Smoking History as a Potential Predictor of Immune Checkpoint Inhibitor Efficacy in Metastatic Non-Small Cell Lung Cancer.
11 Jun 2021-Journal of the National Cancer Institute (Oxford University Press (OUP))-Vol. 113, Iss: 12, pp 1761-1769
TL;DR: In this article, a study was conducted on 644 advanced non-small cell lung cancer (NSCLC) patients treated with ICI monotherapy between April 2013 and September 2020 at the Dana-Farber Cancer Institute and Brigham and Women's Hospital.
Abstract: BACKGROUND Despite the therapeutic efficacy of immune checkpoint inhibitors (ICIs) in a subset of patients, consistent and easily obtainable predictors of efficacy remain elusive. METHODS This study was conducted on 644 advanced non-small cell lung cancer (NSCLC) patients treated with ICI monotherapy between April 2013 and September 2020 at the Dana-Farber Cancer Institute and Brigham and Women's Hospital. Patient smoking history, clinicopathological characteristics, tumor mutation burden (TMB) by clinical targeted next generation sequencing, and PD-L1 tumor proportion score (TPS) by immunohistochemistry were prospectively collected. The association of smoking history with clinical outcomes of ICI monotherapy in metastatic NSCLC patients was evaluated after adjusting for other potential predictors. All statistical tests were 2-sided. RESULTS Of 644 advanced NSCLC patients 105 (16.3%) were never smokers, 375 (58.2%) were former smokers (median pack-years = 28), and 164 (25.4%) were current smokers (median pack-years = 40). Multivariable logistic and Cox proportional hazards regression analyses suggested that doubling of smoking pack-years is statistically significantly associated with improved clinical outcomes of patients treated with ICI monotherapy (objective response rate odds ratio = 1.21, 95% confidence interval [CI] = 1.09-1.36, P < .001; progression-free survival hazard ratio = 0.92, 95% CI = 0.88-0.95, P < .001; overall survival hazard ratio = 0.94, 95% CI = 0.90-0.99, P = .01). Predictive models incorporating pack-years and PD-L1 TPS yielded additional information and achieved similar model performance compared to using TMB and PD-L1 TPS. CONCLUSIONS Increased smoking exposure had a statistically significant association with improved clinical outcomes in metastatic NSCLC treated with ICI monotherapy independent of PD-L1 TPS. Pack-years may serve as a consistent and readily obtainable surrogate of ICI efficacy when TMB is not available to inform prompt clinical decisions and allow more patients to benefit from ICIs.
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TL;DR: Agarwal et al. as discussed by the authors proposed a multilocus assays that provide integrative characteristics of the tumor genome, such as the analysis of tumor mutation burden or deficiency of DNA repair.
Abstract: The administration of many cancer drugs is tailored to genetic tests. Some genomic events, e.g., alterations of EGFR or BRAF oncogenes, result in the conformational change of the corresponding proteins and call for the use of mutation-specific compounds. Other genetic perturbations, e.g., HER2 amplifications, ALK translocations or MET exon 14 skipping mutations, cause overproduction of the entire protein or its kinase domain. There are multilocus assays that provide integrative characteristics of the tumor genome, such as the analysis of tumor mutation burden or deficiency of DNA repair. Treatment planning for non-small cell lung cancer requires testing for EGFR, ALK, ROS1, BRAF, MET, RET and KRAS gene alterations. Colorectal cancer patients need to undergo KRAS, NRAS, BRAF, HER2 and microsatellite instability analysis. The genomic examination of breast cancer includes testing for HER2 amplification and PIK3CA activation. Melanomas are currently subjected to BRAF and, in some instances, KIT genetic analysis. Predictive DNA assays have also been developed for thyroid cancers, cholangiocarcinomas and urinary bladder tumors. There is an increasing utilization of agnostic testing which involves the analysis of all potentially actionable genes across all tumor types. The invention of genomically tailored treatment has resulted in a spectacular improvement in disease outcomes for a significant portion of cancer patients.
17 citations
TL;DR: In this paper , the role of combination chemotherapy with immune checkpoint inhibitors (ICI) over ICI monotherapy in non-small cell lung cancer (NSCLC) remains underexplored.
Abstract: The role of combination chemotherapy with immune checkpoint inhibitors (ICI) (ICI-chemo) over ICI monotherapy (ICI-mono) in non-small cell lung cancer (NSCLC) remains underexplored. In this retrospective study of 1133 NSCLC patients, treatment with ICI-mono vs ICI-chemo associate with higher rates of early progression, but similar long-term progression-free and overall survival. Sequential vs concurrent ICI and chemotherapy have similar long-term survival, suggesting no synergism from combination therapy. Integrative modeling identified PD-L1, disease burden (Stage IVb; liver metastases), and STK11 and JAK2 alterations as features associate with a higher likelihood of early progression on ICI-mono. CDKN2A alterations associate with worse long-term outcomes in ICI-chemo patients. These results are validated in independent external (n = 89) and internal (n = 393) cohorts. This real-world study suggests that ICI-chemo may protect against early progression but does not influence overall survival, and nominates features that identify those patients at risk for early progression who may maximally benefit from ICI-chemo.
6 citations
TL;DR: In this paper, the authors show that CT scan-based evaluation is not able to accurately reflect the pathological response to immunotherapy and that smoking signature is a superior marker to programmed death-ligand 1 (PD-L1) expression in predicting the benefit of immunotherapy in non-small cell lung cancer patients.
Abstract: Background There is a paucity of biomarkers that can predict the degree of pathological response [e.g., pathological complete response (pCR) or major response (pMR)] to immunotherapy. Neoadjuvant immunotherapy provides an ideal setting for exploring responsive biomarkers because the pathological responses can be directly and accurately evaluated. Methods We retrospectively collected the clinicopathological characteristics and treatment outcomes of non-small cell lung cancer (NSCLC) patients who received neoadjuvant immunotherapy or chemo-immunotherapy followed by surgery between 2018 and 2020 at a large academic thoracic cancer center. Clinicopathological factors associated with pathological response were analyzed. Results A total of 39 patients (35 males and 4 females) were included. The most common histological subtype was lung squamous cell carcinoma (LUSC) (n=28, 71.8%), followed by lung adenocarcinoma (LUAD) (n=11, 28.2%). After neoadjuvant treatment, computed tomography (CT) scan-based evaluation showed poor agreement with the postoperatively pathological examination (weighted kappa =0.0225; P=0.795), suggesting the poor performance of CT scans in evaluating the response to immunotherapy. Importantly, we found that the smoking signature displayed a better performance than programmed death-ligand 1 (PD-L1) expression in predicting the pathological response (area under the curve: 0.690 vs. 0.456; P=0.0259), which might have resulted from increased tumor mutational burden (TMB) and/or microsatellite instability (MSI) relating to smoking exposure. Conclusions These findings suggest that CT scan-based evaluation is not able to accurately reflect the pathological response to immunotherapy and that smoking signature is a superior marker to PD-L1 expression in predicting the benefit of immunotherapy in NSCLC patients.
5 citations
TL;DR: The present meta-analysis confirms earlier evidence of the negative impact of smoking during radiation therapy, with or without chemotherapy, on treatment efficacy and radiation-induced toxicity as well as a negative impact on the efficacy of EGFR-TKIs and a positive impact onThe efficacy of checkpoint inhibitors.
Abstract: Simple Summary The impact of smoking on cancer treatment efficacy and toxicity regardless of cancer type was investigated in this meta-analysis. Smoking during radiotherapy/chemoradiotherapy was associated with worse outcomes and a higher risk for toxicity. Smoking during treatment with EGFR tyrosine kinase inhibitors in lung cancer patients was associated with a worse prognosis, whereas smoking was associated with better outcomes in patients treated with checkpoint inhibitors. No association between smoking and treatment efficacy of chemotherapy was observed, though with low certainty of evidence. Our results can be used by oncology and radiotherapy staff to give patients more convincing information on the benefits that can be derived from smoking cessation before cancer treatment. Abstract Aim: The aim of the present systematic review and meta-analysis was to summarize the current evidence on the potential impact of smoking during cancer treatment on treatment efficacy and toxicity irrespective of cancer type. Methods: A systematic literature search was performed using two electronic databases for potentially eligible studies. Only studies based on multivariable analysis for the association between smoking, compared to non-smokers (never or former), and treatment efficacy or toxicity were included. Pooled Hazard Ratios (HRs) or Odds Ratios (ORs) and corresponding 95% Confidence Intervals (CIs) were estimated through random-effects meta-analyses. Results: In total, 97 eligible studies were identified, of which 79 were eligible for the pooled analyses. Smoking during radiation therapy, with or without chemotherapy, was associated with an increased risk of locoregional recurrence (pooled HR: 1.56; 95% CI: 1.28–1.91 for radiation therapy; pooled HR: 4.28; 95% CI: 2.06–8.90 for chemoradiotherapy) and worse disease-free survival (pooled HR: 1.88; 95% CI: 1.21–2.90 for radiation therapy; pooled HR: 1.92; 95% CI: 1.41–2.62 for chemoradiotherapy) as well as a higher risk for radiation-induced toxicity (pooled OR: 1.84; 95% CI: 1.32–2.56 for radiation therapy; pooled OR: 2.43; 95% CI: 1.43–4.07 for chemoradiotherapy) with low-to-moderate certainty of evidence. Smoking during treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) in patients with lung cancer was associated with worse progression-free survival compared to non-smokers (pooled HR: 1.43; 95% CI: 1.14–1.80; moderate certainty of evidence), whereas smoking was associated with improved progression-free survival in patients treated with checkpoint inhibitors (HR: 0.70; 95% CI: 0.58–0.84; moderate certainty of evidence). No statistically significant associations were observed between smoking and treatment efficacy or toxicity to chemotherapy. Conclusion: The present meta-analysis confirms earlier evidence of the negative impact of smoking during radiation therapy, with or without chemotherapy, on treatment efficacy and radiation-induced toxicity as well as a negative impact of smoking on the efficacy of EGFR-TKIs and a positive impact on the efficacy of checkpoint inhibitors. The evidence is too weak to draw firm conclusions on the potential association between smoking and chemotherapy, whereas there is no evidence for pooled analyses regarding other types of systemic oncological therapy.
5 citations
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TL;DR: Nivolumab was associated with even greater efficacy than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression (≥1, ≥5%, and ≥10%) of the PD-1 ligand.
Abstract: BackgroundNivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, disrupts PD-1–mediated signaling and may restore antitumor immunity. MethodsIn this randomized, open-label, international phase 3 study, we assigned patients with nonsquamous non–small-cell lung cancer (NSCLC) that had progressed during or after platinum-based doublet chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. ResultsOverall survival was longer with nivolumab than with docetaxel. The median overall survival was 12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292 patients in the nivolumab group and 9.4 months (95% CI, 8.1 to 10.7) among 290 patients in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P=0.002). At 1 year, the overall survival rate was 51% (95% CI, 45 to 56) with nivolumab ve...
7,474 citations
TL;DR: Treatment efficacy was associated with a higher number of mutations in the tumors, and a tumor-specific T cell response paralleled tumor regression in one patient, suggesting that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.
Abstract: Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.
6,215 citations