The Armed Conflict and the Impact on Patients With Cancer in Ukraine: Urgent Considerations.

On February 24, 2022, a war began within the Ukrainian borders. At least 3.0 million Ukrainian inhabitants have already fled the country. Critical infrastructure, including hospitals, has been damaged. Children with cancer were urgently transported to foreign countries, in an effort to minimize interruption of their life-saving treatments. Most adults did not have that option. War breeds cancer-delaying diagnosis, preventing treatment, and increasing risk. We project that a modest delay in care of only 4 months for five prevalent types of cancer will lead to an excess of over 3,600 cancer deaths in the subsequent years. It is critical that we establish plans to mitigate that risk as soon as possible.

Discovery of targeted expression data for novel antibody-based and chimeric antigen receptor-based therapeutics in soft tissue sarcomas using RNA-sequencing: clinical implications.

Recent failure of phase 3 trials and paucity of druggable oncogenic drivers hamper developmental therapeutics in sarcomas. Antibody-based therapeutics, like antibody-drug conjugates (ADCs) and chimeric antigen receptor (CAR)-based therapeutics, have emerged as promising strategies for anticancer drug delivery. The efficacy of these novel therapies is highly dependent on expression of the antibody target. We used RNA sequencing data from Cancer Genome Atlas (TCGA) to analyze expression of target antigens in sarcoma subtypes including dedifferentiated liposarcoma (DDLPS; n = 50), uterine leiomyosarcoma (ULMS; n = 27), leiomyosarcoma (STLMS; n = 53), undifferentiated pleomorphic sarcoma (UPS; n = 44), myxofibrosarcoma (MFS; n = 17), synovial sarcoma (SS; n = 10), and malignant peripheral nerve sheath tumor (MPNST; n = 5). We searched published literature and clinicaltrial.gov for ADC targets, bispecific antibodies, immunotoxins, radioimmunoconjugates, SPEAR T-cells, and CAR's that are in clinical trials. CD70 expression was significantly higher in DDLPS, UPS, and MFS than SS and STLMS. CDH3 expression was greater in LMS and ULMS than UPS (P < 0.001), MFS (P < 0.001), and DDLPS (P < 0.001). ERBB2 expression was low; however, it was overexpressed in MPNST when compared with UPS (P < 0.001), and MFS (P < 0.01). GPNMB was highly expressed in most sarcomas, with the exception of SS. LRRC15 also appeared to be a relevant target, especially in UPS. MSLN expression was relatively low except in SS and MPNST. PDGFRA was also highly expressed in most sarcomas with the exception of ULMS and STLMS. TNFRSF8 seems to be most appropriate in DDLPS, as well as MFS. AXL was expressed especially in MFS and STLMS. Sarcoma subtypes express multiple target genes relevant for ADCs, SPEAR T-cells and CAR's, warranting further clinical validation and evaluation.

Phase I Study of the BRAF Inhibitor Vemurafenib in Combination With the Mammalian Target of Rapamycin Inhibitor Everolimus in Patients With BRAF-Mutated Malignancies.

PURPOSE: Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway represents a mechanism of primary and acquired resistance to BRAF-targeted therapy, but the two pathways have yet to be cotargeted in humans. We performed a phase I study to evaluate the safety and activity of the BRAF inhibitor vemurafenib in combination with the mammalian target of rapamycin inhibitor everolimus in BRAF-mutated advanced solid tumors. PATIENTS AND METHODS: We performed a 3+3 dose-escalation study with escalating doses of both oral (PO) vemurafenib administered twice a day and PO everolimus administered daily. RESULTS: Twenty patients with advanced cancers were enrolled. The median adult age was 64 years (range, 17 to 85 years); two pediatric patients were 10 and 13 years old. Patients were heavily pretreated with prior BRAF or MEK inhibitors (n = 11), phase I clinical trial therapy (n = 10), surgery (n = 18), radiation therapy (n = 11), and chemotherapy (n=13). One of the two pediatric patients initially experienced grade 3 rash, but after dermatologic intervention, the patient remains on trial with partial response and no dose reduction at time of analysis. Four dose-limiting toxicities (rash, n = 1; fatigue, n = 3) were observed at dose level 2. Therefore, dose level 1 (vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily) was the maximum-tolerated dose. Overall, four patients (22%) had a partial response and nine patients (50%) had stable disease as best response. One pediatric patient with pleomorphic xanthroastrocytoma remains on protocol with continued clinical response after 38 cycles. CONCLUSION: The combination of vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily is safe and well tolerated and has activity across histologies, with partial responses noted in advanced non-small-cell lung cancer, melanoma, optic nerve glioma, and xanthroastrocytoma, including patients who previously experienced progression on BRAF and/or MEK inhibitor therapy. Further investigation in a larger cohort of molecularly matched patients is warranted.

Phase I combination of pazopanib and everolimus in PIK3CA mutation positive/PTEN loss patients with advanced solid tumors refractory to standard therapy.

PURPOSE: Combining agents that block both the VEGF and PI3K/AKT/mTOR pathways may be synergistic. We explored a novel dosing schedule to assess safety, toxicity and activity in patients with advanced solid tumors. PATIENTS AND METHODS: Patients with refractory solid tumors were enrolled in a modified 3 + 3 Phase I dose escalation study to determine dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of a combination of everolimus (mTOR inhibitor) and pazopanib (tyrosine kinase inhibitor with anti-VEGF activity). An expansion cohort selected for patients with molecular alterations in the PI3K/AKT/mTOR pathway. RESULTS: Sixty-two patients were enrolled; median age was 60 years; 29 were women. The MTD was pazopanib 600 mg every other day (QOD) alternating with everolimus 10 mg PO QOD. DLTs were grade 3 thrombocytopenia and creatinine elevation. Most common toxicities of any grade were thrombocytopenia, transaminitis, leukopenia/neutropenia and lipid abnormalities. Among 52 patients evaluable for response, the clinical benefit rate (CBR) was 27 % (14/52) including four partial responses (PR), and 10 stable disease (SD) ≥6 months. 26 of 45 patients evaluated for molecular alterations had at least one alteration in the PI3K/AKT/mTOR pathway. CBR in patients with a matched alteration was 27 % (7/26) versus 26 % (5/19) for patients without an alteration (p = 0.764). However, 64% of those with CBR and molecular testing done for alteration in the PI3K/AKT/mTOR pathway were positive. CONCLUSION: Combination treatment with pazopanib and everolimus was well tolerated and demonstrated activity in solid tumors. Further exploration of this combination and molecular correlation with treatment outcomes is warranted.