Antibody-drug conjugates in advanced lung cancer: Is this a new frontier?

Over the past decade, the lung cancer landscape has been dominated by targeted and immunotherapeutic approaches that have drastically shifted treatment paradigms for patients with advanced non-small cell lung cancer (NSCLC). Despite these scientific and clinical advances, there are still many unmet needs underscoring the importance of novel strategies. Antibody-drug conjugates (ADCs) represent one such strategy that is beginning to alter the therapeutic strategies for patients with advanced NSCLC. The rationale of ADCs is simple: selectively deliver cytotoxic payloads through an antibody-mediated process to target antigens expressed by cancer cells, sparing normal tissue and inflicting damage to tumors. Although this concept has been the leading view, preclinical and clinical observations are demonstrating that only a nascent mechanistic understanding of these agents exists. In this review, we discuss the underlying biology of ADCs and their structure and potential mechanisms of action, examine approved and promising ADC targets in lung cancer, and review emerging ADC targets and combinatorial strategies. Importantly, we address the unanswered questions surrounding ADCs in lung cancer, including biomarker selection, treatment sequencing, and mechanisms of resistance, as well as management of unique ADC-associated toxicities.

Elucidating the Heterogeneity of Immunotherapy Response and Immune-Related Toxicities by Longitudinal ctDNA and Immune Cell Compartment Tracking in Lung Cancer.

PURPOSE: Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect-especially in the setting of stable disease-calls for the development of molecularly informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAE). EXPERIMENTAL DESIGN: We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. RESULTS: Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank P = 0.0003) and overall survival (log-rank P = 0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant T-cell receptor (TCR) clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an irAE. CONCLUSIONS: Molecular responses assist with the interpretation of heterogeneous clinical responses, especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefits and irAEs during immunotherapy.

Neoadjuvant Immunotherapy for Non-Small Cell Lung Cancer.

Immune checkpoint blockade (ICB) has improved outcomes for patients with advanced non-small cell lung carcinoma (NSCLC). Building off of this, it has been hypothesized that the utilization of ICB early during the disease course may be advantageous, particularly in the neoadjuvant setting prior to definitive surgical resection. Preclinical studies have suggested that a more potent immune response may be induced by neoadjuvant ICB in the presence of a higher antigen burden and intact tumor draining lymph nodes. Recent clinical trials evaluating neoadjuvant ICB with or without chemotherapy combinations in patients with resectable NSCLC led to improved pathological responses and longer event-free survival when neoadjuvant ICB was added to chemotherapy. Surgical outcomes were also supportive of this approach, with encouraging rates of pathological downstaging. Additionally, the availability of pre-treatment biopsy samples and post-treatment surgical resection tissues facilitates the conducting of correlative studies that continue to improve our understanding of the mechanisms of response and resistance to ICB. As long-term survival outcomes from ongoing clinical trials are awaited, several important questions require further investigation, including the optimal duration of neoadjuvant therapy, the clinical endpoints most predictive of long-term outcomes, and translational studies that should be investigated in future trial designs. Additionally, the optimal clinical management of patients with residual disease at the time of surgical resection and those who experience recurrence remains to be determined. In this review, we will (1) discuss the rationale behind neoadjuvant ICB-based therapy in NSCLC, (2) summarize the clinical data available thus far, and (3) highlight unanswered questions that need to be addressed in future studies to maximize the clinical benefits of this approach.

Elucidating the heterogeneity of immunotherapy response and immune-related toxicities by longitudinal ctDNA and immune cell compartment tracking in lung cancer.

Purpose: Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect -especially in the setting of stable disease-call for the development of molecularly-informed real-time minimally invasive predictive biomarkers. In addition to capturing tumor regression, liquid biopsies may be informative in evaluating immune-related adverse events (irAEs). Experimental design: We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response for each patient. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. Results: Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank p=0.0003) and overall survival (log-rank p=0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, peripheral blood T-cell repertoire reshaping, assessed by significant TCR clonotypic expansions and regressions were noted on-treatment. Conclusions: Molecular responses assist with interpretation of heterogeneous clinical responses especially for patients with stable disease. Our complementary assessment of the tumor and immune compartments by liquid biopsies provides an approach for monitoring of clinical benefit and immune-related toxicities for patients with NSCLC receiving immunotherapy. Statement of translational relevance: Longitudinal dynamic changes in cell-free tumor load and reshaping of the peripheral T-cell repertoire capture clinical outcomes and immune-related toxicities during immunotherapy for patients with non-small cell lung cancer.

Antibody-Drug Conjugates for Lung Cancer: Payloads and Progress.

Antibody Drug Conjugates (ADCs) are a novel class of therapeutic that structurally comprise an antibody directed at a tumor epitope connected via a linker to a cytotoxic payload that have shown significant antitumor activity across a range of malignancies including lung cancer. In this article we review the pharmacology of ADCs, describe results of trials with ADCs directed at targets in lung cancer including Trophoblast cell-surface antigen 2(TROP2), HER3, MET, Carcinoembryonic antigen-related cell adhesion molecular 5(CECAM-5) and HER2. Trastuzumab Deruxtecan (also known as DS-8201a or T-DXd) an ADC directed at HER2 recently became the first ADC to receive FDA approval in lung cancer, on the basis of its activity in tumors with HER2 mutations, demonstrated in the Destiny-Lung01 and Lung02 trials.

Adagrasib: a novel inhibitor for KRASG12C-mutated non-small-cell lung cancer.

Adagrasib is a recently US FDA-approved novel KRASG12C targeted therapy with clinical efficacy in patients with advanced, pretreated KRASG12C-mutated non-small-cell lung cancer. KRYSTAL-I reported an objective response rate of 42.9% with median duration of response of 8.5 months. Treatment-related adverse events were primarily gastrointestinal and occurred in 97.4% of patients, with grade 3+ treatment-related adverse events occurring in 44.8% of patients. This review details the preclinical and clinical data for adagrasib in the treatment of non-small-cell lung cancer. We also outline practical clinical administration guidelines for this novel therapy, including management of toxicities. Finally, we discuss the implications of resistance mechanisms, summarize other KRASG12C inhibitors currently in development and outline future directions for adagrasib-based combination therapies.

Adagrasib is a new oral (taken by mouth) treatment option for patients with non-small-cell lung cancer (NSCLC) with KRAS^G12C mutations. KRAS is a gene that regulates signaling pathways, which are responsible for cell growth and division. A mutation in KRAS can cause cells to multiply and cause cancer. Clinical trials have shown that adagrasib causes cancer reduction or resolution in 42.9% of people with NSCLC with KRAS^G12C mutations who receive the drug. Side effects of adagrasib are primarily gastrointestinal (nausea, vomiting, diarrhea). This review outlines guidelines for the management of side effects. New studies are looking at how adagrasib can be safely combined with other therapies to better treat NSCLC with KRAS^G12C mutations.

Five-Year Clinical Outcomes after Neoadjuvant Nivolumab in Resectable Non-Small Cell Lung Cancer.

PURPOSE: Neoadjuvant anti-PD-1 therapy has shown promise for resectable non-small cell lung cancer (NSCLC). We reported the first phase I/II trial of neoadjuvant nivolumab in resectable NSCLC, finding it to be safe and feasible with encouraging major pathological responses (MPR). We now present 5-year clinical outcomes from this trial, representing to our knowledge, the longest follow-up data for neoadjuvant anti-PD-1 in any cancer type. PATIENTS AND METHODS: Two doses of nivolumab (3 mg/kg) were administered for 4 weeks before surgery to 21 patients with Stage I-IIIA NSCLC. 5-year recurrence-free survival (RFS), overall survival (OS), and associations with MPR and PD-L1, were evaluated. RESULTS: With a median follow-up of 63 months, 5-year RFS and OS rates were 60% and 80%, respectively. The presence of MPR and pre-treatment tumor PD-L1 positivity (TPS ≥1%) each trended toward favorable RFS; HR, 0.61 [95% confidence interval (CI), 0.15-2.44] and HR, 0.36 (95% CI, 0.07-1.85), respectively. At 5-year follow-up, 8 of 9 (89%) patients with MPR were alive and disease-free. There were no cancer-related deaths among patients with MPR. In contrast, 6/11 patients without MPR experienced tumor relapse, and 3 died. CONCLUSIONS: Five-year clinical outcomes for neoadjuvant nivolumab in resectable NSCLC compare favorably with historical outcomes. MPR and PD-L1 positivity trended toward improved RFS, though definitive conclusions are limited by cohort size.

Association of Pathologic Complete Response and Long-Term Survival Outcomes Among Patients Treated With Neoadjuvant Chemotherapy or Chemoradiotherapy for NSCLC: A Meta-Analysis.

Introduction: Increased efforts to optimize outcomes for early stage NSCLC through the investigation of novel perioperative treatment strategies are ongoing. An emerging question is the role of pathologic response and its association with long-term clinical outcomes after neoadjuvant therapy. Methods: To investigate the association of pathologic complete response (pCR) and event-free survival (EFS) and overall survival (OS), we performed a systematic review and meta-analysis identifying studies reporting on the prognostic impact of pCR after neoadjuvant chemotherapy or chemoradiotherapy. To evaluate this prognostic value, an aggregated data (AD) meta-analyses was conducted to estimate the pooled hazard ratios (HRs) of EFS and OS for pCR. Using reconstructed individual patient data (IPD), pooled Kaplan-Meier curves were obtained to estimate this association in a more granular fashion. Subgroup analyses were conducted to further explore the impacts of study-level characteristics. Results: A total of 28 studies comprising 7011 patients were included in the AD meta-analysis, of which, IPD was available for 6274 patients from 24 studies. Results from our AD meta-analysis revealed a pooled pCR rate of 18% (95% confidence interval [CI]: 15%-21%), including significant improvements in OS (HR = 0.50, 95% CI: 0.45-0.56) and EFS (HR = 0.46, 95% CI: 0.37-0.57) on the basis of pCR status. Our IPD analysis revealed a 5-year OS rate of 63% (95% CI: 59.6-67.4) for patients with a pCR compared with 39% (95% CI: 34.5-44.5) for those without a pCR. Conclusions: pCR after neoadjuvant chemotherapy plus or minus radiotherapy is associated with significant improvements in EFS and survival for patients with resectable NSCLC.

Peripheral blood immune cell dynamics reflect antitumor immune responses and predict clinical response to immunotherapy.

BACKGROUND: Despite treatment advancements with immunotherapy, our understanding of response relies on tissue-based, static tumor features such as tumor mutation burden (TMB) and programmed death-ligand 1 (PD-L1) expression. These approaches are limited in capturing the plasticity of tumor-immune system interactions under selective pressure of immune checkpoint blockade and predicting therapeutic response and long-term outcomes. Here, we investigate the relationship between serial assessment of peripheral blood cell counts and tumor burden dynamics in the context of an evolving tumor ecosystem during immune checkpoint blockade. METHODS: Using machine learning, we integrated dynamics in peripheral blood immune cell subsets, including neutrophil-lymphocyte ratio (NLR), from 239 patients with metastatic non-small cell lung cancer (NSCLC) and predicted clinical outcome with immune checkpoint blockade. We then sought to interpret NLR dynamics in the context of transcriptomic and T cell repertoire trajectories for 26 patients with early stage NSCLC who received neoadjuvant immune checkpoint blockade. We further determined the relationship between NLR dynamics, pathologic response and circulating tumor DNA (ctDNA) clearance. RESULTS: Integrated dynamics of peripheral blood cell counts, predominantly NLR dynamics and changes in eosinophil levels, predicted clinical outcome, outperforming both TMB and PD-L1 expression. As early changes in NLR were a key predictor of response, we linked NLR dynamics with serial RNA sequencing deconvolution and T cell receptor sequencing to investigate differential tumor microenvironment reshaping during therapy for patients with reduction in peripheral NLR. Reductions in NLR were associated with induction of interferon-γ responses driving the expression of antigen presentation and proinflammatory gene sets coupled with reshaping of the intratumoral T cell repertoire. In addition, NLR dynamics reflected tumor regression assessed by pathological responses and complemented ctDNA kinetics in predicting long-term outcome. Elevated peripheral eosinophil levels during immune checkpoint blockade were correlated with therapeutic response in both metastatic and early stage cohorts. CONCLUSIONS: Our findings suggest that early dynamics in peripheral blood immune cell subsets reflect changes in the tumor microenvironment and capture antitumor immune responses, ultimately reflecting clinical outcomes with immune checkpoint blockade.

Has the Enemy "MET" Its Match? Subgroup Analysis Results from VISION Study.

Emerging therapies have recently received approval for the treatment of MET exon 14 skipping non-small cell lung cancer (NSCLC). Further characterization of these therapies, such as tepotinib, is needed to identify patient subgroups most likely to derive benefit from these novel agents. See related article by Le et al., p. 1117.

Post-operative ctDNA monitoring in stage I colon cancer: A case report.

Circulating tumor DNA (ctDNA) level monitoring after surgery for colon cancer has been studied in stage II and III colon cancer to risk-stratify patients for adjuvant therapy. However, there is less data regarding the role of this diagnostic tool in the management of stage I disease, where current recommended surveillance is limited to screening colonoscopy at one year. In this report, we describe the case of a 57-year-old man with stage I colon cancer who underwent complete resection with adequate lymph node surgical sampling, normal preoperative CEA and no evidence of metastatic disease on initial imaging. The patient elected to undergo serial ctDNA monitoring after surgery. Rising ctDNA levels, five months after resection, prompted cross-sectional imaging which demonstrated metastatic disease to the liver. The patient subsequently received five cycles of leucovorin, 5-fluorouracil, oxaliplatin, and irinotecan with bevacizumab (FOLFOXIRI-Bev) and definitive microwave ablation to the liver metastases, with resulting undetectable ctDNA levels. The patient's imaging and colonoscopy one-year post-operatively showed no evidence of disease, with ctDNA levels remaining undetectable. This report highlights the value of ctDNA monitoring in patients with early-stage colon cancer and suggests that further, large-scale studies may be warranted to determine its appropriate clinical use.

Immune-mediated ototoxicity associated with immune checkpoint inhibitors in patients with melanoma.

Immune checkpoint inhibitors (ICIs) are associated with a range of organ-specific toxicities known as immune-related adverse events (irAEs). Immune-mediated ototoxicity from ICIs is poorly described. Herein, we describe the clinical presentation, diagnostic evaluation and management of six ICI-treated patients who developed immune-mediated ototoxicity, identified by a multidisciplinary immune-related toxicity team. This is the largest case series to date and identifies bilateral high-frequency hearing loss and tinnitus as the most common reported symptoms and can be associated with abnormal speech reception thresholds and word recognition ability on audiogram in select patients. We propose multidisciplinary evaluation of patients with suspected otologic irAEs including referral to otolaryngology, audiometry evaluation±magnetic resonance imaging for evaluation of suspected immune-mediated ototoxicity.

Multimodal genomic features predict outcome of immune checkpoint blockade in non-small-cell lung cancer.

Despite progress in immunotherapy, identifying patients that respond has remained a challenge. Through analysis of whole-exome and targeted sequence data from 5,449 tumors, we found a significant correlation between tumor mutation burden (TMB) and tumor purity, suggesting that low tumor purity tumors are likely to have inaccurate TMB estimates. We developed a new method to estimate a corrected TMB (cTMB) that was adjusted for tumor purity and more accurately predicted outcome to immune checkpoint blockade (ICB). To identify improved predictive markers together with cTMB, we performed whole-exome sequencing for 104 lung tumors treated with ICB. Through comprehensive analyses of sequence and structural alterations, we discovered a significant enrichment in activating mutations in receptor tyrosine kinase (RTK) genes in nonresponding tumors in three immunotherapy treated cohorts. An integrated multivariable model incorporating cTMB, RTK mutations, smoking-related mutational signature and human leukocyte antigen status provided an improved predictor of response to immunotherapy that was independently validated.

Rescue therapy for patients with anti-PD-1-refractory Merkel cell carcinoma: a multicenter, retrospective case series.

Merkel cell carcinoma (MCC) is a rare but clinically aggressive cancer with a high mortality rate. In recent years, antibodies blocking the interactions among PD-1 and its ligands have generated durable tumor regressions in patients with advanced MCC. However, there is a paucity of data regarding effective therapy for patients whose disease is refractory to PD-1 pathway blockade. This retrospective case series describes a heterogeneous group of patients treated with additional immune checkpoint blocking therapy after MCC progression through anti-PD-1. Among 13 patients treated with anti-CTLA-4, alone or in combination with anti-PD-1, objective responses were seen in 4 (31%). Additionally, one patient with MCC refractory to anti-PD-1 and anti-CTLA-4 experienced tumor regression with anti-PD-L1. Our report - the largest case series to date describing this patient population - provides evidence that sequentially-administered salvage immune checkpoint blocking therapy can potentially activate anti-tumor immunity in patients with advanced anti-PD-1-refractory MCC and provides a strong rationale for formally testing these agents in multicenter clinical trials. Additionally, to the best of our knowledge, our report is the first to demonstrate possible anti-tumor activity of second-line treatment with a PD-L1 antibody in a patient with anti-PD-1-refractory disease.

Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.

Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (N = 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57-18.35; P = 0.007 and HR 6.91; 95% CI, 1.37-34.97; P = 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non-small cell lung cancer (N = 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies.Significance: Rapid and sensitive detection of circulating tumor DNA dynamic changes and T-cell expansion can be used to guide immune targeted therapy for patients with lung cancer.See related commentary by Zou and Meyerson, p. 1038.

PD-1 Blockade in Early-Stage Lung Cancer.

Early-stage non-small cell lung cancer is a potentially curable disease, but with relapse rates exceeding 50% with standard treatments, this is a patient population in critical need of therapy innovation. Immunotherapy with immune checkpoint blockade has revolutionized the treatment strategy for advanced lung cancer. However, the role of this therapy in earlier-stage disease is largely unknown. The study of immunotherapy in earlier-stage disease has many advantages, including assessment of pathologic response and incorporation of translational scientific analyses to evaluate antitumor immune responses. Multiple clinical trials are currently under way, with promising early results.