CCTG BR34: A Randomized Phase 2 Trial of Durvalumab and Tremelimumab With or Without Platinum-Based Chemotherapy in Patients With Metastatic NSCLC.

INTRODUCTION: First-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition, or combination with chemotherapy. We compared outcomes with combination chemoimmunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC. METHODS: This open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naive, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum-doublet chemotherapy. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, and safety. RESULTS: A total of 301 patients were randomized. Median OS was 16.6 months (95% confidence interval [CI]: 12.6-19.1) with chemotherapy plus immunotherapy and 14.1 months (95% CI: 10.6-18.3) with immunotherapy (hazard ratio = 0.88, 90% CI: 0.67-1.16, p = 0.46). Median progression-free survival with chemotherapy plus immunotherapy was 7.7 months (95% CI: 5.5-8.5) and 3.2 months (95% CI: 2.7-5.1) with immunotherapy (hazard ratio = 0.67, 95% CI: 0.52-0.88). The overall response rate with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy (adjusted OR = 1.69, 95% CI: 1.04-2.76). The percentage of patients with grade 3 or higher adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of programmed death-ligand 1 expression and blood-based tumor mutation burden revealed no differential treatment effect on OS. CONCLUSIONS: The addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared with durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment.

Temporal evolution of submicron particles during extreme fireworks.

Evolution of submicron particles in terms of particle number concentration and mobility-equivalent diameter was measured during Diwali festival-specific intensive pyrotechnic displays in Varanasi over central Indo-Gangetic Plain (IGP). A scanning mobility particle sizer coupled with an optical particle sizer was used to fit in an overlapping size range, and particle number concentration was analyzed to have an insight into the new particle formation and subsequent evolution of particles from nucleation to accumulation mode. Further, variation in black carbon (BC) concentration and aerosol ionic composition was measured simultaneously. Frequent fluctuation in particle number concentration in and around Diwali festival was evidenced, primarily influenced by local emission sources and meteorology, with three distinct peaks in number concentrations (dN/dlogDp, 3.1-4.5 × 104 cm3) coinciding well with peak firework emission period (18:00-23:00 h). Submicron particle size distribution revealed a single peak covering a size range of 80-130 nm, and for all instances, number concentration maximum coincided with geometric mean minimum, indicating the emission primarily in the ultrafine range (< 0.1 µm). Interestingly, during peak firework emissions, besides rise in accumulation mode, an event of new particle formation was identified with increase in nucleation and small Aitken mode, before being dispersed to background aerosols. On an integral scale, a clear distinction was noted between a normal and an episodic event, with a definite shift in the formation of ultrafine particles compared with the accumulation mode. The BC diurnal profile was typical, with a prominent nocturnal peak (12.0 ± 3.9 µg m-3) corresponding to a decrease in the boundary layer height. A slight variation in maximum BC concentration (16.8 µg m-3) was noted in the night of the event coinciding well with firework emissions. An increase in some specific ionic species was also noted in combination with an increase in the overall cation to anion ratio, which was explained in terms of heterogeneous transformation of NOx and catalytic conversion of SO2. Graphical abstract Time-resolved evolution of particle size distribution during normal and episodic events.

Early discontinuation but not the timing of adjuvant therapy affects survival of patients with high-risk colorectal cancer: a population-based study.

BACKGROUND: Adjuvant therapy results in significant improvement in survival of patients with high-risk colorectal cancer. Little is known about the significance of timing and early discontinuation of adjuvant treatment in such patients. Our study aims to determine the prognostic impact of timing and completion of adjuvant therapy in patients with high-risk colorectal cancer. METHODS: Medical records of patients with stage III colon and stage II/III rectal cancer diagnosed between 1993 and 2000 in the province of Saskatchewan were reviewed. Cox proportional hazards models were used to analyze the impact of timing and completion of adjuvant therapy on survival. RESULTS: Six hundred sixty-three eligible patients with a median age of 66 years were identified. Sixty-five percent patients received adjuvant <56 days after surgery and 79% patients completed planned treatment. Median follow-up was 54.6 months. Five-year disease-free survival and overall survival of patients who received adjuvant therapy <56 days after surgery was 54.6% and 59.5%, respectively, compared with 51.9% and 57.1%, respectively, of patients who received therapy ≥56 days after surgery (P = NS). The five-year disease disease-free survival and overall survival of patients who completed planned treatment was 56.7% and 62.3%, respectively, compared with 42.1% and 45%, respectively, of patients who required early treatment discontinuation (P < .0001). On multivariate analysis, age ≥65 years, T4 tumor, grade 3 cancer, node-positive disease, rectal tumor, and early treatment discontinuation were identified as poor prognostic factors. CONCLUSIONS: Although time to adjuvant therapy following surgical resection did not impact the outcomes, failure to complete planned therapy was associated with adverse prognosis.