumor immunosensitization, including its ability to induce immunogenic cell death and promote proinflammatory remodeling of the tumor microenvironment, had been established in previous work and was a logical therapeutic partner for immunotherapy in the growing neoadjuvant disease space.^36–39 From 2017 to 2020, 60 patients with stage I–IIIA (AJCC 7th edition) NSCLC were enrolled into a phase II clinical trial comparing neoadjuvant durvalumab alone versus neoadjuvant durvalumab plus stereotactic radiotherapy.⁴⁰ All patients received two cycles of durvalumab with half of patients receiving three consecutive daily fractions of 8 Gy (total 24 Gy) to the primary tumor only. This sub-ablative radiation dose was selected based on previous evidence of efficacy in combination with immunotherapy while avoiding potential overlapping organ toxicities.⁴¹ Radiation was initiated on the same day but prior to the first dose of durvalumab. The primary endpoint of this study was MPR in the primary tumor. After neoadjuvant treatment and resection, 16 patients (53.3%) in the durvalumab plus radiotherapy group achieved an MPR in comparison to two patients (6.7%) in the monotherapy group leading to a statistically significant difference in MPR rates (p < 0.0001). Two patients in the monotherapy arm and three patients in the combination arm did not undergo surgery due to disease progression. Although progression-free survival (PFS) and OS were not evaluated, nor were patients risk stratified by PD-L1 or clinical stage, this study has provided evidence for feasibility and consideration for future, large-scale studies involving neoadjuvant radiation plus immunotherapy.

Neoadjuvant immunotherapy with chemotherapy

Cytotoxic chemotherapy, which is thought to stimulate the immune system by inducing immunogenic tumor death cell and increasing antigen cross-presentation by dendritic cells, directly stimulating T-cell and B-cell responses, and inhibiting tumor-induced suppressive mechanisms,^42–44 may further enhance the immunomodulatory effects of PD-1 and PD-L1 inhibition. The combination of chemotherapy with antibodies against PD-1 and PD-L1 has demonstrated a survival benefit over chemotherapy alone for metastatic NSCLC independent of PD-L1 status.²³ As a result, several single-arm phase II trials (Table 1), including the Columbia trial, NADIM, and SAKK 16/14, were conducted to investigate combined chemotherapy and immunotherapy in the neoadjuvant setting.

Table 1.

Summary of primary endpoints, pathological and surgical outcomes in phase II/III neoadjuvant chemoimmunotherapy trials.

Trial	Population and treatment	Size	Primary endpoint	Rates of MPR and pCR	Rate of R0 resection among patients who received surgery
Columbia trial, Shu et al. (NCT02716038)⁴⁵	Carboplatin, nab-paclitaxel, and atezolizumab × 2 cycles for stage IB-IIIA	n = 30 (single arm)	Rate of MPR: 57% (95% CI: 37–75)	MPR: 57% (95% CI: 37–75), pCR: 33% (95% CI: 17–53)	87% (26/29)
NADIM (NCT03081689)⁴⁸	Neoadjuvant paclitaxel, carboplatin, and nivolumab × 3 cycles followed by 1 year of adjuvant nivolumab for stage IIIA	n = 46 (single arm)	24-month PFS: 77.1% (95% CI: 59.9–87.7)	MPR: 83%, pCR: 63%	100%¹ (41/41)
SAKK 16/14 (NCT02572843)⁵¹	Neoadjuvant cisplatin and docetaxel × 2 cycles, neoadjuvant durvalumab × 2 cycles, followed by adjuvant durvalumab for 1 year for stage IIIA(N2)	n = 67 (single arm)	1-year EFS: 73% (two-sided 90% CI: 63–82)	MPR: 62%, pCR: 18%	93% (51/55)
NADIM II (NCT03838159)⁵²	Neoadjuvant carboplatin, paclitaxel, nivolumab × 3 cycles versus neoadjuvant carboplatin and paclitaxel × 3 cycles in stage IIIA	n = 87 (two-arm randomized trial)	pCR rate: 36.2% with nivolumab + chemotherapy versus 6.8% with chemotherapy alone (RR, 5.25, 99% CI: 1.32–20.87, p = 0.0071)	MPR: 52% (nivolumab + chemotherapy) versus 14% (chemotherapy alone), pCR: 36.2% (nivolumab + chemotherapy) versus 6.8% (chemotherapy alone), RR, 5.25, p = 0.0071	Not reported; rate of definitive surgery was 91% (chemo + nivolumab) versus 69% (chemo alone)
CheckMate 816 (NCT02998528)⁵³	Neoadjuvant nivolumab plus platinum-based chemotherapy versus neoadjuvant platinum-based chemotherapy alone in stage IB-IIIA	n = 358 (179 to neoadjuvant nivo + chemotherapy; 176 to neoadjuvant chemotherapy alone)	Median EFS: 31.6 months (nivolumab + chemotherapy) versus 20.8 months (chemotherapy alone); HR: 0.63 (97.38% CI: 0.43–0.91; p = 0.005), pCR: 24% (nivo + chemotherapy) versus 2.2% (chemotherapy alone); OR: 13.94 (99% CI: 3.49–55.785, p < 0.001)	MPR: 36.9% (nivolumab + chemotherapy) versus 8.9% (chemotherapy alone); OR: 5.70, 95% CI: 3.16–10.26, pCR: 24% (nivo + chemotherapy) versus 2.2% (chemotherapy alone); OR: 13.9, p < 0.001	83.2% (chemo + nivo) versus 77.8% (chemo alone)

EFS, event-free survival; HR, hazard ratio; MPR, major pathological response; pCR, pathological complete response; PFS, progression-free survival; OR, odds ratio; RR, relative risk.

In the Columbia trial, Shu et al. conducted a multicenter open-label single-arm phase II trial in New York and Boston that included 30 patients with resectable stage IB–IIIA NSCLC.⁴⁵ Most (77%) patients had stage IIIA disease at the time of presentation. Patients received two cycles of neoadjuvant nab-paclitaxel, carboplatin, and atezolizumab, and those without disease progression after the first two cycles received an additional two cycles of treatment prior to surgery.

The trial met its primary endpoint of MPR, which was achieved in 17 patients (57%, 95% CI: 37–75).⁴⁵ Ten (33%, 95% CI: 17–53) patients had a pCR following neoadjuvant chemoimmunotherapy, representing an improvement over historical data for neoadjuvant chemotherapy alone, in which only 5–8% of patients achieve a pCR.^46,47 In all, 19 patients (63%) met RECIST criteria for partial response with neoadjuvant treatment, while nine (30%) had stable disease and two (7%) had progressive disease. Median DFS was 17.9 months (95% CI: 14.3 to not reached), and median OS was not reached (95% CI: 27.6 months to not reached). In post-hoc analyses, median DFS was numerically higher in patients with MPR compared to those who did not have MPR [34.5 months versus 14.3 months, hazard ratio (HR) 0.7], but this was not statistically significant (p = 0.71).⁴⁵ The most common grade 3–4 AEs were neutropenia (50% of patients), increased AST (7%), increased ALT (7%), and thrombocytopenia (7%). In addition to achieving its primary endpoint of MPR, the Columbia trial demonstrated promising rates of pCR and radiographic response with neoadjuvant chemoimmunotherapy.

NADIM was a multicenter open-label single-arm phase II trial conducted in Spain that included 46 patients with resectable stage IIIA NSCLC.⁴⁸ Patients with stage I–II disease were excluded, and 74% of patients had N2 disease at baseline, reflecting a population with advanced disease. Patients were planned to receive three cycles of neoadjuvant paclitaxel, carboplatin, and nivolumab followed by 1 year of nivolumab after surgical resection.⁴⁸ The trial met its primary endpoint of PFS at 24 months, which was 77.1% (95% CI: 59.9–87.7) in the intention-to-treat population. OS at 24 months was 89.9% (95% CI: 74.5–96.2). Objective response rate (ORR) to neoadjuvant therapy was 76%, including a 4% complete response rate and 72% partial response rate. No patients had disease progression during neoadjuvant therapy. In terms of pathological response, which was a secondary endpoint, 34 (83%, 95% CI: 68–93) patients had a MPR, and 26 (63%; 62–91) met a pCR. Overall, the frequency of treatment-related AEs was similar to what had historically been observed with induction chemotherapy alone or immunotherapy alone.

In an updated report, PFS at 3 years was 69.6% (95% CI: 54.1–80.7).⁴⁹ OS at 3 years remained remarkably high at 81.9% in the intention-to-treat population and 91% in the per-protocol population,⁴⁹ significantly higher than historical survival data seen with neoadjuvant treatment in resectable NSCLC.^15,50 Longer follow-up time did not reveal any unexpected toxicities or death. NADIM therefore supports the long-term safety and efficacy of neoadjuvant chemoimmunotherapy for patients with resectable stage IIIA NSCLC.

SAKK 16/14 was the largest single-arm phase II trial for perioperative anti-PD L1 therapy in addition to neoadjuvant chemotherapy. It was an open-label, multicenter, single-arm phase II trial conducted within the SAKK network in Switzerland that treated 67 patients with stage IIIA NSCLC with proven N2 disease.⁵¹ Patients were treated with a sequential approach that included three cycles of neoadjuvant cisplatin and docetaxel followed by two cycles of neoadjuvant durvalumab followed by surgical resection. After surgery, durvalumab was continued for 1 year. The primary endpoint was 1-year event-free survival (EFS), while secondary endpoints included EFS, OS, ORR to neoadjuvant treatment, pCR, and MPR.

The study met its primary endpoint of 1-year EFS, which was 73% (two-sided 90% CI: 63–82).⁵¹ In all, 34 (62%) patients who underwent surgery achieved an MPR, including 10 (18%) who achieved a pCR.⁵¹ Median EFS and median OS were not reached, but OS at 1 year was 91% (95% CI: 81–96) and OS at 2 years was 83% (95% CI: 71–90). Among the 62 patients who received neoadjuvant chemotherapy and durvalumab, ORR was 58% (95% CI: 45–71), which included 4 (7%) patients with CR and 32 (52%) with PR. Seven (11%) patients progressed during neoadjuvant therapy.⁵¹ In total, 51 (88%) patients experienced an AE of grade ⩾3, most commonly neutropenia (18% of patients), diarrhea (13%), and fatigue (13%). This included two fatal AEs; however, one was due to respiratory failure from disease progression and the other resulted from bronchopulmonary hemorrhage after surgery that was deemed unrelated to study treatment.⁵¹ SAKK 16/14 further supported combined neoadjuvant chemoimmunotherapy as a safe and tolerable approach and met its primary endpoint of increased 1-year EFS for patients with stage IIIA (N2) disease.

In light of promising single-arm phase II trials demonstrating a benefit for neoadjuvant chemoimmunotherapy, NADIM II was conducted and was the first randomized study in this treatment setting.⁵² It was an open-label, multicenter randomized two-arm phase II trial that included 87 patients with resectable stage IIIA NSCLC. Patients with EGFR/ALK alterations were excluded.⁵² Patients were randomized to receive either neoadjuvant carboplatin, paclitaxel, and nivolumab for three cycles or neoadjuvant carboplatin and paclitaxel for three cycles. Patients with R0 resection received adjuvant nivolumab for 6 months. The primary endpoint was the rate of pCR in the intention-to-treat population. Secondary endpoints included MPR, ORR, toxicity, and potential predictive biomarkers.

The rate of pCR was significantly increased in patients who received neoadjuvant nivolumab with chemotherapy compared to those who received chemotherapy alone [36.2% versus 6.8%, relative risk (RR): 5.25, 99% CI: 1.32–20.87, p = 0.0071].⁵² Patients treated with nivolumab and chemotherapy also had higher rates of MPR (52% versus 14%) and ORR (74% versus 48%). There was, however, a higher rate of grade 3–4 TRAEs in patients who received nivolumab with chemotherapy compared to those who received chemotherapy alone (24% versus 10%). Nevertheless, NADIM II provided evidence that in a randomized setting, neoadjuvant chemoimmunotherapy leads to superior pathological responses.

These successful phase II trials supported further study of neoadjuvant chemoimmunotherapy in the phase III setting. CheckMate-816 was an international, open-label, randomized phase III trial in which patients with resectable stage IB to IIIA NSCLC were enrolled and were randomized to receive either neoadjuvant nivolumab plus a platinum-based doublet regimen or neoadjuvant platinum-based chemotherapy alone.⁵³ Patients with known ALK or EGFR mutations were excluded. The two primary endpoints of the trial were EFS and pCR. Secondary endpoints included MPR, time to death or distant metastases, and OS. Among 773 who were enrolled in the study, 505 underwent randomization and 358 were ultimately assigned to receive study treatment.⁵³ Baseline characteristics were well-balanced between the two groups; most (64%) patients had stage IIIA disease, and most (72%) received cisplatin rather than carboplatin. In the nivolumab-plus-chemotherapy group (n = 179), 93.8% fully completed the prespecified neoadjuvant treatment and 83.2% underwent definitive surgery. In the chemotherapy only group (n = 179), 84.7% of patients completed neoadjuvant treatment and 75.4% underwent definitive surgery.

CheckMate-816 met both primary endpoints of EFS and pCR. Median EFS was significantly longer with nivolumab plus chemotherapy (31.6 months, 95% CI: 30.2 to not reached) than with chemotherapy alone (20.8 months, 95% CI: 14.0–26.7), with an HR of 0.63 (97.38% CI: 0.43–0.91; p = 0.005).⁵³ The EFS benefit with chemoimmunotherapy was consistent across most key subgroups including age, smoking status, and tumor mutational burden (TMB). However, subgroup analysis suggested that the degree of benefit varied by stage at diagnosis, tumor histology, and PD-L1 expression level; greater benefit was seen in patients with stage IIIA disease over stage IB or II at baseline, in patients with nonsquamous histology, in patients with PD-L1 ⩾ 1% as compared to <1%, and in patients with PD-L1 ⩾ 50% as compared to 1–49%. The rate of pCR was significantly higher with nivolumab plus chemotherapy (24%, 95% CI: 18–31) than with chemotherapy alone (2.2%, 95% CI: 0.6–5.6), with an odds ratio (OR) of 13.94 (99% CI: 3.49–55.785, p < 0.001). This was consistent across all key subgroups, including age, smoking status, disease stage at baseline, tumor histology, PD-L1 expression level, and TMB.

In terms of secondary endpoints, rate of MPR was higher with nivolumab plus chemotherapy compared to chemotherapy alone (36.9% versus 8.9%, OR: 5.70, 95% CI: 3.16–10.26).⁵³ Time to death or distant metastases also favored nivolumab plus chemotherapy (HR: 0.53, 95% CI: 0.36–0.77). Median OS was not reached in either arm; while OS favored the nivolumab plus chemotherapy group (HR: 0.57; 99.67% CI: 0.30–1.07, p = 0.008), the p value did not reach the threshold for statistical significance (0.0033). There were no significant differences in the rate of AEs.

CheckMate-816 was a confirmatory randomized trial that definitively established a benefit for neoadjuvant anti-PD-1 in addition to chemotherapy over chemotherapy alone for resectable NSCLC.⁵³ Patients with stage IIIA disease comprised the majority of the study population and appeared to derive greater EFS benefit with chemoimmunotherapy compared to patients with stage IB-II disease, highlighting the importance of this treatment approach for patients with more locally advanced disease and worse prognosis. OS data are not yet mature; while analyses appeared to favor nivolumab plus chemotherapy, this did not reach statistical significance.

Surgical outcomes

Across all trials, neoadjuvant chemoimmunotherapy has led to high rates of complete or R0 surgical resections without causing significant surgical delays or complications. Overall, the data strongly suggest that this treatment approach leads to better surgical outcomes, which likely contributes to improvements in survival.

In Shu et al., 97% patients treated with neoadjuvant nab-paclitaxel, carboplatin, and atezolizumab proceeded to the operating room with intention of surgery and 87% had an R0 surgical resection.⁴⁵ Among patients with N2 at baseline, 69% had downstaging of nodal status with neoadjuvant chemoimmunotherapy. There were no treatment-related surgical delays or surgical complications, and there were no treatment-related deaths.⁴⁵ In NADIM, 89% of patients proceeded with surgery following neoadjuvant therapy.⁴⁸ Among those who proceeded with surgery, 90% had achieved clinical disease stage downstaging after neoadjuvant therapy, and all patients achieved complete tumor resection. Postoperative complications were observed in 29% of patients who underwent surgery and although most patients experienced a TRAE during neoadjuvant treatment, none led to delay in surgery or death. In SAKK 16/14, 55 (82%) patients underwent surgical resection; those who did not proceed with surgery either had disease progression (n = 6), treatment toxicity (n = 3), or inoperability (n = 3).⁵¹ Nodal downstaging was observed in 37 (67%) patients. Among patients who underwent resection, one (2%) patient died in the 30-day post-operative period for a reason that was deemed unrelated to study treatment. In all, 51 (93%) achieved an R0 surgical resection, and 6 (11%) received postoperative radiotherapy, most commonly due to incomplete resection.

In the randomized NADIM II study, patients who received nivolumab plus chemotherapy had significantly higher rate of definitive surgery (91% versus 69%) compared to patients who underwent chemotherapy alone.⁵² In CheckMate-816, a higher percentage of patients who received neoadjuvant chemoimmunotherapy underwent definitive surgery than patients who received chemotherapy alone (83.2% versus 75.4%).⁵³ There were no differences in frequency of surgical delays between the two groups; events leading to delayed surgery occurred in 3.4% of patients receiving nivolumab plus chemotherapy and 5.1% in those receive chemotherapy alone. Patients who received nivolumab plus chemotherapy had fewer surgery cancellations (including for disease progression), shorter median duration of surgery, fewer cases of pneumonectomy, and more commonly underwent minimally invasive surgery. Among patients who underwent surgery, rate of R0 resection was higher in those who received nivolumab plus chemotherapy compared to chemotherapy alone (83.2% versus 77.8%).⁵³ The surgical complication rates were similar (41.6% in the nivolumab plus chemotherapy group; 46.7% in the chemotherapy alone group).

Appropriate endpoints in neoadjuvant therapy

Although OS remains the gold-standard endpoint for phase III trials, NSCLC trials that use this outcome measure take much longer to complete. This is especially true in the resectable disease setting, where most trials that use OS as the primary endpoint take more than 10 years after enrollment to complete.⁴⁶ For this reason, other survival endpoints such as PFS, DFS, EFS, and surrogate survival endpoints such as pathological response have been used. In metastatic trials, PFS is easy to measure and captures more events compared to OS, which, in turn, reduces the time and cost of completing a trial. Compared to prior decades, more phase III trials for advanced NSCLC used PFS as the primary endpoint from 2001 to 2010.⁵⁴ For neoadjuvant trials, DFS has also been proposed as a surrogate endpoint of OS for patients undergoing curative therapies. A meta-analysis conducted in patients with resectable NSCLC found that in adjuvant chemotherapy trials, the correlation between DFS and OS was strong at both the individual and trial levels.⁵⁵

In the neoadjuvant therapy setting, pathological response has been evaluated as a surrogate survival endpoint.⁴⁶ In the neoadjuvant chemotherapy setting, pCR has been shown to be predictive of OS,⁴⁷ but the rarity of pCR after chemotherapy limited its use as a surrogate endpoint. Retrospective data have shown that MPR (defined as ⩽10% viable tumor cells from tissue specimens) after neoadjuvant chemotherapy is associated with both OS and DFS.^35,56 In one study, 5-year OS and DFS were significantly prolonged in patients with MPR compared to patients with >10% viable tumor cells on tissue specimens, even after controlling for pathologic stage.³⁵ In a follow-up report, the combination of primary tumor MPR and lymph MPR was significantly associated with OS.⁵⁶ Therefore, MPR has been proposed as a surrogate of OS in patients with resectable NSCLC who undergo neoadjuvant chemotherapy.

However, MPR may be an insufficient endpoint as it can be quite subjective. When the initial phase II trials of neoadjuvant chemoimmunotherapy were published, many of them used MPR as a primary endpoint, but as the field continued to develop, researchers realized that pCR is likely a more reliable endpoint due to greater interobserver agreement. Since the methodologies used to assess pathologic response after neoadjuvant therapy were varied and only described to a limited extent in early NSCLC trials, the International Association for the Study of Lung Cancer published standardized pathologic assessment guidelines for NSCLC after neoadjuvant therapy in 2020.^57,58 For tumors ⩽3 cm, these guidelines recommend sampling the entire tumor, and for those >3 cm, they recommend taking 0.5 cm thick cross-sections of the tumor at maximum dimension and sampling the most representative section of viable tumor.⁵⁸ Pathologic response should be calculated as the estimated size of viable tumor divided by tumor bed size. More recently, pathologists have developed a novel MPR calculator tool to further standardize calculations of viable tumor within the tumor bed to make pathologic response assessment more rigorous.⁵⁷ Importantly, it remains to be seen whether MPR or pCR correlate consistently with prolonged survival in this treatment setting.¹⁸

While the phase II trials were mostly too small to demonstrate a statistically significant correlation between pCR and DFS, exploratory analyses from CheckMate-816 showed that median EFS was longer in patients who achieve pCR than in patients without pCR, though data for OS are not yet mature.⁵³ Among patients who received nivolumab + chemotherapy, median EFS was not reached in patients who achieved pCR versus 26.6 months for patients without pCR, and an HR of 0.13 (0.05–0.37).⁵³

Ongoing clinical trials

Although CheckMate-816 showed a benefit for EFS and pCR in patients treated with neoadjuvant chemoimmunotherapy, mature data for OS have not yet been published. There are several other ongoing randomized phase III trials at the time of this review that are studying neoadjuvant chemoimmunotherapy in resectable NSCLC (Table 2).⁵⁹ These include IMpower030, with neoadjuvant atezolizumab in addition to platinum doublet chemotherapy,⁶⁰ KEYNOTE-671, with neoadjuvant pembrolizumab in addition to platinum doublet chemotherapy,⁶¹ AEGEAN, with neoadjuvant durvalumab in addition to platinum-based chemotherapy,⁶² and CheckMate 77T, with neoadjuvant nivolumab and platinum doublet chemotherapy.⁶³

Table 2.

Snapshot of ongoing multicenter phase II/III clinical trials of neoadjuvant chemoimmunotherapy in NSCLC.

Clinical trial	Phase	Disease stage	Experimental arm	Comparator arm	Primary endpoint
IMpower 030⁶⁰	III	Stage II–IIIB (TNM 8th edition)	Neoadjuvant platinum-doublet plus atezolizumab × 4 cycles followed by adjuvant atezolizumab × 16 cycles	Neoadjuvant platinum-doublet plus placebo × 4 cycles followed by observation	EFS
KEYNOTE 671⁶¹	III	Stage II–IIIB (TNM 8th edition)	Neoadjuvant platinum-doublet plus pembrolizumab × 4 cycles followed by adjuvant pembrolizumab × 13 cycles	Neoadjuvant platinum-doublet plus placebo × 4 cycles followed by adjuvant placebo × 13 cycles	EFS, OS
AEGEAN⁶²	III	Stage II–IIIB (T3N2), (TNM 8th edition)	Neoadjuvant platinum-doublet plus durvalumab × 4 cycles followed by adjuvant durvalumab × 12 cycles	Neoadjuvant platinum-doublet plus placebo × 4 cycles followed by adjuvant placebo × 12 cycles	pCR, EFS
CheckMate 77T⁶³	III	Stage II–IIIB (T3N2), (TNM 8th edition)	Neoadjuvant platinum-doublet plus nivolumab × 4 cycles followed by adjuvant nivolumab × 1 year	Neoadjuvant platinum-doublet plus placebo × 4 cycles followed by adjuvant placebo × 1 year	EFS
NCT04379635	III	Stage II–IIIA (TNM 8th edition)	Neoadjuvant platinum-doublet plus tislelizumab followed by adjuvant tislelizumab	Neoadjuvant platinum-doublet plus placebo followed by adjuvant placebo	ORR; R0 resection rate
NeoCOAST-2⁶⁴	II	Stage II–IIIB (TNM 8th edition)	Neoadjuvant platinum-doublet plus durvalumab and oleclumab followed by adjuvant durvalumab and oleclumab (Arm 1); neoadjuvant platinum-doublet plus durvalumab and monalizumab followed by adjuvant durvalumab and monalizumab (Arm 2); neoadjuvant platinum-doublet plus MEDI5752 followed by adjuvant MEDI5752 (Arm 3)	N/A	pCR; AEs
SKYSCRAPER-05⁶⁵	II	Stage II–IIIB (TNM 8th edition)	Neoadjuvant atezolizumab plus tiragolumab × 4 cycles followed by adjuvant atezolizumab plus tiragolumab or adjuvant chemotherapy (PD-L1 high); neoadjuvant platinum-doublet plus atezolizumab plus tiragolumab × 4 cycles followed by adjuvant atezolizumab plus tiragolumab (PD-L1 all comers)	N/A	MPR, treatment-related surgical delays, surgical cancellations/complications, safety
NCT04991025	II	Stage II–III	Neoadjuvant platinum-doublet plus nivolumab and certolizumab	N/A	pCR

AEs, adverse events; EFS, event-free survival; MPR, major pathological response; NSCLC, non-small-cell lung cancer; pCR, pathological complete response; PD-L1, programmed death ligand 1; PFS, progression-free survival; OR, odds ratio; ORR, objective response rate.

Patient selection for neoadjuvant chemoimmunotherapy

Circulating tumor DNA as a biomarker

In the updated report of 3-year OS in NADIM, the exploratory endpoints of baseline circulating tumor DNA (ctDNA) and ctDNA clearance after treatment were shown to correlate significantly with survival.⁴⁹ Baseline ctDNA, which was detected in 30 of 43 (69.8%) patient serum samples, was significantly associated with tumor size.⁴⁹ Patients with low ctDNA levels (<1% MAF) at baseline had significantly improved PFS (HR: 0.20, 95% CI: 0.06–0.63; p = 0.006) and OS (HR: 0.07, 95% CI: 0.01–0.39; p = 0.002) compared to patients with high ctDNA levels at baseline. Patients with undetectable ctDNA (<0.1% MAF) after neoadjuvant treatment had improved PFS (adjusted HR: 0.26, 95% CI: 0.07–0.93; p = 0.038) and OS (HR: 0.04, 95% CI: 0.00–0.55, p = 0.015). Neither radiographic response nor pathological response correlated with survival.⁴⁹

In CheckMate-816, ctDNA analyses were also exploratory.⁵³ ctDNA was evaluable in 89 (25%) patients, and ctDNA clearance was defined as clearance from detectable ctDNA levels before cycle 1 of neoadjuvant therapy to undetectable ctDNA levels before cycle 3. EFS appeared to be longer in patients with ctDNA clearance in both the nivolumab plus chemotherapy group (HR: 0.60, 95% CI: 0.20–1.82) and the chemotherapy alone group (HR: 0.63, 95% CI: 0.20–2.01).⁵³ The association between ctDNA clearance and longer EFS is consistent with what was seen in NADIM and provided additional support for ctDNA as a potential marker of clinical benefit.

Although we are awaiting more substantial data, we believe that changes in ctDNA may be a superior marker of survival compared to radiographic or pathological response. These changes may someday allow us to risk stratify patients more effectively and tailor treatment more efficiently.

PD-L1 and TMB as biomarkers

PD-L1 expression is used as a biomarker for patient selection for immunotherapy in both the adjuvant and metastatic settings.^16,17 While there is some evidence to support PD-L1 status as a predictive marker of treatment benefit and survival in the neoadjuvant setting,⁵³ the data are inconsistent and there are no guidelines to support the routine use of PD-L1 status as a biomarker to determine eligibility for neoadjuvant chemoimmunotherapy.

In the Columbia phase II trial by Shu et al., 55% of patients had PD-L1 expression ⩾1% at baseline, but there was no association between PD-L1 expression and MPR.⁴⁵ In NADIM, PD-L1 data were only available for 61% of patients (n = 28). Of these patients, 18 (64%) had a PD-L1 tumor proportion score (TPS) ⩾ 1%. PD-L1 TPS of ⩾25% appeared to be associated with MPR, and PD-L1 TPS was significantly higher in patients with pCR compared to those with incomplete pathological response (p = 0.042).⁴⁸ PD-L1 TPS, however, was not significantly associated with either PFS or OS. In SAKK 16/14, 32 (48%) patients had PD-L1 ⩾ 1% and 13 (19%) had PD-L1 ⩾ 25% at baseline. Although patients with PD-L1 expression ⩾25% had a higher rate of pCR (OR: 4.8, 95% CI: 1.0–22.8, p = 0.47), there was no association between PD-L1 expression and EFS at 1-year, MPR or rate of nodal downstaging.⁵¹

In the randomized NADIM II trial, there appeared to be a relationship between pCR and PD-L1 TPS score, as patients with pCR had higher PD-L1 TPS than patients who were non-responders (p = 0.0035).⁵² In subgroup analyses of CheckMate-816, the EFS benefit of nivolumab plus chemotherapy appeared to be augmented in patients with higher PD-L1 expression. The HR for EFS was 0.85 (0.54–132) in patients with PD-L1 <1%, 0.41 (0.24–0.70) in patients with PD-L1 ⩾ 1%, 0.58 (0.30–1.12) in patients with PD-L1 1–49%, and 0.24 (0.10–0.61) in patients with PD-L1 ⩾ 50%.⁵³

TMB is a controversial biomarker of immunotherapy outcomes that has inconsistently demonstrated predictive value in metastatic NSCLC irrespective of PD-L1 status,^25,66,67 but there are no data to suggest a predictive role for immunotherapy in the neoadjuvant setting.^49,53 In CheckMate-816, subgroup analysis did not show any difference in EFS benefit or pCR between patients with TMB < 12.3 mutations/megabase and those with ⩾12.3% mutations/megabase.⁵³

Disease stage at baseline

Disease stage is an important consideration for adjuvant therapy in resectable NSCLC. Patients with stage II and III disease are routinely offered adjuvant therapy, but those with earlier stage disease may actually have a worse survival if given treatment after surgery.¹ Subgroup analyses in IMpower010 suggested a stronger trend toward benefit with adjuvant atezolizumab for stage IIIA disease compared to stage IIA–IIB disease, but the study was not statistically powered to make any conclusions.¹⁷ With neoadjuvant chemoimmunotherapy, many of the phase II trials only included patients with advanced stage,^48,51 and even the ones that allowed earlier stage disease often skewed heavily towards stage III disease,⁴⁵ possibly reflecting surgical preferences as well.

Subgroup analyses in CheckMate-816, which enrolled patients with stage IB–IIIA disease, showed that the EFS benefit with chemoimmunotherapy appeared to be higher in patients with stage IIIA disease compared to patients with stage I/II disease.⁵³ However, the trial was not powered to conclusively establish this difference. Still, this supports the theory that effectiveness of immunotherapy may be enhanced by the presence of higher tumor burden, but further investigation is needed prior to routinely incorporating disease stage in the assessment of patient eligibility for neoadjuvant chemoimmunotherapy.

Sequencing perioperative systemic treatments

The optimal management and sequence of systemic therapies relative to surgery for resectable NSCLC remains unclear. Adjuvant chemotherapy is now routinely offered to stage II–IIIA patients based on data from the LACE meta-analysis,¹ and additional adjuvant immunotherapy can be offered to patients in the United States with stage II–IIIA disease and PD-L1 ⩾ 1% based on IMpower010.¹⁷ Although CheckMate-816 demonstrated that neoadjuvant chemoimmunotherapy is superior to neoadjuvant chemotherapy alone,⁵³ it is still unknown whether systemic therapy is generally better delivered in the neoadjuvant or adjuvant setting. Many prefer neoadjuvant systemic treatment given the possibility of tumor downstaging, pathological response, improved surgical outcomes, early assessment of response to systemic therapies, and higher likelihood of treatment compliance and tolerability prior to surgery.^13,53 Some may be more hesitant to adopt a neoadjuvant approach, however, as it delays a potentially definitive resection. There are also no robust data to support neoadjuvant chemoimmunotherapy for patients with EGFR or ALK mutations, as these patients were excluded from NADIM II and CheckMate-816 but would receive adjuvant osimertinib (in some cases in addition to chemotherapy) per the ADAURA trial⁶⁸ or chemotherapy alone, respectively.

CheckMate-816 did not include any adjuvant systemic therapy in the treatment regimen, but SAKK 16/14 and NADIM II treated patients with both neoadjuvant chemoimmunotherapy and adjuvant immunotherapy. Further study on the benefit of a perioperative approach that includes both neoadjuvant and adjuvant chemoimmunotherapy is warranted. The ongoing CheckMate 77T, IMpower030, KEYNOTE-617, and AEGEAN trials incorporate adjuvant immunotherapy in addition to neoadjuvant chemoimmunotherapy.^60–63

Changes and challenges to multidisciplinary management

The high MPR and pCR rates and improved surgical outcomes and survival numbers seen in neoadjuvant chemoimmunotherapy trials suggest that with adoption of this treatment strategy, we can improve upon the historically dismal numbers of locally advanced NSCLC. Importantly, we can provide this treatment without sacrificing surgical outcomes – in CheckMate-816, the surgery-related AEs were lower in the nivolumab plus chemotherapy arm than in the chemotherapy arm (41.6% versus 46.7%) and the median duration of surgery was also lower in the experimental arm.⁵³ More patients were able to undergo minimally invasive surgery in the experimental arm as well. Still, this treatment paradigm does mean that surgery will be delayed while patients undergo neoadjuvant treatment and that surgical oncologists will need to alter their surgical approach depending on their patients’ treatment response. It is therefore imperative that these patients are managed by a robust multidisciplinary team that can handle treatment logistics and assess the patient-specific risks and benefits of a perioperative treatment approach. The workflow for surgeons may have to change as well, as they may need to refer patients whom they would previously take directly to the OR.

The evaluation of treatment response poses a potential challenge since radiographic assessments may not always accurately reflect the benefit of chemoimmunotherapy. Atypical radiologic response patterns (pseudoprogression) can be seen with immunotherapy.⁶⁹ In a pilot study by Forde et al., for instance, two patients treated with neoadjuvant nivolumab were found to have larger tumors on presurgical CT scans but minimal or no residual tumor in the resected surgical specimen.³¹ The misleading imaging findings were thought to reflect immune cell infiltration and fibrotic tissue repair rather than true tumor growth. This is similar to the NIF observed in the NEOSTAR study, where patients with radiographic nodal growth were found to have immune cell infiltration without tumor on nodal pathologic review.³³ In the SAKK 16/14 trial, only 70% of patients who achieved a pCR and 56% of patients who achieved MPR had a complete or partial response on imaging.⁵¹ The discordance between radiographic response and true response to neoadjuvant therapy may add additional challenges to surgical planning, further highlighting the importance of multidisciplinary team involvement in the care of these patients.

Conclusion

In conclusion, we have come a long way and made significant progress in the neoadjuvant treatment of lung cancer. Most importantly, we have learned that surgery after immunotherapy is feasible. We have also found that neoadjuvant chemotherapy plus immunotherapy is more effective than neoadjuvant immunotherapy alone. Still, as we move forward in the field, we need to learn how to risk stratify patients and individualize their therapy. Perhaps someday, patients with high PD-L1 scores will receive neoadjuvant immunotherapy alone, or patients who do not clear their ctDNA after two cycles of therapy will have additional chemotherapy added into the mix. After surgical resection, how do we decide who should undergo more adjuvant treatment? Is it the patients who responded well to neoadjuvant treatment and met a pCR, or conversely is it the patients who responded less well and may need additional therapy? Can newer agents such as an anti-TIGIT monoclonal antibody or STAT3 inhibitor augment the response? What we know with certainty is that the treatment paradigm now values a multidisciplinary team more than ever.

Footnotes

Acknowledgements

Not applicable.

Declarations

ORCID iDs

Lanyi Nora Chen

Alexander Z. Wei

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Neoadjuvant immunotherapy in resectable non-small-cell lung cancer

Abstract

Keywords

Introduction

Neoadjuvant immunotherapy

Neoadjuvant immunotherapy with RT

Neoadjuvant immunotherapy with chemotherapy

Surgical outcomes

Appropriate endpoints in neoadjuvant therapy

Ongoing clinical trials

Patient selection for neoadjuvant chemoimmunotherapy

Circulating tumor DNA as a biomarker

PD-L1 and TMB as biomarkers

Disease stage at baseline

Sequencing perioperative systemic treatments

Changes and challenges to multidisciplinary management

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iDs

References