Response to tumor-infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+ T-myeloid cell networks in melanoma.

Adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell-intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8+ TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor-reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network-based biomarkers that could improve patient selection and guide the design of ACT clinical trials.

Randomized phase II selection trial of FLASH and conventional radiotherapy for patients with localized cutaneous squamous cell carcinoma or basal cell carcinoma: A study protocol.

Background: Cutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most prevalent skin cancers in western countries. Surgery is the standard of care for these cancers and conventional external radiotherapy (CONV-RT) with conventional dose rate (0.03-0.06 Gy/sec) represents a good alternative when the patients or tumors are not amenable to surgery but routinely generates skin side effects. Low energy electron FLASH radiotherapy (FLASH-RT) is a new form of radiotherapy exploiting the biological advantage of the FLASH effect, which consists in delivering radiation dose in milliseconds instead of minutes in CONV-RT. In pre-clinical studies, when compared to CONV-RT, FLASH-RT induced a robust, reproducible and remarkable sparing of the normal healthy tissues, while the efficacy on tumors was preserved. In this context, we aim to prospectively evaluate FLASH-RT versus CONV-RT with regards to toxicity and oncological outcome in localized cutaneous BCC and SCC. Methods: This is a randomized selection, non-comparative, phase II study of curative FLASH-RT versus CONV-RT in patients with T1-T2 N0 M0 cutaneous BCC and SCC. Patients will be randomly allocated to low energy electron FLASH-RT (dose rate: 220-270 Gy/s) or to CONV-RT arm. Small lesions (T1) will receive a single dose of 22 Gy and large lesions (T2) will receive 30 Gy in 5 fractions of 6 Gy over two weeks.The primary endpoint evaluates safety at 6 weeks after RT through grade ≥ 3 toxicity and efficacy through local control rate at 12 months. Approximately 60 patients in total will be randomized, considering on average 1-2 lesions and a maximum of 3 lesions per patients corresponding to the total of 96 lesions required. FLASH-RT will be performed using the Mobetron® (IntraOp, USA) with high dose rate functionality.LANCE (NCT05724875) is the first randomized trial evaluating FLASH-RT and CONV-RT in a curative setting.

Characteristics and Survival Outcomes of Patients With Metastatic RET Fusion-Positive Solid Tumors Receiving Non-RET Inhibitor Standards of Care in a Real-World Setting.

PURPOSE: RET fusions are oncogenic drivers across different solid tumors. However, the genomic landscape and natural history of patients with RET fusion-positive solid tumors are not well known. We describe the clinical characteristics of RET tyrosine kinase inhibitor (TKI)-naïve patients with RET fusion-positive solid tumors (excluding non-small-cell lung cancer [NSCLC]), treated in a real-world setting and assess the prognostic effect of RET fusions. METHODS: Data for RET TKI-naïve patients with metastatic solid tumors (excluding NSCLC) who had ≥one Foundation Medicine comprehensive genomic profiling test (January 1, 2011-March 31, 2022) were obtained from a deidentified nationwide (US-based) clinicogenomic database. The primary objective of this study was to compare the overall survival (OS) of patients with RET fusion-positive tumors versus matched patients with RET wild-type (RET-WT) tumors. Patients with RET-WT solid tumors were matched (4:1) to patients with RET fusion-positive tumors on the basis of preselected covariates. RESULTS: The study population included 26 patients in the RET fusion-positive cohort, 7,220 patients in the RET-WT cohort (before matching), and 104 patients in the matched RET-WT cohort. Co-occurring genomic alterations were rare in the RET fusion-positive cohort. Median OS was consistently lower in patients with RET fusion-positive tumors versus those with RET-WT tumors, using three different analyses (hazard ratios, 2.0, 1.7, and 2.2). CONCLUSION: These data suggest that RET fusions represent a negative prognostic factor in patients with metastatic solid tumors and highlight the need for wider genomic testing and use of RET-specific TKIs that could improve patient outcomes. Our study also highlights the value of real-world data when studying rare cancers or cancers with rare genomic alterations.

The impact of erythropoiesis-stimulating agents administration concomitantly with adjuvant anti-HER2 treatments on the outcomes of patients with early breast cancer: a sub-analysis of the ALTTO study.

PURPOSE: To assess whether erythropoiesis-stimulating agents (ESA) administration impacts the outcomes of patients with HER2-positive early breast cancer (EBC). METHODS: ALTTO (NCT00490139) patients were categorized by ESA use during adjuvant anti-HER2 treatment. Disease-free-survival (DFS), overall survival (OS), and time-to-distant recurrence (TTDR) were analyzed by ESA administration, with subgroup analyses according to prognostic factors. Log-rank tests and Cox modeling were performed. Adverse events (AEs) of ESA-interest were compared. RESULTS: Among 8381 patients recruited in ALTTO, 123 (1.5%) received ESA concomitantly with study treatment. The median age of patients receiving ESA was 54 years, 39.0% premenopausal, most had tumor size > 2 cm (56.9%), node-positive (58.5%), and positive estrogen receptor expression (61.8%). Median follow-up was shorter in the ESA group [6.1 years (IQR 5.3-7.0) vs. 6.9 years (6.0-7.1); p < 0.001]. There was no DFS difference by ESA administration (log-rank p = 0.70), with 3- and 7-year DFS of 89.2% (95% CI 81.8-93.8%) and 81.6% (71.4-88.5%) in ESA group vs. 88.3% (87.6-89.0%) and 80.0% (79.1-80.9%) in No-ESA group. In subgroup analyses, the interaction of ESA administration with menopausal status was statistically significant (unadjusted p = 0.024; stratified p = 0.033), favoring premenopausal women receiving ESA. We observed no significant association of ESA administration with OS (log-rank p = 0.57; 7-year OS in ESA 88.6% vs. 90.0% in non-ESA) or TTDR. ESA-interest AEs were experienced by eight (6.5%) patients receiving ESA and 417 (5.1%) in the No-ESA group (p = 0.41). CONCLUSION: ESA administration to patients receiving adjuvant anti-HER2 treatment for HER2-positive EBC was safe and not associated with a negative impact on survival outcomes.

PD-1-expressing macrophages and CD8 T cells are independent predictors of clinical benefit from PD-1 inhibition in advanced mesothelioma.

BACKGROUND: Few tissue biomarkers exist to date that could enrich patient with cancer populations to benefit from immune checkpoint blockade by programmed cell death protein 1/ligand-1 (PD-/L-1) inhibitors. PD-L1 expression has value in this context in some tumor types but is an imperfect predictor of clinical benefit. In malignant pleural mesothelioma, PD-L1 expression is not predictive of the benefit from PD-1 blockade. We aimed to identify novel markers in malignant pleural mesothelioma to select patients better. METHODS: We performed a multiplex-immune histochemistry analysis of tumor samples from the phase III PROMISE-meso study, which randomized 144 pretreated patients to receive either pembrolizumab or standard second-line chemotherapy. Our panel focused on CD8+T cell, CD68+macrophages, and the expression of PD-1 and PD-L1 on these and cancer cells. We analyzed single and double positive cells within cancer tissues (infiltrating immune cells) and in the stroma. In addition, we performed cell neighborhood analysis. The cell counts were compared with clinical outcomes, including responses, progression-free and overall survivals. RESULTS: We confirmed the absence of predictive value for PD-L1 in this cohort of patients. Furthermore, total CD8 T cells, CD68+macrophages, or inflammatory subtypes (desert, excluded, inflamed) did not predict outcomes. In contrast, PD-1-expressing CD8+T cells (exhausted T cells) and PD-1-expressing CD68+macrophages were both independent predictors of progression-free survival benefit from pembrolizumab. Patients with tumors simultaneously harboring PD1+T cells and PD-1+macrophages benefited the most from immune therapy. CONCLUSION: We analyzed a large cohort of patients within a phase III study and found that not only PD-1+CD8 T cells but also PD-1+CD68+ macrophages are predictive. This data provides evidence for the first time for the existence of PD-1+macrophages in mesothelioma and their clinical relevance for immune checkpoint blockade.

A phase 1 trial of adoptive transfer of vaccine-primed autologous circulating T cells in ovarian cancer.

We have previously shown that vaccination with tumor-pulsed dendritic cells amplifies neoantigen recognition in ovarian cancer. Here, in a phase 1 clinical study ( NCT01312376 /UPCC26810) including 19 patients, we show that such responses are further reinvigorated by subsequent adoptive transfer of vaccine-primed, ex vivo-expanded autologous peripheral blood T cells. The treatment is safe, and epitope spreading with novel neopeptide reactivities was observed after cell infusion in patients who experienced clinical benefit, suggesting reinvigoration of tumor-sculpting immunity.

European Epidemiology of Pleural Mesothelioma-Real-Life Data From a Joint Analysis of the Mesoscape Database of the European Thoracic Oncology Platform and the European Society of Thoracic Surgery Mesothelioma Database.

INTRODUCTION: Pleural mesothelioma (PM) is an aggressive malignancy with increasing prevalence and poor prognosis. Real-life data are a unique approach to reflect the reality of PM epidemiology, treatment, and prognosis in Europe. METHODS: A joint analysis of the European Thoracic Oncology Platform Mesoscape and the European Society of Thoracic Surgeons (ESTS) databases was performed to better understand the characteristics and epidemiology of PM, including histologic subtype, staging, and treatment. Overall survival (OS) was assessed, adjusting for parameters of clinical interest. RESULTS: The analysis included 2766 patients (Mesoscape: 497/10 centers/ESTS: 2269/77 centers). The primary histologic subtype was epithelioid (71%), with 57% patients on stages III to IV. Within Mesoscape, the patients received either multimodality (59%) or palliative intention treatment (41%). The median follow-up was 47.2 months, on the basis of 1103 patients (Mesoscape: 491/ESTS: 612), with 823 deaths, and median OS was 17.4 months. In multivariable analysis, female sex, epithelioid subtype, and lower stage were associated with longer OS, when stratifying by cohort, age, and Eastern Cooperative Oncology Group Performance Status. Within Mesoscape, multimodality treatment including surgery was predictive of longer OS (hazard ratio = 0.56, 95% confidence interval: 0.45-0.69), adjusting for sex, histologic subtype, and Eastern Cooperative Oncology Group Performance Status. Overall, surgical candidates with a macroscopic complete resection had a significantly longer median OS compared with patients with R2 (25.2 m versus 16.4 m; log-rank p < 0.001). CONCLUSIONS: This combined European Thoracic Oncology Platform/ESTS database analysis offers one of the largest databases with detailed clinical and pathologic outcome. Our finding reflects a benefit for selected patients that undergo multimodality treatment, including macroscopic complete resection, and represents a valuable resource to inform the epidemiology and treatment options for individual patients.

Assessment of RANK/RANK-L prevalence and clinical significance in NSCLC European Thoracic Oncology Platform Lungscape cohort and SPLENDOUR randomized clinical trial.

BACKGROUND: The primary objective of this study is to evaluate the clinical significance of RANK/L expression, in both a retrospective cohort of surgically resected stage I-III NSCLC (Lungscape) and a randomized clinical trial-cohort (SPLENDOUR) of advanced NSCLC treated with chemotherapy alone or in combination with denosumab. METHODS: RANK-L expression was assessed on tissue microarrays (TMAs) in Lungscape and whole sections in SPLENDOUR, using immunohistochemistry, with H-scores values > 0 indicating positivity. Prevalence of RANK positivity and its association with clinicopathological characteristics, and patient outcome was explored in a subset of the ETOP Lungscape cohort and in SPLENDOUR. Also investigated were the prevalence of RANK overexpression (proportion of positive cancer cells ≥ 50%) in the Lungscape cohort, and RANK-L in the SPLENDOUR trial. RESULTS: In the Lungscape cohort, RANK expression was assessed at a median follow-up of 46 months (N = 488 patients; 4 centers); 35% were female, 44/49/6% adenocarcinomas (AC)/squamous cell carcinomas (SCC)/other, 48/27/25% with stage I/II/III. Median RFS/TTR/OS were 58/Not reached/74 months. Prevalence of RANK expression was 31% (95%CI:27%-35%); significantly higher in AC: 50% (95%CI:43%-57%) vs SCC: 12% (95%CI:8%-16%) (p < 0.001); more frequent in females (42% vs 25%, p < 0.001) and tumors ≤ 4 cm (35.3% vs 23.3%, p = 0.0065). No association with outcome was found. In the SPLENDOUR trial (463 patients), the prevalence of membranous and cytoplasmic RANK positivity was 34% (95%CI:30%-38%) and 9% (95%CI:7%-12%), respectively, while prevalence for RANK-L was 5% (95%CI:3%-7%) and 36% (95%CI:31%-40%), respectively. Cytoplasmic RANK-L positivity was more common among females (47% vs 31%, p = 0.001) and in non-SCC histology (45% vs 10%, p < 0.0001). At the pre-specified 1% significance level, no prognostic or predictive effect was found. CONCLUSIONS: Both cohorts indicate that RANK expression is more common in adenocarcinoma/non-squamous NSCLC and in female patients. No prognostic effect is found, and in the clinical trial involving addition of denosumab to chemotherapy no predictive effect is detected.

Immune checkpoint inhibitor therapy and outcomes from SARS-CoV-2 infection in patients with cancer: a joint analysis of OnCovid and ESMO-CoCARE registries.

BACKGROUND: As management and prevention strategies against COVID-19 evolve, it is still uncertain whether prior exposure to immune checkpoint inhibitors (ICIs) affects COVID-19 severity in patients with cancer. METHODS: In a joint analysis of ICI recipients from OnCovid (NCT04393974) and European Society for Medical Oncology (ESMO) CoCARE registries, we assessed severity and mortality from SARS-CoV-2 in vaccinated and unvaccinated patients with cancer and explored whether prior immune-related adverse events (irAEs) influenced outcome from COVID-19. FINDINGS: The study population consisted of 240 patients diagnosed with COVID-19 between January 2020 and February 2022 exposed to ICI within 3 months prior to COVID-19 diagnosis, with a 30-day case fatality rate (CFR30) of 23.6% (95% CI 17.8 to 30.7%). Overall, 42 (17.5%) were fully vaccinated prior to COVID-19 and experienced decreased CFR30 (4.8% vs 28.1%, p=0.0009), hospitalization rate (27.5% vs 63.2%, p<0.0001), requirement of oxygen therapy (15.8% vs 41.5%, p=0.0030), COVID-19 complication rate (11.9% vs 34.6%, p=0.0040), with a reduced need for COVID-19-specific therapy (26.3% vs 57.9%, p=0.0004) compared with unvaccinated patients. Inverse probability of treatment weighting (IPTW)-fitted multivariable analysis, following a clustered-robust correction for the data source (OnCovid vs ESMO CoCARE), confirmed that vaccinated patients experienced a decreased risk of death at 30 days (adjusted OR, aOR 0.08, 95% CI 0.01 to 0.69).Overall, 38 patients (15.8%) experienced at least one irAE of any grade at any time prior to COVID-19, at a median time of 3.2 months (range 0.13-48.7) from COVID-19 diagnosis. IrAEs occurred independently of baseline characteristics except for primary tumor (p=0.0373) and were associated with a significantly decreased CFR30 (10.8% vs 26.0%, p=0.0462) additionally confirmed by the IPTW-fitted multivariable analysis (aOR 0.47, 95% CI 0.33 to 0.67). Patients who experienced irAEs also presented a higher median absolute lymphocyte count at COVID-19 (1.4 vs 0.8 109 cells/L, p=0.0098). CONCLUSION: Anti-SARS-CoV-2 vaccination reduces morbidity and mortality from COVID-19 in ICI recipients. History of irAEs might identify patients with pre-existing protection from COVID-19, warranting further investigation of adaptive immune determinants of protection from SARS-CoV-2.

Prognostic impact of tumour mutational burden in resected stage I and II lung adenocarcinomas from a European Thoracic Oncology Platform Lungscape cohort.

BACKGROUND: The primary objective of this study is to evaluate tumor mutational burden (TMB), its associations with selected clinicopathological and molecular characteristics as well as its clinical significance, in a retrospective cohort of surgically resected stage I-II lung adenocarcinomas, subset of the ETOP Lungscape cohort. METHODS: TMB was evaluated on tumor DNA extracted from resected primary lung adenocarcinomas, based on FoundationOne®CDx (F1CDx) genomic profiling, centrally performed at the University Hospital Zurich. The F1CDx test sequences the complete exons of 324 cancer-related genes and detects substitutions, insertions and deletions (indels), copy number alterations and gene rearrangements. In addition, the genomic biomarkers TMB and microsatellite instability (MSI) are analyzed. RESULTS: In the Lungscape cohort, TMB was assessed in 78 surgically resected lung adenocarcinomas from two Swiss centers (62 % males, 55 %/45 % stage I/II). Median TMB was 7.6 Muts/Mb, with TMB high (≥10 Muts/Mb) in 40 % of cases (95 %CI:29 %-52 %). The most frequently mutated genes were TP53/KRAS/EGFR/MLL2 detected in 58 %/38 %/33 %/30 % of samples, respectively. TMB was significantly higher among males (TMB high: 50 % vs 23 % in females, p = 0.032), as well as among current/former smokers (TMB high: 44 % vs 8 % in never smokers, p = 0.023). Furthermore, TMB was significantly higher in TP53 mutated than in non-mutated patients (TMB high: 60 % vs 12 %, p < 0.001), while it was higher in EGFR non-mutated patients compared to EGFR mutated (TMB high: 48 % vs 23 %, p = 0.049). At a median follow-up time of 56.1 months (IQR:38.8-72.0), none of the three outcome variables (OS, RFS, TTR) differed significantly by TMB status (all p-values > 5 %). This was also true when adjusting for clinicopathological characteristics. CONCLUSIONS: While presence of TP53 mutations and absence of EGFR mutations are associated with high TMB, increased TMB had no significant prognostic impact in patients with resected stage I/II lung adenocarcinoma beyond T and N classification, in both unadjusted and adjusted analyses.

Outcomes of patients with small and node-negative HER2-positive early breast cancer treated with adjuvant chemotherapy and anti-HER2 therapy-a sub-analysis of the ALTTO study.

BACKGROUND: Patients with small node-negative HER2-positive breast cancer are commonly treated with paclitaxel and 1 year of adjuvant trastuzumab. We performed a sub-analysis of the ALTTO trial to explore the long-term outcomes of patients with small node-negative tumours. METHODS: The ALTTO trial randomised 8381 patients with early HER2-positive BC treated with adjuvant chemotherapy (anthracycline/taxane- or taxane/carboplatin-based), to trastuzumab (T), lapatinib (L), their sequence (T → L) or their combination (L + T). Patients with tumours ≤3 cm and node-negative were included in this sub-analysis. RESULTS: A total of 2821 patients were analysed (median follow-up of 7 years). The median age was 52 years, and most patients had tumours ≤2 cm (64.3%). The 7-year disease-free survival (DFS) was 88.1% (95% CI: 86.7-89.3%). DFS was similar for arms T, T + L and T⟶L and significantly lower for arm L (stratified log-rank P = 0.031). The 7-year overall survival rate was 95.9% (95% CI: [95.0-96.6%) and the 7-year time-to-distant recurrence was 93.4% (95% CI: 92.3-94.4%). CONCLUSION: With most patients treated with anthracycline-based regimens, ALTTO shows that patients with small tumours treated with trastuzumab and concomitant chemotherapy have excellent long-term outcomes, similar to those of the APT trial. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00490139.

Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial.

BACKGROUND: Pembrolizumab is a standard-of-care for advanced non-small-cell lung cancer (NSCLC). We assessed pembrolizumab as adjuvant therapy for completely resected stage IB-IIIA NSCLC. METHODS: In this randomised, triple-blind, phase 3 trial (PEARLS/KEYNOTE-091), patients were recruited from 196 medical centres in 29 countries. Eligible patients were aged 18 years or older, with completely resected, pathologically confirmed stage IB (tumours of ≥4 cm in diameter), II, or IIIA NSCLC per the American Joint Committee on Cancer staging system (7th edition) of any histology or PD-L1 expression level, and an Eastern Cooperative Oncology Group performance status of 0 or 1; adjuvant chemotherapy was to be considered for stage IB disease and was strongly recommended for stage II and IIIA disease, according to national and local guidelines. Using a central interactive voice-response system, eligible participants were randomly assigned (1:1), using a minimisation technique and stratified by disease stage, previous adjuvant chemotherapy, PD-L1 expression, and geographical region, to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks for up to 18 cycles. Participants, investigators, and analysts were masked to treatment assignment. Dual primary endpoints were disease-free survival in the overall population and in the population with PD-L1 tumour proportion score (TPS) of 50% or greater. Efficacy was assessed in the intention-to-treat (ITT) population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants randomly assigned to treatment who received at least one dose of study treatment. Here we report results of the second interim analysis, prespecified to occur when approximately 118 disease-free survival events had occurred in the PD-L1 TPS of 50% or greater population. This study is registered with ClinicalTrials.gov, NCT02504372, and is active but not recruiting. FINDINGS: Between Jan 20, 2016, and May 6, 2020, 1177 (60%) of 1955 screened participants were randomly assigned to pembrolizumab (n=590, including n=168 with PD-L1 TPS of ≥50%) or placebo (n=587; including n=165 with PD-L1 TPS of ≥50%) and included in the ITT population. Median follow-up as of data cutoff (Sept 20, 2021) for this interim analysis was 35·6 months (IQR 27·1-45·5). In the overall population, median disease-free survival was 53·6 months (95% CI 39·2 to not reached) in the pembrolizumab group versus 42·0 months (31·3 to not reached) in the placebo group (HR 0·76 [95% CI 0·63-0·91], p=0·0014). In the PD-L1 TPS of 50% or greater population, median disease-free survival was not reached in either the pembrolizumab group (95% CI 44·3 to not reached) or the placebo group (95% CI 35·8 to not reached; HR 0·82 [95% CI 0·57-1·18]; p=0·14). Grade 3 or worse adverse events occurred in 198 (34%) of 580 participants who received pembrolizumab and 150 (26%) of 581 participants who received placebo. Grade 3 or worse events that occurred in at least ten participants in either treatment group were hypertension (35 [6%]) and pneumonia (12 [2%]) with pembrolizumab and hypertension (32 [6%]) with placebo. Serious adverse events occurred in 142 (24%) participants in the pembrolizumab group and 90 (15%) in the placebo group; serious adverse events that occurred in more than 1% of participants were pneumonia (13 [2%]), pneumonitis (12 [2%]), and diarrhoea (seven [1%]) with pembrolizumab and pneumonia (nine [2%]) with placebo. Treatment-related adverse events led to death in four (1%) participants treated with pembrolizumab (one due to both cardiogenic shock and myocarditis, one due to both septic shock and myocarditis, one due to pneumonia, and one due to sudden death) and in no participants treated with placebo. INTERPRETATION: Pembrolizumab significantly improved disease-free survival compared with placebo and was not associated with new safety signals in completely resected, PD-L1-unselected, stage IB-IIIA NSCLC. Pembrolizumab is potentially a new treatment option for stage IB-IIIA NSCLC after complete resection and, when recommended, adjuvant chemotherapy, regardless of PD-L1 expression. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Alectinib for the treatment of pretreated RET-rearranged advanced NSCLC: Results of the ETOP ALERT-lung trial.

BACKGROUND: Alectinib, a highly selective next generation ALK-inhibitor, has exhibited potent anti-tumour activity in RET-rearranged NSCLC in the preclinical stage. METHODS: ALERT-lung is a single-arm, phase II trial evaluating the activity of alectinib for the treatment of pretreated RET-rearranged advanced NSCLC. Alectinib was administered orally, 600 mg, twice per day until progression, refusal or unacceptable toxicity (treatment could continue beyond progression, if patient was deriving clinical benefit). Patient recruitment closed prematurely due to discouraging results for alectinib in a phase I/II study in the same indication. RESULTS: All 14 patients who enrolled until the premature accrual closure, received at lease one dose of alectinib. Among them, median age was 61 years, majority (71 %) was female, never smokers, of ECOG PS 1. No objective response (complete or partial response) was recorded. Of the 13 evaluable patients, three (23 %) achieved and maintained disease stabilisation for 24 weeks. Up to 31 March 2021 (median follow-up 15.9 months), 12 PFS-events (92 %) were observed, with median PFS of 3.7 months (95 % C.I.: 1.8 - 7.3 months). Overall, three deaths (23 %) were reported. Seven patients (50 %) experienced grade ≥ 3 adverse events, while three discontinued treatment due to erythema multiforme of grade 3, related to alectinib. No treatment-related serious adverse event was reported. CONCLUSIONS: Accrual into our trial was terminated early in response to other reports of limited activity of alectinib in patients with RET-fusion NSCLC and the emergence of more potent selective RET-inhibitors. Also in our trial, alectinib did not show the expected potential for anti-tumour activity in NSCLC.

A prognostic score for patients with malignant pleural mesothelioma (MPM) receiving second-line immunotherapy or chemotherapy in the ETOP 9-15 PROMISE-meso phase III trial.

INTRODUCTION: Clinical and laboratory parameters associated with response for patients with advanced pre-treated malignant pleural mesothelioma (MPM) are lacking. We aimed to identify prognostic and predictive markers among patients with relapsed MPM who were randomised into the ETOP 9-15 PROMISE-meso phase III trial, evaluating pembrolizumab and chemotherapy. METHODS: Baseline clinical and laboratory parameters were investigated for prognostic or predictive value on progression-free survival (PFS) and overall survival (OS) in a retrospective analysis, based on the full cohort of 144 MPM patients. These consisted of immune-inflammatory indexes (neutrophil-lymphocyte ratio [NLR], systemic immune-inflammatory index [SII], lactate dehydrogenase [LDH]) along with other already known prognostic baseline characteristics and laboratory values. Cut-offs were chosen independently of outcome. Based on Cox multivariable analysis for PFS in the whole cohort, a risk factor model was built to illustrate the prognostic stratification of patients by the combination of the derived independent prognostic factors, taking into account the EORTC score, a validated prognostic score in MPM. All models were stratified by histology and adjusted by treatment. RESULTS: In the stratified multivariable analysis in the whole cohort, high SII (hazard ratio (HR) 2.06; 95%CI 1.39-3.05) and low haemoglobin (HR 1.62; 95%CI 1.06-2.50) were associated with worse PFS. Based on these two prognostic factors, a mesothelioma risk score (MRS) was constructed with three PFS risk prognosis categories: favourable, intermediate and poor with 0, 1 and 2 risk factors, respectively (corresponding percent of cohort: 24%, 34% and 42% and median PFS: 5.8, 4.2 and 2.1 months). The derived MRS stratified the prognosis for PFS and OS, overall and within each of the EORTC groups. No significant predictors of treatment benefit were identified. CONCLUSIONS: The proposed MRS is prognostic of patient outcome and it fine-tunes the prognosis of patients with pre-treated MPM alone or when used with the already established EORTC score.

Essential medicines list in national cancer control plans: a secondary analysis from a global study.

With the advent of innovative therapeutics for and the rising costs of cancer management, low-income and middle-income countries face increasing challenges to deliver effective and sustainable health care. Understanding of how countries are selecting and prioritising essential cancer interventions is poor, including in the formulation of policies for essential medicines. We did an in-depth subanalysis from a global dataset of national cancer control plans (NCCPs), aiming to identify possible determinants of inclusion of policies related to essential medicines in the NCCP. The results showed poor global comprehensiveness of NCCPs, and substantial deficits in policies for financial hardships due to cancer care, specifically for access to cancer medicines. Specification of budget allocations, policy of protection from catastrophic health expenditure, and national treatment guidelines in the NCCPs contributed to more consistent policies on essential cancer medicines. The bedrock to deliver effective cancer programmes resides in the assurance of comprehensive, consistent, and coherent policy formulation, to orient resource selection and health investments, ultimately delivering equitable health for all.

Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy.

Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here, we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an IFN-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4+ and CD8+ T cells. LDRT elicited predominantly CD4+ cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand RAE1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide, and immune checkpoint blockade to patients with immune-desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4+ cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low T cell-infiltrated tumors. SIGNIFICANCE: Low-dose radiation reprogrammed the tumor microenvironment of tumors with scarce immune infiltration and together with immunotherapy induced simultaneous mobilization of innate and adaptive immunity, predominantly CD4+ effector T cells, to achieve tumor control dependent on NKG2D. The combination induced important responses in patients with metastatic immune-cold tumors.This article is highlighted in the In This Issue feature, p. 1.

Combined, patient-level, analysis of two randomised trials evaluating the addition of denosumab to standard first-line chemotherapy in advanced NSCLC - The ETOP/EORTC SPLENDOUR and AMGEN-249 trials.

INTRODUCTION: The efficacy of adding denosumab to standard first-line chemotherapy for advanced NSCLC patients has been evaluated in two separate randomised trials (SPLENDOUR and AMGEN-249). In this pooled analysis, we will assess the combination-treatment effect in the largest available population, in order to conclude about the potential impact of denosumab in NSCLC. METHODS: Both trials included in this combined analysis, were randomised (SPLENDOUR 1:1, AMGEN-249 2:1) multi-centre trials stratified by histology, bone metastasis, geographical region and for SPLENDOUR only, ECOG PS. Cox proportional hazards models, were used to assess the treatment effect with respect to overall survival (OS; primary endpoint) and progression-free survival (PFS; secondary endpoint). Heterogeneity between trials was assessed, and subgroup analyses were performed. RESULTS: The pooled analysis was based on 740 randomised patients (SPLENDOUR:514; AMGEN-249:226), with 407 patients in the chemotherapy-denosumab arm and 333 in the chemotherapy-alone arm. In the chemotherapy-denosumab arm, at a median follow-up of 22.0 months, 277 (68.1%) deaths were reported with median OS 9.2 months (95%CI:[8.0-10.7]), while in the chemotherapy-alone arm, with similar median follow-up of 20.3 months, 230 (69.1%) deaths with median OS 9.9 months (95%CI:[8.2-11.2]). No significant denosumab effect was found (HR = 0.98; 95%CI:[0.82-1.18]; P = 0.85). Among subgroups, interaction was found between treatment and histology subtypes (P = 0.020), with a statistically significant benefit in the squamous group (HR = 0.70; 95%CI:[0.49-0.98]; P = 0.038), from 7.6 to 9.0 months median OS. With respect to PFS, 363 (89.2%) and 298 (89.5%) events were reported in the chemotherapy-denosumab and chemotherapy-alone arms, respectively, with corresponding medians 4.8 months (95%CI:[4.4-5.3]) and 4.9 months (95%CI:[4.3-5.4]). HR for PFS was 0.97(95%CI:[0.83-1.15]; P = 0.76), indicating that no significant denosumab benefit existed for PFS. CONCLUSION: In this pooled analysis, no statistically significant improvement was shown in PFS/OS with the combination of denosumab and chemotherapy for advanced NSCLC and no meaningful benefit in any of the subgroups.

SARS-CoV-2 seroprevalence in healthcare workers of a Swiss tertiary care centre at the end of the first wave: a cross-sectional study.

OBJECTIVE: To assess the SARS-CoV-2 transmission in healthcare workers (HCWs) using seroprevalence as a surrogate marker of infection in our tertiary care centre according to exposure. DESIGN: Seroprevalence cross-sectional study. SETTING: Single centre at the end of the first COVID-19 wave in Lausanne, Switzerland. PARTICIPANTS: 1874 of 4074 responders randomly selected (46% response rate), stratified by work category among the 13 474 (13.9%) HCWs. MAIN OUTCOME MEASURES: Evaluation of SARS-CoV-2 serostatus paired with a questionnaire of SARS-CoV-2 acquisition risk factors internal and external to the workplace. RESULTS: The overall SARS-CoV-2 seroprevalence rate among HCWs was 10.0% (95% CI 8.7% to 11.5%). HCWs with daily patient contact did not experience increased rates of seropositivity relative to those without (10.3% vs 9.6%, respectively, p=0.64). HCWs with direct contact with patients with COVID-19 or working in COVID-19 units did not experience increased seropositivity rates relative to their counterparts (10.4% vs 9.8%, p=0.69 and 10.6% vs 9.9%, p=0.69, respectively). However, specific locations of contact with patients irrespective of COVID-19 status-in patient rooms or reception areas-did correlate with increased rates of seropositivity (11.9% vs 7.5%, p=0.019 and 14.3% vs 9.2%, p=0.025, respectively). In contrast, HCWs with a suspected or proven SARS-CoV-2-infected household contact had significantly higher seropositivity rates than those without such contacts (19.0% vs 8.7%, p<0.001 and 42.1% vs 9.4%, p<0.001, respectively). Finally, consistent use of a mask on public transportation correlated with decreased seroprevalence (5.3% for mask users vs 11.2% for intermittent or no mask use, p=0.030). CONCLUSIONS: The overall seroprevalence was 10% without significant differences in seroprevalence between HCWs exposed to patients with COVID-19 and HCWs not exposed. This suggests that, once fully in place, protective measures limited SARS-CoV-2 occupational acquisition within the hospital environment. SARS-CoV-2 seroconversion among HCWs was associated primarily with community risk factors, particularly household transmission.

Prognostic Impact of KRAS G12C Mutation in Patients With NSCLC: Results From the European Thoracic Oncology Platform Lungscape Project.

INTRODUCTION: KRAS mutations, the most frequent gain-of-function alterations in NSCLC, are currently emerging as potential predictive therapeutic targets. The role of KRAS-G12C (Kr_G12C) is of special interest after the recent discovery and preclinical analyses of two different Kr_G12C covalent inhibitors (AMG-510, MRTX849). METHODS: KRAS mutations were evaluated in formalin-fixed, paraffin-embedded tissue sections by a microfluidic-based multiplex polymerase chain reaction platform as a component of the previously published European Thoracic Oncology Platform Lungscape 003 Multiplex Mutation study, of clinically annotated, resected, stage I to III NSCLC. In this study, -Kr_G12C mutation prevalence and its association with clinicopathologic characteristics, molecular profiles, and postoperative patient outcome (overall survival, relapse-free survival, time-to-relapse) were explored. RESULTS: KRAS gene was tested in 2055 Lungscape cases (adenocarcinomas: 1014 [49%]) with I or II or III stage respective distribution of 53% or 24% or 22% and median follow-up of 57 months. KRAS mutation prevalence in the adenocarcinoma cohort was 38.0% (95% confidence interval (CI): 35.0% to 41.0%), with Kr_G12C mutation representing 17.0% (95% CI: 14.7% to 19.4%). In the "histologic-subtype" cohort, Kr_G12C prevalence was 10.5% (95% CI: 9.2% to 11.9%). When adjusting for clinicopathologic characteristics, a significant negative prognostic effect of Kr_G12C presence versus other KRAS mutations or nonexistence of KRAS mutation was identified in the adenocarcinoma cohort alone and in the "histologic-subtype" cohort. For overall survival in adenocarcinomas, hazard ratio (HR)G12C versus other KRAS is equal to 1.39 (95% CI: 1.03 to 1.89, p = 0.031) and HRG12C versus no KRAS is equal to 1.32 (95% CI: 1.03 to 1.69, p = 0.028) (both also significant in the "histologic-subtype" cohort). For time-to-relapse, HRG12C versus other KRAS is equal to 1.41 (95% CI: 1.03 to 1.92, p = 0.030). In addition, among all patients, for relapse-free survival, HRG12C versus no KRAS is equal to 1.27 (95% CI: 1.04 to 1.54, p = 0.017). CONCLUSIONS: In this large, clinically annotated stage I to III NSCLC cohort, the specific Kr_G12C mutation is significantly associated with poorer prognosis (adjusting for clinicopathologic characteristics) among adenocarcinomas and in unselected NSCLCs.

Progression-Free and Overall Survival for Concurrent Nivolumab With Standard Concurrent Chemoradiotherapy in Locally Advanced Stage IIIA-B NSCLC: Results From the European Thoracic Oncology Platform NICOLAS Phase II Trial (European Thoracic Oncology Platform 6-14).

INTRODUCTION: The NICOLAS study is the first completed single-arm phase II trial in stage III NSCLC evaluating hierarchically first the safety and then the efficacy of adding nivolumab concurrently to standard definitive concurrent chemoradiotherapy. The safety end point was reported earlier; here, we present the efficacy results. METHODS: Stage IIIA-B unresectable treatment-naive patients with NSCLC received three cycles of platinum-based chemotherapy and concurrent radiotherapy (66 Gy, 33 fractions), along with nivolumab (360 mg, 3-weekly). Nivolumab was continued as monotherapy consolidation for a maximum of 1 year (480 mg, 4-weekly). The primary end point was 1-year progression-free survival (PFS), with a target improvement compared with historical data of at least 15%, from 45% to 60%. To test this efficacy hypothesis, a sample size of 74 assessable patients provided a power of 83% with a one-sided alpha of 5%. RESULTS: A total of 79 patients were enrolled with a median follow-up of 21.0 months (interquartile range: 15.8-25.8 mo) for the primary PFS analysis. A total of 35.4% of the patients had stage IIIA, and 63.3% had stage IIIB disease. The 1-year PFS was 53.7% (95% confidence interval [CI]: 42.0%-64.0%) and the median PFS was 12.7 months (95% CI: 10.1-22.8 mo). Because 37 PFS events occurred in the first year posttreatment among the first 74 assessable patients, a 1-year PFS rate of at least 45% could not be rejected (p = 0.23). At an extended follow-up (median 32.6 mo), 37 deaths have been recorded, with a median overall survival (OS) of 38.8 months (95% CI: 26.8 mo-not estimable) and a 2-year OS rate of 63.7% (95% CI: 51.9%-73.4%). The OS of patients with stage IIIA disease was found to be significantly higher than patients with stage IIIB disease, with a 2-year OS of 81% and 56%, respectively (p = 0.037). CONCLUSIONS: PFS and OS are arithmetically higher in studies involving the same population. However, on the basis of the formal hierarchical efficacy analysis, we could not reject that the 1-year PFS rate is at least 45%.