Chemotherapy + PD-1/PD-L1 Blockade Should Be the Preferred Option in the Neoadjuvant Therapy of NSCLC

Abstract

Lung cancer remains the leading cause of cancer death worldwide.1Bray F. Ferlay J. Soerjomataram I. Siegel R.L. Torre L.A. Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence an mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2018; 68: 394-424Google Scholar Even for the earliest stages of NSCLC, survival is comparatively poor and lags behind surgical breast, colon, and prostate cancers by large margins. Over 20% of patients with stage I NSCLC, 50% with stage II, and a staggering 60% with stage IIIA are dead within 5 years—despite receiving curative-intent surgery.2Pfannschmidt J. Muley T. Bülzebruck H. Hoffmann H. Dienemann H. Prognostic assessment after surgical resection for non-small cell lung cancer: Experiences in 2083 patients.Lung Cancer. 2007; 55: 371-377Google Scholar In surgically resected patients, the risk of distant metastases may even be greater than the risk of local and regional recurrence,3Dziedzic D.A. Rudzinski P. Langfort R. Orlowski T. Polish Lung Cancer Study Group (PLCSG). Risk factors for local and distant recurrence after surgical treatment in patients with non-small-cell lung cancer.Clin Lung Cancer. 2016; 17: e157-e167Google Scholar highlighting the need for earlier and better systemic control. Before very recent advances in the systemic therapy of early-stage lung cancer, medical oncologists were left with few therapeutic options to improve these poor survival rates. Recommended neoadjuvant and adjuvant chemotherapy (chemo) options for patients with resectable disease offered a real but, in truth, modest, 5% absolute improvement over surgery alone in 5-year overall survival (OS).4Arriagada R. Auperin A. et al.NSCLC Meta-analyses Collaborative GroupAdjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data.Lancet. 2010; 375: 1267-1277Google Scholar During the golden age of lung cancer therapeutics from approximately 2008 onward, a disconnect emerged between advanced lung cancer (emergence of molecular-guided therapies, the immunotherapy revolution, and >20 new systemic therapy approvals) and resectable lung cancer (zero new therapies and a degree of therapeutic nihilism). Despite the fact that major therapeutic breakthroughs for advanced lung cancer have become almost routine, although few patients are actually cured of metastatic disease, standard treatment for a patient diagnosed with having stage II NSCLC in 2018 was essentially unchanged from 2008. This falls far short of the impressive expectations that have resulted from the molecular and immunotherapeutic advancements of the past decade and has left patients and clinicians with a clear unmet need in the field of early-stage lung cancer management. Several recently reported neoadjuvant clinical trials (Table 1) incorporating immune checkpoint inhibitors (ICIs) either alone or in combination with chemo have presented promising results. This has pushed clinicians to rethink the treatment paradigm for early-stage NSCLC, and in doing so, has spurred welcome discussion and controversy over the optimal course of management.Table 1Neoadjuvant Immunotherapy Trials in NSCLCJournal/ConferenceFirst AuthorYearTrial IDTrial PhasePrimary End PointNeoadjuvant RegimenNature Medicine (NeoStar)21Cascone T. William Jr., W.N. Weissferdt A. et al.Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial.Nat Med. 2021; 27: 504-514Google ScholarCascone et al.2021NCT03158129IIMPRIpilimumab/nivolumab vs. nivolumabLancet Oncology (NADIM)28Provencio M. Nadal E. Insa A. et al.Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.Lancet Oncol. 2020; 21: 1413-1422Google ScholarProvencio et al.2020NCT03081689IIPFS at 24 moCarbo/taxol + nivolumabWorld Lung/Journal of Thoracic Oncology (LCMC3)42Lee J. Chaft J. Nicholas A. et al.Surgical and clinical outcomes with neoadjuvant atezolizumab in resectable stage IB-IIIB NSCLC: LCMC3 trial primary analysis.J Thorac Oncol. 2021; 16: 59-61Google ScholarLee et al.2021NCT02927301IIMPRAtezolizumabLung Cancer (NEOMUN)43Eichhorn F. Klotz L.V. Kriegsmann M. et al.Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience.Lung Cancer. 2021; 153: 150-157Google ScholarEichhorn et al.2021NCT03197467IISafetyPembrolizumabAACR (CheckMate 816)30Spicer J. Wang C. Tanaka F. et al.Surgical outcomes from the phase 3 CheckMate 816 trial: nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC).J Clinical Oncol. 2021; 39 (8503–8503)Google ScholarForde et al.2021NCT02998528IIIpCRNivolumab + chemotherapyJournal of Thoracic Oncology44Gao S. Li N. Gao S. et al.Neoadjuvant PD-1 inhibitor (sintilimab) in NSCLC.J Thorac Oncol. 2020; 15: 816-826Google ScholarGao et al.2020ChiCTR-OIC-17013726IbSafetySintilimabLancet Oncology27Shu C.A. Gainor J.F. Awad M.M. et al.Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.Lancet Oncol. 2020; 21: 786-795Google ScholarShu et al.2020NCT02716038IIMPRAtezolizumab + chemotherapyESMO45Lei J. Yan X. Zhao J. Tian F. Lu Q. 62MO – a randomised, controlled, multicenter phase II trial of camrelizumab combined with albumin-bound paclitaxel and cisplatin as neoadjuvant treatment in locally advanced NSCLC.Ann Oncol. 2020; 31: S1441-S1451Google ScholarLei et al.2020NCT04338620IIpCRCamrelizumab + chemotherapyOncoimmunology (NeoTAP01)46Zhao Z.R. Yang C.P. Chen S. et al.Phase 2 trial of neoadjuvant toripalimab with chemotherapy for resectable stage III non-small-cell lung cancer.Oncoimmunology. 2021; 10: 1996000Google ScholarZhao et al.2021NCT04304248IIMPRToripalimab + chemotherapyJournal of Clinical Oncology29Forde P.M. Spicer J. Lu S. Nivolumab (NIVO)+ platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial.Cancer Res. 2021; 81 (CT003)Google ScholarRothschild et al.2021NCT02572843II1-y EFSDurvalumab + chemotherapyCarbo, carboplatin; EFS, event-free survival; ID, identification; MPR, major pathologic response; pCR, pathologic complete response; PFS, progression-free survival. Open table in a new tab Carbo, carboplatin; EFS, event-free survival; ID, identification; MPR, major pathologic response; pCR, pathologic complete response; PFS, progression-free survival. Analogous to the recent advances in the neoadjuvant space, trials evaluating the safety and efficacy of ICIs in the adjuvant setting led to the approval of the Food and Drug Administration of adjuvant atezolizumab after definitive resection and subsequent adjuvant chemo, on the basis of data from IMpower010.5Felip E. Altorki N. Zhou C. et al.Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.Lancet. 2021; 398: 1344-1357Google Scholar In this randomized phase 3 multicenter study, eligible patients with stages IB to IIIA (per seventh edition of the American Joint Committee on Cancer [AJCC] staging system) received 1 year of atezolizumab versus best supportive care, after completing definitive anatomical resection followed by adjuvant cisplatin-based chemo. In patients with resected stages II to IIIA NSCLC and tumor programmed death-ligand 1 (PD-L1) expression of more than or equal to 1%, 36-month disease-free survival (DFS) was 60.0% in the treatment arm compared with 48.2% in the best supportive care group (hazard ratio [HR] = 0.66, 95% confidence interval: 0.50–0.88, p = 0.0039), meeting the complex preset hierarchical primary end point for the study and ultimately guiding the scope of the Food and Drug Administration approval. The DFS benefit observed was mainly driven by the cohort of patients with high PD-L1–expressing (≥50%) tumors, similar to outcomes with single-agent programmed cell death protein 1 (PD-1) pathway blockade in advanced NSCLC. Toxicity in the atezolizumab arm was in line with historical rates of single-agent ICI in metastatic settings. Notably, for patients with tumor PD-L1 expression less than 1% and 1% to 49%, atezolizumab did not lead to a statistically significant improvement in DFS (HR = 0.97 [0.72–1.31] and HR = 0.87 [0.60–1.26], respectively), suggesting much of the benefit was driven by the population of PD-L1 high–expressing tumors (≥50%) in the treatment arm. The OS data from IMpower010 are still maturing and have yet to be reported, but will also provide added insight into the eventual prioritization of adjuvant atezolizumab versus emerging neoadjuvant chemoimmunotherapy options. In addition, the uncertain DFS benefit of adjuvant ICI for low PD-L1–expressing tumors and smaller tumors (IB and II) points to the continued need for further therapeutic development in early-stage NSCLC. Despite these caveats, this recent breakthrough has brought much-needed excitement and hope for patients dealing with resectable NSCLC, whose predecessors have watched on as novel systemic therapies have captured headlines and prolonged survival only for patients with more advanced NSCLC. Despite the recent advancement of adjuvant ICI, our foundational understanding of the mechanism of ICIs along with convincing preclinical evidence suggests improved efficacy of neoadjuvant compared with adjuvant immune therapy.6Liu J. Blake S.J. Yong M.C. et al.improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease.Cancer Discov. 2016; 6: 1382-1399Google Scholar It has been hypothesized that by initiating immune checkpoint blockade (ICB) while the tumor is “in situ,” this will leverage higher levels of endogenous tumor and tumor-associated antigen,7Topalian S.L. Taube J.M. Pardoll D.M. Neoadjuvant checkpoint blockade for cancer immunotherapy.Science. 2020; 367 (eaax0182)Google Scholar thereby enhancing T-cell priming, leading to greater expansion of tumor-specific T-cell clones.8Caushi J.X. Zhang J. Ji Z. et al.Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers.Nature. 2021; 596: 126-132Google Scholar These clones may persist even beyond time of resection to perpetuate immune surveillance and eliminate micrometastatic disease.9Friedman J. Moore E.C. Zolkind P. et al.Neoadjuvant PD-1 immune checkpoint blockade reverses functional immunodominance among tumor antigen-specific T cells.Clin Cancer Res. 2020; 26: 679689Google Scholar Testing this hypothesis, Liu et al.,6Liu J. Blake S.J. Yong M.C. et al.improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease.Cancer Discov. 2016; 6: 1382-1399Google Scholar using two murine models, found significantly greater tumor-specific T-cell activation and therapeutic efficacy of neoadjuvant compared with adjuvant immune therapy; these findings, interestingly, were not appreciated when comparing neoadjuvant versus adjuvant chemo, suggesting, at least in part, that the specific mechanism behind neoadjuvant ICI efficacy is at play. Within preclinical lung cancer models, Cascone et al.10Cascone T. Hamdi H. Zhang F. et al.Superior efficacy of neoadjuvant compared to adjuvant immune checkpoint blockade in non-small cell lung cancer.Cancer Research. 2018; 78 (1719–1719)Google Scholar also noted superior recurrence and survival outcomes for mice treated with neoadjuvant ICI compared with adjuvant therapy. In the clinic, similar observations were noted in a randomized phase 1b clinical study (OpACIN trial) investigating safety of neoadjuvant nivolumab (nivo) and ipilimumab in patients with high-risk resectable melanoma, with pertinent immune correlate end points comparing neoadjuvant versus adjuvant therapy capacity to generate tumor-resident T-cell clones.11Blank C.U. Rozeman E.A. Fanchi L.F. et al.Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma.Nat Med. 2018; 24: 1655-1661Google Scholar Investigators observed greater expansion of tumor-resident T-cell clones and more favorable interferon gamma signatures in patients treated with neoadjuvant compared with adjuvant ICIs. In addition, evidence suggests that tumor burden, even in treatment-naive settings,12Suzuki S. Haratani K. Hayashi H. et al.Association of tumour burden with the efficacy of programmed cell death-1/programmed cell death ligand-1 inhibitors for treatment-naïve advanced non-small-cell lung cancer.European J Cancer. 2022; 161: 44-54Google Scholar may play a role in efficacy of ICI, further supporting the rationale for incorporating these agents into early-stage disease. Proposed mechanisms behind this observation between tumor volume and ICI efficacy include the following: (1) poor T-cell immune infiltration into the tumor microenvironment owing to poor vascularization and heterogeneous fibrotic changes13Kim S.I. Cassella C.R. Byrne K.T. Tumor burden and immunotherapy: impact on immune infiltration and therapeutic outcomes.Front Immunol. 2021; 11: 629722Google Scholar and (2) relative increased proportions of immune-suppressive cell populations, including myeloid-derived suppressor cells14Kramer E.D. Abrams S.I. Granulocytic myeloid-derived suppressor cells as negative regulators of anticancer immunity.Front Immunol. 2020; 11: 1963Google Scholar and tumor-associated macrophages,15Mantovani A. Marchesi F. Malesci A. Laghi L. Allavena P. Tumour-associated macrophages as treatment targets in oncology.Nat Rev Clin Oncol. 2017; 14: 399-416Google Scholar affecting both CD8+ T-cell trafficking and cytotoxic effects.16Bayne L.J. Beatty G.L. Jhala N. et al.Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer.Cancer Cell. 2012; 21: 822-835Google Scholar One concern regarding incorporation of more aggressive combination regimens in the neoadjuvant space has been the potential risk of toxicity and delay of curative-intent surgery, particularly with some of the more dramatic immune-related adverse events that can occur with ICIs. To test the safety of ICI agents in this setting, an initial pilot study was first published evaluating safety and feasibility of two preoperative doses of nivo before definitive resection for patients with stages I to IIIA (per AJCC seventh edition) NSCLC. There were 21 patients enrolled, 20 of whom underwent complete tumor resection without treatment-related surgical delays, with the remaining patient found to have inoperable disease at time of surgery. Treatment-related adverse events (TRAEs) occurred in five of 22 patients, with only one event graded 3 or higher. Among the 20 patients’ tumors available for pathologic assessment, two (10%) achieved a pathologic complete response (pCR), defined as 0% residual tumor within the primary and nodal resection specimens.17Travis W.D. Dacic S. Wistuba I. et al.IASLC Multidisciplinary Recommendations for pathologic assessment of lung cancer resection specimens after neoadjuvant therapy.J Thorac Oncol. 2020; 15: 709-740Google Scholar Major pathologic response (MPR), defined as no more than 10% viable tumor cells in the resected primary tumor, was noted in 9 of 20 patients (45%). Neoadjuvant nivo induced expansion of mutation-associated, neoantigen-specific T-cell clones in the peripheral blood, noted within 2 to 4 weeks after treatment.18Forde P.M. Chaft J.E. Smith K.N. et al.Neoadjuvant PD-1 blockade in resectable lung cancer.N Engl J Med. 2018; 378: 1976-1986Google Scholar Extended follow-up data for this cohort of patients revealed a 24-month recurrence-free survival rate of 69%, with one long-term dermatologic immune-related adverse event reported.19Reuss J.E. Smith K.N. Anagnostou V. et al.Neoadjuvant nivolumab in resectable non-small cell lung cancer: Extended follow-up and molecular markers of response.J Clinical Oncol. 2019; 37 (8524–8524)Google Scholar Since the initial publication of this neoadjuvant ICI trial in 2018, several early phase trials have assessed the safety and efficacy of single-agent or dual-agent ICI in NSCLC (Table 1). Most of the studies testing neoadjuvant single-agent ICI revealed it to be safe and feasible before curative-intent surgery. Nevertheless, a study reported by Reuss et al.20Reuss J.E. Anagnostou V. Cottrell T.R. et al.Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer.J Immunother Cancer. 2020; 8e001282Google Scholar of neoadjuvant ipilimumab plus nivo underwent early termination of the study arm. Although the combination was feasible, with all patients having received each scheduled dose, six of nine enrolled patients (67%) experienced TRAEs, with 33% being grade 3 or higher.20Reuss J.E. Anagnostou V. Cottrell T.R. et al.Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer.J Immunother Cancer. 2020; 8e001282Google Scholar In contrast, a phase 2 study by Cascone et al.21Cascone T. William Jr., W.N. Weissferdt A. et al.Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial.Nat Med. 2021; 27: 504-514Google Scholar evaluating efficacy of neoadjuvant ipilimumab plus nivo versus nivo monotherapy—with MPR as the primary end point—reported a total resectability rate of 89% among all enrolled patients with 100% undergoing R0 resection. Grade 3 to 5 TRAEs were 10% with ipilimumab plus nivo and 13% for nivo alone.21Cascone T. William Jr., W.N. Weissferdt A. et al.Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial.Nat Med. 2021; 27: 504-514Google Scholar These conflicting safety signals suggest the need for further investigation of neoadjuvant dual ICI to identify patient populations most likely to derive clinical benefit. As we know from extensive clinical data in the advanced/metastatic setting, single-agent22Reck M. Rodríguez-Abreu D. Robinson A.G. et al.Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50.J Clin Oncol. 2021; 39: 2339-2349Google Scholar or even dual-agent ICI23Paz-Ares L.G. Ramalingam S.S. Ciuleanu T.E. et al.First-line nivolumab plus ipilimumab in advanced nsclc: 4-year outcomes from the randomized, open-label, phase 3 CheckMate 227 Part 1 trial.J Thorac Oncol. 2022; 17: 289-308Google Scholar regimens—although capable of inducing impressive and durable responses—still leave most of the patients without significant clinical benefit. For this reason, strategies combining chemo with ICI24Gadgeel S. Rodríguez-Abreu D. Speranza G. et al.Updated Analysis from KEYNOTE-189: Pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer.J Clin Oncol. 2020; 38: 1505-1517Google Scholar,25Paz-Ares L. Ciuleanu T.E. Cobo M. et al.First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial.Lancet Oncol. 2021; 22: 198-211Google Scholar have been explored to help boost response rates and offer benefit for patients less likely to respond to ICI alone—such as those with lower tumor PD-L1 expression scores or tumor mutational burden. Similarly, when evaluating ICIs in the neoadjuvant setting, although efficacy of these agents—measured largely by pathologic response data—has been encouraging, there are still many patients without deep tumor pathologic responses to single or dual ICI therapy. To further optimize outcomes, several studies have explored the safety and efficacy of combining neoadjuvant chemo with ICIs. Biological rationales for this combination strategy, as studied in the advanced/metastatic setting, include the recognition that chemo induces tumor lysis, leading to the release of tumor antigens, enhancing immune responses, and ultimately leading to improved rates of pathologic response and clinical outcomes.26Bracci L. Schiavoni G. Sistigu A. Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer.Cell Death Differ. 2014; 21: 15-25Google Scholar Among the first neoadjuvant chemoimmunotherapy trials was a single-arm, phase 2 trial of up to four cycles of atezolizumab in combination with nab-paclitaxel in patients with resectable stages IB to IIIA NSCLC reported by Shu et al.27Shu C.A. Gainor J.F. Awad M.M. et al.Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.Lancet Oncol. 2020; 21: 786-795Google Scholar The study enrolled 30 patients, of whom 97% underwent surgery, with 87% undergoing successful R0 resection. pCR and MPR were reported at 33% and 57%, respectively, both of which are comparatively higher than historical rates after either neoadjuvant chemo or single-agent ICI. From a toxicity standpoint, grade 3 to 5 adverse events were mainly attributable to chemo, with neutropenia in 50% of patients. Building on this, several early-stage clinical trials have reported the safety and efficacy of neoadjuvant chemoimmunotherapy, with rates of pCR ranging from 9% to 63%, with particularly promising two-year follow-up data noted in the phase 2 NADIM trial.28Provencio M. Nadal E. Insa A. et al.Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.Lancet Oncol. 2020; 21: 1413-1422Google Scholar Some trials such as NADIM and SAKK 16/1429—investigating three cycles of preoperative durvalumab combined with cisplatin and taxotere—have focused on higher risk resectable patients, restricting enrollment to stage IIIA disease. At this time, it is unclear if there is improved benefit of neoadjuvant chemoimmunotherapy for lower risk (I/II) versus higher risk stage IIIA resectable patients, though this is certainly an area of interest which data from future larger scale, randomized studies may help elucidate. Promising data from early phase neoadjuvant chemoimmunotherapy trials have been followed by recently presented results of pathologic and surgical outcomes from the international, multicenter, randomized phase 3 study CheckMate 81629Forde P.M. Spicer J. Lu S. Nivolumab (NIVO)+ platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial.Cancer Res. 2021; 81 (CT003)Google Scholar comparing neoadjuvant nivo with platinum-doublet chemo (nivo + chemo) versus chemo alone before definitive resection for patients with clinical stages IB to IIIA (per AJCC seventh edition) NSCLC. Results of the pathologic response primary end point revealed a statistically significant difference in pCR between nivo plus chemo versus chemo alone (24% versus 2.2%, respectively, OR = 13.94 [99% confidence interval: 3.49–55.75], p < 0.0001) and significantly deeper pathologic responses in the tumors resected from those patients who received chemoimmunotherapy. The addition of nivo to neoadjuvant chemo also led to higher rates of circulating-tumor (ct)DNA clearance, defined as change from detectable levels of ctDNA at cycle 1 to undetectable ctDNA levels at cycle 3, at 54% versus 34%. In terms of toxicity, nivo plus chemo did not increase TRAEs and led to zero treatment-related deaths, compared with three in the chemo arm. From a surgical perspective, patients who received nivo plus chemo were more likely to undergo surgical resection and had lower rates of pneumonectomy (17% versus 25%), a high-risk surgical procedure. Rates of R0 resection were numerically higher with the addition of nivo (83% versus 78%), and generally, similar to better surgical outcomes were noted with nivo plus chemo for all surgical metrics, including shorter duration of surgery, less blood loss, and no increase in postoperative hospitalization duration.30Spicer J. Wang C. Tanaka F. et al.Surgical outcomes from the phase 3 CheckMate 816 trial: nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC).J Clinical Oncol. 2021; 39 (8503–8503)Google Scholar These favorable surgical results may help mollify prior concerns from early reports highlighting fibrotic changes post-ICI making pulmonary resection more challenging.31Chaft J.E. Hellmann M.D. Velez M.J. Travis W.D. Rusch V.W. Initial experience with lung cancer resection after treatment with T-Cell checkpoint inhibitors.Ann Thorac Surg. 2017; 104: e217-e218Google Scholar Although these intraoperative observations may occur as a result of ICI response, it seems that they do not impact surgical or clinical outcomes in aggregate, and in part may be representative of timing between neoadjuvant therapy and surgery,32Sasankan P. Hyde J. Wang S. Geraci T.C. Cerfolio R.J. Pulmonary resection after immunotherapy.J Vis Surg. 2021; 7: 29Google Scholar a potential future area of interest, particularly as neoadjuvant ICI becomes further incorporated into standard of care. Recent ongoing and previously reported early phase neoadjuvant NSCLC ICI trials have increasingly relied on pathologic end points such as pCR and MPR, with more established clinical end points such as event-free survival (for neoadjuvant trials), DFS, and OS still maturing. This has led to controversy over the utility and surrogacy of early pathologic end points when considering incorporation of neoadjuvant ICI into practice. Using historical data from studies evaluating neoadjuvant chemo, pathologic response has been correlated with survival outcomes,33Waser N.A. Adam A. Schweikert B. et al.1243P- Pathologic response as early endpoint for survival following neoadjuvant therapy (NEO-AT) in resectable non-small cell lung cancer (rNSCLC): Systematic literature review and meta-analysis.Ann Oncol. 2020; 31: S744-S753Google Scholar and therefore proposed as a clinically meaningful surrogate end point.34Hellmann M.D. Chaft J.E. William Jr., W.N. et al.Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint.Lancet Oncol. 2014; 15: e42-e50Google Scholar Survival outcomes associated with pCR after neoadjuvant chemo have previously been reported, reinforcing its prognostic impact. In a pooled analysis of two French randomized phase 3 trials including patients with stages IB to IIIA NSCLC, the collective 8.3% of patients with pCR had an improved 80% five-year survival, compared with 56% in non-pCR patients (p = 0.0007).35Mouillet G. Monnet E. Milleron B. et al.Pathologic complete response to preoperative chemotherapy predicts cure in early-stage non-small-cell lung cancer: combined analysis of two IFCT randomized trials.J Thorac Oncol. 2012; 7: 841-849Google Scholar Certainly, as these new immunotherapeutic agents are explored in the neoadjuvant setting, these correlations between pathologic response and survival will need to be validated, and with multiple phase 3 neoadjuvant trials ongoing, there will be ample opportunity to do so. Nevertheless, given the underlying mechanism of response with ICIs—including continued immunosurveillance of micrometastatic disease—clinicians and patients may be encouraged by the collective interim results of these neoadjuvant chemoimmunotherapy trials, underscored and reinforced by a recent press report of positive event-free survival findings from CheckMate 816.36Bristol-Myers SquibbNeoadjuvant opdivo (nivolumab) plus chemotherapy significantly improves event-free survival in patients with resectable non-small cell lung cancer in phase 3 CheckMate -816 trial.https://news.bms.com/news/details/2021/Neoadjuvant-Opdivo-nivolumab-Plus-Chemotherapy-Significantly-Improves-Event-Free-Survival-in-Patients-with-Resectable-Non-Small-Cell-Lung-Cancer-in-Phase-3-CheckMate-816-Trial/default.aspxGoogle Scholar Conceptually, neoadjuvant therapy has clear clinical advantages over solely adjuvant therapy, given that early response to therapy can be evaluated both radiographically, with preimaging and postimaging of the intact primary tumor, and pathologically, at the time of resection. The recent approval of adjuvant atezolizumab, given for an entire year after surgery, mandates a long course of expensive and potentially toxic therapy for patients who may already have been cured of their cancer by surgery and perioperative chemo. In contrast, the benefit of a relatively short course of three to four cycles of neoadjuvant chemoimmunotherapy can be assessed in a multifaceted manner, by radiographic response, pathologic response at the time of surgical resection, and emerging technologies such as dynamic liquid biopsies that assess minimal residual disease after surgery. Postoperatively, after neoadjuvant therapy, the patient and clinician have time to regroup and consider the indication (or absence of indication) for further therapy. This has the potential to limit unnecessary treatment exposure to the same systemic agents for those patients who are unlikely to derive benefit (those with minimal or no pathologic response) and for those who may have already achieved maximal benefit (tumors with pCR or near pCR). In turn, this can reduce the treatment-related toxicity (encompassing physical, psychosocial, and financial aspects) that ensues from a long course of adjuvant therapy in the absence of clinically apparent disease.