Nikhil H. Ramaiya

Inflammatory myofibroblastic tumor (IMT) is a distinctive mesenchymal neoplasm characterized by a spindle-cell proliferation with an inflammatory infiltrate. Approximately half of IMTs carry rearrangements of the anaplastic lymphoma kinase (ALK) locus on chromosome 2p23, causing aberrant ALK expression. We report a sustained partial response to the ALK inhibitor crizotinib (PF-02341066, Pfizer) in a patient with ALK-translocated IMT, as compared with no observed activity in another patient without the ALK translocation. These results support the dependence of ALK-rearranged tumors on ALK-mediated signaling and suggest a therapeutic strategy for genomically identified patients with the aggressive form of this soft-tissue tumor. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).

IMPORTANCE: Programmed cell death 1 (PD-1) inhibitor-related pneumonitis is a rare but clinically serious and potentially life-threatening adverse event. Little is known about its incidence across different tumor types and treatment regimens. OBJECTIVE: To compare the incidence of PD-1 inhibitor-related pneumonitis among different tumor types and therapeutic regimens. DATA SOURCES: A PubMed search through November 10, 2015, and a review of references from relevant articles. For the PubMed search, the following keywords or corresponding Medical Subject Heading terms were used: nivolumab, pembrolizumab, and PD-1 inhibitor. STUDY SELECTION: Twenty-six original articles of PD-1 inhibitor trial results were identified. Among them, 20 studies of melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) were eligible for a meta-analysis. DATA EXTRACTION AND SYNTHESIS: The data were extracted by 1 primary reviewer and then independently reviewed by 2 secondary reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Comparisons of the incidence were based on marginal, exact generalized linear models with generalized estimating equations. MAIN OUTCOMES AND MEASURES: Incidence of all-grade and grade 3 or higher pneumonitis and pneumonitis-related deaths. RESULTS: Twenty studies of single-tumor-type trials of PD-1 inhibitor (12 melanoma studies, 5 NSCLC studies, and 3 RCC studies) (a total of 4496 unique patients) were included in the meta-analysis. The overall incidence of pneumonitis during PD-1 inhibitor monotherapy was 2.7% (95% CI, 1.9%-3.6%) for all-grade and 0.8% (95% CI, 0.4%-1.2%) for grade 3 or higher pneumonitis. The incidence was higher in NSCLC for all-grade (4.1% vs 1.6%; P = .002) and grade 3 or higher pneumonitis (1.8% vs 0.2%; P < .001) compared with melanoma. The incidence in RCC was higher than in melanoma for all-grade pneumonitis (4.1% vs 1.6%; P < .001) but not for grade 3 or higher pneumonitis. Four pneumonitis-related deaths were observed in patients with NSCLC in the monotherapy group. Pneumonitis was more frequent during combination therapy than monotherapy for all-grade (6.6% vs 1.6%; P < .001) and grade 3 or higher pneumonitis (1.5% vs 0.2%; P = .001) in melanoma, with 1 pneumonitis-related death during combination therapy. Multivariable analyses demonstrated higher odds of pneumonitis in NSCLC for all-grade (odds ratio [OR], 1.43; 95% CI, 1.08-1.89; P = .005) and grade 3 or higher pneumonitis (OR, 2.85; 95% CI, 1.60-5.08; P < .001) and in RCC for all-grade pneumonitis (OR, 1.59; 95% CI, 1.32-1.92; P < .001) compared with melanoma. The combination therapy had significantly higher odds than monotherapy for all-grade (OR, 2.04; 95% CI, 1.69-2.50; P < .001) and grade 3 or higher pneumonitis (OR, 2.86; 95% CI, 1.79- 4.35; P < .001). CONCLUSIONS AND RELEVANCE: The incidence of PD-1 inhibitor-related pneumonitis was higher in NSCLC and RCC and during combination therapy. These findings contribute to enhance awareness among clinicians and support further investigations to meet the clinical needs.

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) functions as a negative regulator of endogenous and vaccine-induced antitumor immunity. The administration of fully human anti-CTLA-4 blocking monoclonal antibodies to advanced-cancer patients increases immune-mediated tumor destruction in some subjects. Nonetheless, patients that respond also frequently manifest serious inflammatory pathologies, raising the possibility that the therapeutic and toxic effects of CTLA-4 blockade might be linked. Here we show that periodic infusions of anti-CTLA-4 antibodies after vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF (GVAX) generate clinically meaningful antitumor immunity without grade 3 or 4 toxicity in a majority of metastatic melanoma patients. The application of this sequential immunotherapy to advanced ovarian carcinoma patients also revealed that tumor destruction and severe inflammatory pathology could be dissociated, although further refinements are required to increase clinical responses and to minimize toxicity in this population. The extent of therapy-induced tumor necrosis was linearly related to the natural logarithm of the ratio of intratumoral CD8(+) effector T cells to FoxP3(+) regulatory T cells (Tregs) in posttreatment biopsies. Together, these findings help clarify the immunologic and clinical effects of CTLA-4 antibody blockade in previously vaccinated patients and raise the possibility that selective targeting of antitumor Tregs may constitute a complementary strategy for combination therapy.

Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) with four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (n = 1), hepatitis (n = 2), and uveitis (n = 2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8(+) and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7(+/-)/CD45RO(+) cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 instances of stable disease, and a disease-control rate of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. These findings provide a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of antiangiogenesis agents and immune checkpoint blockade.