BackgroundIn this phase I/II trial, we evaluated the safety and effectiveness of pembrolizumab, with or without concurrent radiotherapy (RT), for lung and liver lesions from metastatic non-small cell lung cancer (mNSCLC).MethodsPatients with lung or liver lesions amenable to RT plus at least one additional non-contiguous lesion were included regardless of programmed death-ligand 1 (PD-L1) status. Pembrolizumab was given at 200 mg every 3 weeks for up to 32 cycles with or without concurrent RT. Metastatic lesions were treated with stereotactic body RT (SBRT; 50 Gy in 4 fractions) if clinically feasible or with traditionally fractionated RT (45 Gy in 15 fractions) if not. The primary end point was the best out-of-field lesion response, and a key secondary end point was progression-free survival (PFS).ResultsThe median follow-up time was 20.4 months. One hundred patients (20 phase I, 80 phase II) were evaluable for toxicity, and 72 phase II patients were evaluable for treatment response. No patients in the phase I group experienced grade 4–5 events; in the phase II group, two had grade 4 events and nine had grade 3 events. The ORR in the combined-modality cohort (irrespective of RT schema) was 22%, vs 25% in the pembrolizumab group (irrespective of receipt of salvage RT) (p=0.99). In the concurrent pembrolizumab+RT groups, the out-of-field ORRs were 38% in the pembrolizumab+SBRT group and 10% in the pembrolizumab+traditional RT group. When examining the pembrolizumab-alone patients, the out-of-field ORRs were 33% in those designated to receive salvage SBRT (if required) and 17% for salvage traditional RT. In all patients, the median PFS for pembrolizumab alone was 5.1 months (95% CI 3.4 to 12.7 months), and pembrolizumab/RT (regardless of schema) was 9.1 months (95% CI 3.6 to 18.4 months) (p=0.52). An exploratory analysis revealed that for patients with low PD-L1 expression, the median PFS was 4.6 vs 20.8 months for pembrolizumab with and without RT, respectively (p=0.004).ConclusionsConcurrent immunoradiotherapy for mNSCLC is safe, although larger trials are required to address which patients benefit most from RT.Trial registration numberNCT02444741.

IMPORTANCE Consensus is lacking as to the optimal radiotherapy dose and fractionation schedule for treating bone metastases.OBJECTIVE To assess the relative efficacy of high-dose, single-fraction stereotactic body radiotherapy (SBRT) vs standard multifraction radiotherapy (MFRT) for alleviation of pain in patients with mostly nonspine bone metastases. DESIGN, SETTING, AND PARTICIPANTSThis prospective, randomized, single-institution phase 2 noninferiority trial conducted at a tertiary cancer care center enrolled 160 patients with radiologically confirmed painful bone metastases from September 19, 2014, through June 19, 2018. Patients were randomly assigned in a 1:1 ratio to receive either single-fraction SBRT (12 Gy for Ն4-cm lesions or 16 Gy for <4-cm lesions) or MFRT to 30 Gy in 10 fractions. MAIN OUTCOMES AND MEASURESThe primary end point was pain response, defined by international consensus criteria as a combination of pain score and analgesic use (daily morphine-equivalent dose). Pain failure (ie, lack of response) was defined as worsening pain score (Ն2 points on a 0-to-10 scale), an increase in morphine-equivalent opioid dose of 50% or more, reirradiation, or pathologic fracture. We hypothesized that SBRT was noninferior to MFRT. RESULTSIn this phase 2 noninferiority trial of 96 men and 64 women (mean [SD] age, 62.4 [10.4] years), 81 patients received SBRT and 79 received MFRT. Among evaluable patients who received treatment per protocol, the single-fraction group had more pain responders than the MFRT group (complete response + partial response) at 2 weeks (34 of 55 [62%] vs 19 of 52 [36%]) (P = .01), 3 months (31 of 43 [72%] vs 17 of 35 [49%]) (P = .03), and 9 months (17 of 22 [77%] vs 12 of 26 [46%]) (P = .03). No differences were found in treatment-related toxic effects or quality-of-life scores after SBRT vs MFRT; local control rates at 1 and 2 years were higher in patients receiving single-fraction SBRT.CONCLUSIONS AND RELEVANCE Delivering high-dose, single-fraction SBRT seems to be an effective treatment option for patients with painful bone metastases. Among evaluable patients, SBRT had higher rates of pain response (complete response + partial response) than did MFRT and thus should be considered for patients expected to have relatively long survival.

BackgroundDespite some successes with checkpoint inhibitors for treating cancer, most patients remain refractory to treatment, possibly due to the inhibitory nature of the tumor stroma that impedes the function and entry of effector cells. We devised a new technique of combining immunotherapy with radiotherapy (XRT), more specifically low-dose XRT, to overcome the stroma and maximize systemic outcomes.MethodsWe bilaterally established 344SQ lung adenocarcinoma tumors in 129Sv/Ev mice. Primary and secondary tumors were irradiated with either high-dose or low-dose of XRT with systemic anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte associated protein 4 administration. Survival and tumor growth were monitored for the various groups, and secondary tumors were phenotyped by flow cytometry for immune populations. Tumor growth factor-beta (TGF-β) cytokine levels were assessed locally after low-dose XRT, and specific immune-cell depletion experiments were conducted to identify the major contributors to the observed systemic antitumor effect.ResultsThrough our preclinical and clinical studies, we observed that when tumor burden was high, there was a necessity of combining high-dose XRT to ‘prime’ T cells at the primary tumor site, with low-dose XRT directed to secondary (metastatic) tumors to ‘modulate the stroma’. Low-dose XRT improved the antitumor outcomes of checkpoint inhibitors by favoring M1 macrophage polarization, enhancing natural killer (NK) cell infiltration, and reducing TGF-β levels. Depletion of CD4+ T cells and NK cells abrogated the observed antitumor effect.ConclusionOur data extend the benefits of low-dose XRT to reprogram the tumor environment and improve the infiltration and function of effector immune cells into secondary tumors.

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To assess the impact of antiviral prophylaxis during the first 3 months after transplantation on the frequency, timing, and outcome of cytomegalovirus (CMV) pneumonia during the first year, 541 adult allogeneic blood and marrow transplant recipients were evaluated. Thirty-four patients (6.3%) developed 35 episodes of CMV pneumonia at a mean of 188 days after transplantation, with an associated mortality rate of 76%. Twenty-six episodes (74%) occurred late (after day 100). Of the patients with late CMV pneumonia almost all (92%) had chronic graft vs. host disease or had received T cell-depleted transplants. Fourteen late CMV pneumonias (54%) were associated with serious concurrent infections, and 100% of these episodes were fatal. In conclusion, although the frequency of CMV pneumonia in the early posttransplantation period may be substantially reduced by prophylaxis, CMV continues to be a major cause of morbidity and mortality in the late period. Some subsets of patients need more prolonged surveillance and prophylaxis and/or preemptive therapy.