Salvage surgery for locally recurrent lung cancer: options for patients who have been treated with high dose radiotherapy

A combination of chemotherapy and high dose radiotherapy is the cornerstone of the treatment of locally-advanced non-small cell lung cancer (NSCLC). For selected patients with early stage NSCLC, stereotactic body radiation therapy (SBRT, also known as SABR, stereotactic ablative radiotherapy) is a good option. Unfortunately, metastases can occur in patients following these treatments. However, in some patients, the recurrence remains localized to the previous irradiated area, so-called local recurrence. For selected patients with such a recurrence, radical salvage surgery - a treatment modality with curative intent - is an option. In this article we describe two patients with local recurrence after high dose radiotherapy, who were subsequently treated operatively. We also discuss which subset of lung cancer patients should be selected for this type of surgery

Interim results of a phase II single arm trial combining afatinib with cetuximab in patients with EGFRex20ins positive NSCLC.

9112 Background: Epidermal growth factor receptor exon 20 insertions (EGFRex20ins) are identified in 4-10% of all EGFR mutations in non-small cell lung cancer (NSCLC) and are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). Treatment options are limited. A case series showed that dual EGFR blockade with afatinib and cetuximab can induce tumor responses with manageable toxicity. We report on the first seventeen EGFRex20ins patients treated with afatinib in combination with cetuximab. Methods: In this Simon’s two stage, single-arm, phase II trial, patients with advanced NSCLC harboring an EGFRex20ins mutation were treated with afatinib 40 mg once daily, in combination with cetuximab 500 mg/m2, every two weeks, in five institutions in the Netherlands. Supportive medication consisted of minocycline, loperamide and skin creams. No previous line of treatment was required and asymptomatic brain metastases were allowed. The primary endpoint was disease control rate (DCR) after 18 weeks of treatment. Secondary endpoints included safety, response rate (RR), duration of response (DOR) and progression-free survival (PFS). Patients were treated until progression or unacceptable toxicity. A Simon’s two stage optimal design was used in order to minimize the number of patients being treated in the event that the regimen proves to be inactive. The estimated sample size of the first stage was 17 patients. At least four successes were required to enter stage 2 of the trial (alpha = 0.10; power = 0.90). Results: Eighteen patients were enrolled between Jan 2019 and Aug 2020; one patient did not meet the eligibility criteria due to absence of measurable disease. Median age was 66.0 years, 65% female, 53% never smoker. 47% of patients were treated as first-line therapy. Median prior lines of treatment was 1 (range 0-6). 53% received prior platinum-based chemotherapy. The primary endpoint was met as disease control was achieved by 10 patients (59%) after 18 weeks of treatment. Median PFS was 5.5 months. Best responses were partial (n = 8, RR 47%), stable (n = 7) or progressive disease (n = 2). Four patients were still on treatment at the cut-off date (Feb 2021). Most common treatment-related adverse events (TRAEs) were diarrhea (71%), rash (65%), paronychia (59%) and dry skin (53%). Grade III TRAEs were reported in 59% of all patients. Grade III TRAEs ≥ 10% included rash (n = 3; 18%) and diarrhea (n = 3; 18%). No grade IV toxicity was observed. One patient died due to respiratory failure after infusion of study medication, probably related to disease progression, possibly treatment related. 82% of patients required a dose reduction. Rate of treatment discontinuation due to AEs was 12% (n = 2). Conclusions: Combination treatment with afatinib and cetuximab demonstrated antitumor activity with a DCR of 59% at 18 weeks and a 47% RR, with manageable toxicity. Clinical trial information: NCT03727724. </jats:p

Updated overall survival (OS) and genomic analysis from a single-arm phase II study of dabrafenib (D) + trametinib (T) in patients (pts) with <i>BRAF</i> V600E mutant (Mut) metastatic non-small cell lung cancer (NSCLC).

9593 Background: The phase II multicenter, open label study, which evaluated efficacy and safety of D+T in pretreated (cohort B) and treatment (tx)-naive (cohort C) pts with BRAF V600E mut metastatic NSCLC. The results of the primary analysis have been reported. Here, we present an updated survival and genomic analysis data for cohorts B and C. Methods: Tx-naïve (n=36) and pretreated (n=57) pts received D 150 mg twice daily + T 2 mg daily. Primary objective: ORR, secondary objectives: PFS, DOR, OS, safety, tolerability and PK of D+T. Tumor samples were centrally tested using a NGS cancer targeted panel (Oncomine Dx Target test, ThermoFisher Scientific). KM curves and Cox regression models were used to evaluate potential associations between baseline genomic landscape and pt efficacy endpoints. Results: As of June 22, 2019, median (m) follow-up was 16.3 mo in tx-naïve pts and 16.6 mo in pretreated pts. mOS was 17.3 mo (95% CI: 12.3, 40.2; 3 yr OS: 40%) and 18.2 mo (95% CI: 14.3, 28.6; 3 yr OS: 33%) with 14/36 and 11/57 pts alive in tx naïve and pretreated pts respectively. Detailed efficacy results are presented in table. 57/62 tumor samples retrieved from 93 pts were centrally confirmed to have BRAF V600E mut; 5 non-confirmed BRAF tumors (3 pts had PR) were positive for c-MET T1010I, KRAS G12V, ALK fusion and 2 JAK3 S493C with mPFS of 13.8 mo while OS was NE due to limited data points. Eleven pts (18%) had concomitant somatic mutations and/or genetic alterations in addition to BRAF V600E mut: 4 had alterations within PI3K pathway4 had concomitant mutations at IDH1 R132X, and 3 pts had additional mutations at BRAF G466V, KRAS G13C and a cMET exon 14 skipping, respectively. Pts whose tumors had concomitant genetic alterations, particularly in PI3K pathway, showed a trend towards decreased PFS and OS. Safety profile was similar to previous reported results. Conclusions: This update of BRF113928 study reported improved and durable OS rates with combination D+T in BRAF V600E mut NSCLC pts. Co-occurring genetic alterations might influence clinical outcomes of such pts. Further validation is ongoing to corroborate current genomic findings. Clinical trial information: NCT01336634 . [Table: see text] </jats:p

Artificial intelligence in digital pathology approach identifies the predictive impact of tertiary lymphoid structures with immune-checkpoints therapy in NSCLC.

9065 Background: The presence of Tertiary Lymphoid Structures (TLS) in multiple cancer types has been recognized as a potential predictive biomarker for response to immune-checkpoint blockade. However, there is no standardized method to quantify their presence. In this context, Artificial Intelligence (AI)-based assessment of histology images may well contribute to improve reproducibility, accuracy and speed of TLS quantification. Methods: We developed an automated workflow for quantification of TLS on digitized H&amp;E slides through A) pixel-level classification of tissue using supervised artificial neural networks model, B) object-level cell classification of candidate TLS regions, C) merging the two approaches for curation and validation of TLS versus non-TLS regions. 433 advanced stage non-small cell lung cancer (NSCLC) patients treated with first or subsequent line of anti-PD-(L)1 single agent at DFCI were included in this study. Results: TLS were detected in 37% (n = 161) of the patients H&amp;E slides, with the highest score of 4.7 TLS per mm2 (interquartile range: Q1 = 0, Q2 = 0, Q3 = 0.03 TLS/mm2). TLS density (per mm2) was significantly higher in surgically resected (n = 246; TLSPOS= 49%) compared to bioptic samples (n = 187; TLSPOS= 21%). No association was observed between TLS and tumor mutational burden (TMB) or PD-L1 protein expression as continuous variables. Among clinically actionable mutations, EGFR (all subtypes) mutated patients (n = 38) had a significantly lower number of TLS compared to patients without EGFR mutations. Patients with ≥ 0.01 TLS/mm2 had a significantly higher objective response rate (32% vs 22%, p = 0.03), a significantly longer median progression-free survival (PFS, 4.8 vs 2.7 months, HR: 0.73, 95% CI: 0.59-0.90, p = 0.004), and a significantly improved median overall survival (OS, 16.5 vs 12.5 months, HR: 0.72, 95% CI: 0.57-0.92, p = 0.008). In multivariable analysis, after adjusting for PD-L1 (≥ vs &lt; 50%), TMB (≥ vs &lt; 10 mu/Mb), sex, age, ECOG score, smoking and line of treatment, TLS/mm2 (≥ vs &lt; 0.01) levels were found to be an independent positive predictive factor for both PFS (HR:0.69, 95% CI: 0.54-0.88, p = 0.003) and OS (HR: 0.70, 95% CI: 0.52-0.93, p = 0.01). Conclusions: These findings suggest that TLS status is an independent predictor of immunotherapy effectiveness in NSCLC, with predictive value similar to that of PD-L1 expression and TMB. This novel AI system has potential for automated identification and quantification of the TLS on digital histopathological slides, and could be utilized in a standard pathology workflow with relative ease. These findings are currently being validated in other solid tumors and cohorts. </jats:p

Digital quantification of lymphocytic infiltration on routine H&amp;E images and immunotherapy response in non–small cell lung cancer.

9066 Background: Current biomarker(s) for immuno-oncology (IO) therapy response prediction in lung cancer are limited. Additional predictive biomarkers are useful to help refine patient selection and guide precision therapy. Methods: Biopsy and surgical specimens stained with hematoxylin-eosin (H&amp;E) were subjected to whole-slide scanning for 446 advanced stage non-small cell lung cancer (NSCLC) treated with single agent immune check point inhibitors (ICI). A machine learning model was trained on H&amp;E images for classification of tumor infiltrating lymphocytes (TILs), tumor cells, and stromal cells in specific tissue types. Results: TIL levels were found to be highly variable, with a range of 12 to 4270 cells/mm2, and median of 319 (Q1 = 159, Q3 = 681). TIL levels were assessed on tissue samples from multiple organs which had shown primary or metastatic NSCLC, and were similar across all specimen sites except the liver, for which median TIL levels were significantly lower, at 90 cells/mm2. There was no correlation between tumor mutational burden (TMB) and TIL levels, while high TIL levels were correlated with high PD-L1 (≥ 50%) expression. Patients who experienced a partial/complete response to ICI therapy had a trend to higher median TILs compared to those who had progressive/stable disease (350 versus 310 cells/mm2, P = 0.09). In a multivariable analysis after controlling for covariates (incl. sex, age, cigarette smoking, ECOG, PD-L1, TMB &amp; treatment line), a higher TIL level (≥ 250 cells/mm2) was an independent predictor of IO response for both progression-free survival (PFS; HRadj 0.70; 95% CI, 0.55 - 0.89; P = 0.003) and overall survival (HRadj 0.73; 95% CI, 0.56 - 0.95; P = 0.02). In a ROC analysis considering single biomarkers, PD-L1 had the highest AUC (0.68, P &lt; 0.001), while TIL (AUC = 0.53, P = 0.08) and TMB (AUC = 0.55, P = 0.05) had similar AUC values for classifying responders from non-responders based on objective response rate. Using weighted linear regression approach to combine the biomarkers, paired PD-L1/TMB had the greatest AUC (0.70, P &lt; 0.001) compared to PD-L1 single assay. In the PD-L1 negative (&lt; 1%, N = 50) subgroup, TIL levels had superior predictive performance for classification of IO responders (AUC = 0.77, P = 0.02) compared to TMB (AUC = 0.57, P = 0.3), such that patients with a high TIL level (≥ 250 cells/mm2) had an improved PFS (median PFS: 2.7 vs 2.2 months; HR = 0.48; 95% CI, 0.26 - 0.87; P = 0.02). Conclusions: Digital TIL quantification with use of machine learning is feasible. TIL levels appear to be a robust and independent biomarker of likelihood of response to IO treatment in NSCLC, especially in the PD-L1 negative subgroup. The findings of this study are under validation in additional lung cancer cohorts. </jats:p

The global burden of adolescent and young adult cancer in 2019: a systematic analysis for the Global Burden of Disease Study 2019

BACKGROUND: In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. METHODS: Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. FINDINGS: There were 1·19 million (95% UI 1·11-1·28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59·6 [54·5-65·7] per 100 000 person-years) and high-middle SDI countries (53·2 [48·8-57·9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14·2 [12·9-15·6] per 100 000 person-years) and middle SDI (13·6 [12·6-14·8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23·5 million (21·9-25·2) DALYs to the global burden of disease, of which 2·7% (1·9-3·6) came from YLDs and 97·3% (96·4-98·1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. INTERPRETATION: Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. FUNDING: Bill & Melinda Gates Foundation, American Lebanese Syrian Associated Charities, St Baldrick's Foundation, and the National Cancer Institute