Randomized open-label controlled study of cancer vaccine OSE2101 versus chemotherapy in HLA-A2-positive patients with advanced non-small-cell lung cancer with resistance to immunotherapy: ATALANTE-1.

BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint blockers (ICBs) ultimately progress either rapidly (primary resistance) or after durable benefit (secondary resistance). The cancer vaccine OSE2101 may invigorate antitumor-specific immune responses after ICB failure. The objective of ATALANTE-1 was to evaluate its efficacy and safety in these patients. PATIENTS AND METHODS: ATALANTE-1 was a two-step open-label study to evaluate the efficacy and safety of OSE2101 compared to standard-of-care (SoC) chemotherapy (CT). Patients with human leukocyte antigen (HLA)-A2-positive advanced NSCLC without actionable alterations, failing sequential or concurrent CT and ICB were randomized (2 : 1) to OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was overall survival (OS). Interim OS futility analysis was planned as per Fleming design. In April 2020 at the time of interim analysis, a decision was taken to prematurely stop the accrual due to coronavirus disease 2019 (COVID-19). Final analysis was carried out in all patients and in the subgroup of patients with ICB secondary resistance defined as failure after ICB monotherapy second line ≥12 weeks. RESULTS: Two hundred and nineteen patients were randomized (139 OSE2101, 80 SoC); 118 had secondary resistance to sequential ICB. Overall, median OS non-significantly favored OSE2101 over SoC {hazard ratio (HR) [95% confidence interval (CI)] 0.86 [0.62-1.19], P = 0.36}. In the secondary resistance subgroup, OSE2101 significantly improved median OS versus SoC [11.1 versus 7.5 months; HR (95% CI) 0.59 (0.38-0.91), P = 0.017], and significantly improved post-progression survival (HR 0.46, P = 0.004), time to Eastern Cooperative Oncology Group (ECOG) performance status deterioration (HR 0.43, P = 0.006) and Quality of Life Questionnaire Core 30 (QLQ-C30) global health status compared to SoC (P = 0.045). Six-month disease control rates and progression-free survival were similar between groups. Grade ≥3 adverse effects occurred in 11.4% of patients with OSE2101 and 35.1% in SoC (P = 0.002). CONCLUSIONS: In HLA-A2-positive patients with advanced NSCLC and secondary resistance to immunotherapy, OSE2101 increased survival with better safety compared to CT. Further evaluation in this population is warranted.

Phase II single-arm study of nivolumab and ipilimumab (Nivo/Ipi) in previously treated classical Kaposi sarcoma (cKS).

BACKGROUND: Classical Kaposi sarcoma (cKS) is a rare human herpesvirus 8-associated sarcoma with limited treatment options. We evaluated the efficacy and safety of nivolumab in combination with ipilimumab in patients with previously treated progressive cKS. PATIENTS AND METHODS: cKS patients with progressive disease after one or more lines of systemic therapy and measurable disease by positron emission tomography/computed tomography and/or physical examination received nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until progression or toxicity for a maximum of 24 months. The primary endpoint was overall response rate; secondary endpoints included 6-month progression-free survival (PFS) rate and safety. Immune correlates were explored using immunohistochemistry, DNA sequencing (596/648 genes) and RNA sequencing (whole transcriptome hybrid capture) of tumor specimens and matched blood. RESULTS: Eighteen male patients (median age 76.5 years) were enrolled between April 2018 and December 2020. At a median follow up of 24.4 months, overall response rate by RECIST v1.1 was 87%. Metabolic complete response as assessed by positron emission tomography/computed tomography was observed in 8 of 13 (62%) assessable patients. Some 6/13 achieved pathological complete response after treatment. In two patients, palliative limb amputation was prevented. Median PFS was not reached. The 6- month and 12-month PFS rate was 76.5% and 58.8%, respectively. Only four patients (22%) experienced grade 3-4 adverse events. The most frequent genomic alteration was biallelic copy number loss of the FOX1A gene. The majority of tumors carried a low tumor mutational burden, were microsatellite stable, mismatch repair proficient, did not express programmed death-ligand 1, and displayed only low lymphocytic infiltrates, rendering them immunologically 'cold'. CONCLUSIONS: This prospectively designed phase II study of nivolumab and ipilimumab demonstrates promising activity of this combination in progressive cKS representing a new treatment option in this population.

Incidence of lung cancer following pneumonia in smokers: a population-based study.

BACKGROUND: Pneumonia is more common in smokers compared with non-smokers. A high 1-year prevalence of lung cancer following hospitalization for pneumonia was demonstrated in heavy smokers. AIM: To assess the association between hospitalization for pneumonia among ever-smokers and subsequent lung cancer risk. DESIGN: Retrospective analysis. METHODS: The study cohort included all ever-smokers aged 55-80 hospitalized for pneumonia between the years 2010-15 covered by a large medical insurer in Israel. Controls were matched to cases by age in a 4:1 ratio. The primary outcome was the association between hospitalization for pneumonia and subsequent 1-year incidence of lung cancer, adjusted for gender, smoking status (past/current) and pack years. Pre-specified sensitivity analyses excluded heavy smokers (smoking history of more than 30 pack years) and patients diagnosed with lung cancer within 30 days of hospitalization, as they probably had clinical or radiological findings suggestive of lung cancer, making them ineligible for screening. RESULTS: Lung cancer was identified in 275 of 12 807 (2.1%) patients following hospitalization for pneumonia and in 44 of 51 228 (0.1%) controls (adjusted odds ratio 22.46, 95% CI 16.29-30.96, P < 0.001). Among patients hospitalized for pneumonia, 1-year lung cancer incidence remained high after excluding heavy smokers and patients diagnosed within 30 days of the index date (1.3% and 1.4%, respectively). CONCLUSIONS: Hospitalization for pneumonia is associated with high 1-year incidence of lung cancer in ever-smokers, supporting the important role of the widely used practice of performing follow up imaging post-pneumonia to exclude occult malignancy.

The Role of 18F-FDG PET/CT on Staging and Prognosis in Patients with Small Cell Lung Cancer.

BACKGROUND: We evaluated 18F-FDG PET/CT in small cell lung cancer (SCLC) staging and assessed metabolic (SUVmax, MTV and TLG) and morphologic (CTvol) variables as predictors for overall survival (OS) and progression-free survival (PFS). METHODS: Patients with newly diagnosed, histopathology-confirmed SCLC, who underwent 18F-FDG PET/CT were evaluated. A Cox proportional hazard model was used to determine the association between the primary tumour SUVmax, MTV, TLG and CTvol with OS and PFS. Similar evaluations were performed when hilar/mediastinal lymphadenopathy was included [total SUVmax (TSUVmax), total MTV (TMTV) and total TLG (TTLG)]. RESULTS: 55 patients were included. 18F-FDG PET/CT changed staging in 6/55 (10.9%) patients who were upstaged to extensive disease. TTLG (>443.8) was a significant variable for OS with HR=2.1 (CI 1.14-3.871, p=0.017). Patients with TTLG>443.8 had a median OS of 13.4 months compared to 25.7 months in patients with TTLG<443.8 (p=0.018). TMTV (>72.4) was significant for PFS with HR=2.3 (CI 1.11-4.8, p=0.025). A median PFS of 12.1 and 26.2 months was found with TMTV greater and less than 72.4, respectively (p=0.005). CONCLUSIONS: 18F-FDG PET/CT improved staging of patients with SCLC, and TTLG and TMTV can be used as prognostic variables for OS and PFS, respectively. KEY POINTS: • Identifying variables that predict the prognosis of patients with SCLC is important. • 18F-FDG PET/CT influences staging of patients with SCLC. • Metabolic parameters could be used as predictors for PFS and OS.

Plasma testosterone and beta HCG levels in the first twenty-four hours of life in neonates with cryptorchidism.

We determined serum concentrations of beta HCG and testosterone by specific radioimmunoassays in eight cryptorchid and 13 normal newborns in the first 24 h of life. Mean serum beta HCG concentration in the cryptorchid infants (18.9 +/- 9.7 miu/ml) did not differ significantly from the control group (26.7 +/- 7.6 miu/ml). Mean serum testosterone level in the cryptorchid newborns (271 +/- 27 ng/dl) also did not differ significantly from the control group (333 +/- 30 ng/dl). These data suggest beta HCG and testosterone concentrations on the first day of life are of the same magnitude in normal and cryptorchid infants.