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No targeted treatments are currently approved for HER2 exon 20 insertion–mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion–mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion–mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody–drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion–mutant lung adenocarcinoma patients. Significance: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion–mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.

Esophageal squamous cancer remains an important cause of mortality worldwide with two new immunotherapy drugs recently approved for metastatic disease.The authors review the epidemiology and genomics of esophageal squamous cell carcinoma. They also examine prior trials involving targeted agents under investigation as well immunotherapies that have been approved and novel combinations.Great advances have been made in characterizing the molecular changes in esophageal carcinoma. However, relatively few drugs have shown benefit in this disease. Targeted therapies have not shown to improve survival although many of these trials did not explore potential biomarkers. Pembrolizumab and nivolumab are now approved for esophageal squamous carcinoma but much more data are needed to understand how these agents may be used in non-metastatic settings. Novel treatments are still required as overall prognosis remains poor.

Neuropathic pain caused by somatosensory nervous system dysfunction is a serious public health problem. Some long noncoding RNAs (lncRNAs) can participate in physiological processes involved in neuropathic pain. However, the effects of lncRNA DGCR5 in neuropathic pain have not been explored. Therefore, in our current study, we concentrated on the biological roles of DGCR5 in neuropathic pain. Here, it was observed that DGCR5 was significantly decreased in chronic sciatic nerve injury (CCI) rat models. DGCR5 overexpression was able to alleviate neuropathic pain development including mechanical and thermal hyperalgesia. In addition, the current understanding of miR-330-3p function in neuropathic pain remains largely incomplete. Here, we found that miR-330-3p was greatly increased in CCI rats and DGCR5 can modulate miR-330-3p expression negatively. Upregulation of DGCR5 repressed inflammation-correlated biomarkers including interleukin 6 (IL-6), tumor necrosis factor α, and IL-1β in CCI rats by sponging miR-330-3p. The negative correlation between DGCR5 and miR-330-3p was confirmed in our current study. Inhibition of miR-330-3p suppressed neuropathic pain progression by restraining neuroinflammation in vivo. In addition, PDCD4 was predicted as a downstream target of miR-330-3p. Furthermore, PDCD4 was significantly increased in CCI rats and DGCR5 regulated PDCD4 expression through sponging miR-330-3p in CCI rat models. Taken these together, it was implied that DGCR5/miR-330-3p/PDCD4 axis participated in neuropathic pain treatment.

Graft-versus-host disease (GVHD) is a common complication of hematopoietic stem cell transplantation but can rarely occur after solid organ transplants. Small bowel and liver transplants are typically implicated, but solid organ transplant-associated GVHD has also been associated with other organs. We present a 40-year-old diabetic woman who underwent renal followed by pancreatic transplantation over a span of 21 months and ultimately developed acute classic GVHD. The diagnosis proved to be challenging in the context of confounding infections and inconclusive bone marrow and skin biopsy findings. She had multiorgan failure at the time of endoscopic confirmation and died after having minimal response to aggressive immunosuppression.

e24047 Background: The incidence of colorectal cancer in patients younger than 50 has been increasing over the past 2 decades. This demographic shift has important implications for survivorship care, in particular regarding issues of future fertility especially in light of USPSTF’s recommendation for colorectal cancer screening to begin at 45. Although ASCO has longstanding recommendations for fertility counseling in patients with cancer, the rates of fertility counseling in younger patients with colorectal cancer are unknown. Methods: Records for new patient visits for colorectal cancer in patients younger than age 55 in a large academic cancer center between 2012 and 2019 were queried for patient demographics, disease characteristics, and documentation of fertility counseling. Associations between demographic/clinical characteristics and fertility counseling were explored. Univariate and multivariable logistical regression analyses were performed using SAS v9.4. Results: Among 194 patients who met inclusion criteria, 39.2% of patients were female, 10.4% were African American, 31.4% had rectal cancer, and 69.6% were treated with curative intent. Approximately 14.5% of patients had Medicaid insurance. Age ranged from 22-55. The overall rate of fertility counseling among all patients was 15.5%. Of these patients, 43.3% were male. In univariate analysis, age less than or equal to 40 (p < 0.01), female gender (p = 0.03) and curative intent therapy (p = 0.03) were associated with fertility counseling. These factors were again statistically significant in multivariate analysis: age < 40, female, and curative intent therapy (Table). Race, stage of cancer, insurance status, prior exposure to chemotherapy, year of diagnosis and colon vs rectal cancer were not associated with counseling. Conclusions: The rate of fertility counseling was very low among patients with colorectal cancer, and exceptionally low among men. Despite changes in the demographics of colorectal cancer, it does not appear that appropriate changes have been made in fertility counseling. Increases in fertility counseling were not seen in more recent years despite recognition of increasing incidence in younger patients. Additional studies to identify barriers to counseling and strategies to improve survivorship care are urgently needed.[Table: see text]

Prolonged treatment with adjuvant valganciclovir has been shown in one retrospective study to exert a significant effect on overall survival (OS) in newly diagnosed patients with glioblastoma multiforme (GBM). However, studies evaluating the effectiveness of valganciclovir in the treatment of recurrent GBM have not been performed. We evaluated the effect of valganciclovir in the recurrent setting in combination with bevacizumab therapy. A retrospective analysis was performed on patients treated for recurrent GBM with off-label valganciclovir and bevacizumab at Vanderbilt University. We identified 13 patients who received valganciclovir plus bevacizumab at some point during their treatment, 8 of whom were started on valganciclovir and bevacizumab concurrently upon first recurrence, whereas 5 had valganciclovir added to their bevacizumab regimen prior to a second recurrence. of these patients, 12 were pathologically confirmed to have GBM, and 1 patient was diagnosed with gliosarcoma. We also identified an institutional cohort of 50 patients who had not been exposed to valganciclovir, but were treated with bevacizumab for first recurrence. The progression-free survival (PFS) at 6 months (PF6) and median OS (mOS) in the valganciclovir plus bevacizumab group was 62% and 13.1 months, respectively, for all 13 patients, and 50% and 11.3 months, respectively, for the 8 concurrently treated patients. In the institutional bevacizumab cohort, the PF6 and mOS were 34% and 8.7 months, respectively. In this retrospective analysis, valganciclovir in combination with bevacizumab exhibited a trend toward improved survival in patients with recurrent GBM. However, given the small sample size and the retrospective nature of this study, a larger prospective study is required to confirm these results.

e24081 Background: The incidence of colorectal cancer in patients younger than 50 has been increasing over the past two decades. This demographic shift has important implications for survivorship care, in particular regarding issues of future fertility. Although ASCO has a longstanding recommendation for fertility counseling in patients with cancer, the rates of fertility counseling in younger patients with colorectal cancer are unknown. Methods: Records for new patient visits for colorectal cancer in patients younger than age 55 in a large academic cancer center between 2016 and 2019 were retrospectively queried for patient demographics, disease characteristics, and documentation of fertility counseling. Associations between patient demographic/clinical characteristics and receipt of fertility counseling were explored. Univariate analyses and multivariable logistical regression analyses were performed using SAS v9.4. Results: Among the 136 patients who met inclusion criteria, 37.5% of patients were female, 16.2% were African American, 31.6% had rectal cancer, 20.7% of patients had Medicaid insurance. 63.7% were treated with curative intent. Age ranged from 22-55 (median = 46). Among all patients, 21/136 (15.4%) had documented fertility counseling. Of these, 11/51 (21.6%) patients were female and 10/85 (11.8%) were men. In univariate chi-square analysis, age less than or equal to 40 was associated with fertility counseling (p < 0.001) and curative intent therapy was numerically but not statistically associated with fertility counseling (p = 0.07). In multivariable analysis with logistical regression, age less than 40 (OR = 3.90, 95% CI [1.95, 7.81]), female gender (OR = 2.37, 95% CI [1.16, 4.84]), and curative intent therapy (OR = 3.26, 95% CI [1.14, 9.35]) were associated with fertility counseling. Race, stage of cancer, insurance status, prior exposure to chemotherapy, and colon vs rectal cancer were not associated with fertility counseling. Conclusions: The rate of fertility counseling was very low among patients with colorectal cancer, and exceptionally low among men with colorectal cancer. Despite changes in the demographics of colorectal cancer, it does not appear that appropriate changes have been made in fertility counseling. Additional studies to identify barriers and implementation strategies for fertility counseling are urgently needed in a disease that affects more young patients each year.

Background. Ipilimumab improves overall survival (OS) in advanced melanoma. Acral melanoma is an uncommon clinical subtype of this disease associated with poor prognosis. The clinical activity of ipilimumab has not been well-defined in advanced acral melanoma. Methods. We retrospectively reviewed the demographics, treatment history, and clinical outcomes for all patients with acral melanoma treated with ipilimumab from two academic centers between February 2006 and June 2013. Using Cox proportional hazards models, we assessed for factors that correlated with OS. Results. A total of 35 patients with acral melanoma received ipilimumab. Melanomas arose on volar surfaces (n = 28) and subungual sites (n = 7); stage M1c disease was present in 54%, and 45% had elevated serum lactate dehydrogenase (LDH). Best response by RECIST 1.1 criteria was complete response in 1 patient, partial response in 3, and stable disease (SD) in 4 for an objective response rate (ORR) of 11.4% and a clinical benefit rate (ORR + SD) at 24 weeks of 22.9%. Median progression-free survival was 2.5 months (95% confidence interval [CI]: 2.3–2.7 months); median OS was 16.7 months (95% CI: 10.9–22.5 months). Normal LDH and absolute lymphocyte count ≥1,000 at 7 weeks predicted longer OS. Immune-related adverse events (irAEs) were noted in 16 patients including 7 with grade 3/4 irAEs (20%). Conclusion. Ipilimumab is clinically active in acral melanoma with similar ORR and OS compared with unselected melanoma populations. Ipilimumab remains a viable therapeutic option for patients with advanced acral melanoma. Implications for Practice: Ipilimumab is a commonly used immune therapy that improves survival in metastatic melanoma. The clinical activity of ipilimumab in certain rare melanoma subtypes, such as uveal or mucosal melanomas, is suboptimal. Acral melanoma is another unusual subtype of this disease that arises on the palms, soles, and nailbeds. In this study of 35 patients with acral melanoma from 2 centers, ipilimumab was found to have activity that appears equivalent to unselected melanoma (response rate of 11.4%, median overall survival of 16.7 months). Ipilimumab remains a viable treatment option for this melanoma subpopulation.

Melanoma has historically been considered a refractory disease with few if any options in the advanced/metastatic setting. Advances in both immune and genetically targeted treatment approaches have revolutionized the spectrum of treatment options for melanoma patients over the last several years. Recently, checkpoint inhibition has become a major focus in the immune-based therapy of cancer, especially melanoma. This concept involves inhibition of regulatory cell surface molecules which act normally to dampen or modulate T-cell activation. Cancer, including melanoma, takes advantage of this physiologic mechanism to turn off T-cell activation and prevent effective T-cell antitumor responses. Checkpoint inhibitors such as anti cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) and anti programmed death-1 (PD-1) can reverse this immune suppression and release T-cell activation. Nivolumab, a monoclonal antibody to the PD-1 receptor, promotes antitumor immunity by removing this key negative regulator of T-cell activation. In phase I/II studies, promising activity and safety have been observed and ongoing phase III trials are comparing nivolumab with other standard of care therapies (chemotherapy, ipilimumab). Efficacy may be even further increased when used in combination with ipilimumab (albeit with increased toxicity). In contrast to typical short-lived responses with cancer therapy in metastatic solid tumors, many responses induced by nivolumab appear durable. In this review, we discuss the evolution of immune therapy in melanoma leading to the development of nivolumab, the clinical experience with this agent, and its future development and clinical potential.

Department of Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 Preston Research Building, Nashville, TN 37232, USA Vanderbilt University School of Medicine, 201 Light Hall, Nashville, TN 37232, USA *Author for correspondence: Tel.: +1 615 936 6398; Fax: +1 615 343 7602; igor.puzanov@vanderbilt.edu The incidence of melanoma in the USA has been increasing over the past decade, with an estimated 9480 deaths expected in 2013 [1]. Metastatic melanoma has historically carried an especially poor prognosis, with a median survival of 6–9 months. In recent years, however, advancements in both immune-based therapies and molecularly targeted agents have greatly expanded the treatment options for patients with this disease. The identification of molecularly defined cohorts in melanoma has facilitated many of these advances and enabled more effective treatment stratification. Oncogenic driver mutations in BRAF are present in 40–50% of advanced melanomas and confer sensitivity to selective BRAF inhibitors (vemurafenib and dabrafenib) and MEK inhibitors (trametinib). These molecularly targeted agents result in improved response rates and clinical outcomes compared with cytotoxic chemotherapy [2,3]. Although less common, CKIT mutations (largely identified in melanomas arising in the acral or mucosal surfaces) may predict benefit from imatinib [4]. Even melanomas with NRAS mutations (present in 15%), long considered to be an ‘undruggable’ target, may respond to recently developed MEK inhibitors [5]. Despite these advances, the remaining 30–40% of melanomas do not harbor identifiable driver mutations by conventional clinical assays and are considered to be ‘pan-negative’ [6]. The lack of clearly actionable mutations or available targeted therapies makes this a challenging cohort in the clinic.

Nearly 60% of melanomas have an activating mutation in the BRAF kinase. Targeted inhibition of mutant BRAF has prolonged overall survival, but responses are highly variable. To investigate the response variability, we utilized a panel of eight BRAF V600E or D mutated melanoma cell lines and treated them with the targeted mutant BRAF inhibitor, PLX4720. Under PLX4720 treatment, the cell lines exhibited a spectrum of concentration-dependent sensitivities based on measured proliferative rates over 96 hours of treatment. Since dysregulated metabolism has been shown to influence therapy resistance, we hypothesized that this spectrum of sensitivity would vary concordantly along a single metabolic phenotype. To test this hypothesis we measured glucose and amino acid uptake, lactate production, extracellular acidification upon mitochondrial inhibition, and proliferative rates under lactogenic glycolysis (oxamic acid) and ATP-synthase (oligomycin) inhibition in the cell lines. Interestingly, we did not find a single metabolic spectrum but rather unique clusters of metabolic phenotypes ranging from glycolysis-, amino-acid-, and oxidative phosphorylation-dependent to high metabolically flexible cell lines. Particularly, some cell lines were extremely sensitive to even low concentrations of oligomycin, whereas the majority of cell lines exhibited concentration-independent decreases of approximately ½ their proliferative rate under vehicle control. Metabolism and cell growth are intimately linked to cell cycle status, so we asked whether sensitivity to PLX4720 is abrogated when cells are selected under PLX4720 treatment. Using a fluorescence ubiquitination cell cycle indicator (FUCCI) to label dividing cells (G2/S/M phases), we pre-treated melanomas with PLX4720 or vehicle, flow-sorted FUCCI+ and FUCCI-cells, then re-treated with PLX4720. This revealed there was no positive selection for PLX4720-resistant subclones, as the PLX4720 treated FUCCI+/- cells pheno-copied the proliferative rates of the vehicle treated FUCCI+/- cells. Taken together, our results suggest that BRAF-mutated melanomas exist in a metabolically rich landscape that may be an important factor in response to targeted BRAF inhibition. The long-term goal is to translate these metabolic differences clinically, possibly by coupling metabolic and oncogene targeted therapies. Citation Format: Keisha N. Hardeman, Chengwei Peng, Bishal Paudel, Darren Tyson, Jamey D. Young, Vito Quaranta, Joshua P. Fessel. BRAF-mutated melanomas exhibit distinct metabolic programs that may determine therapeutic response. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A43.

9056 Background: Ipilimumab (Ipi) improves overall survival (OS) in advanced melanoma. Retrospective studies suggest inferior outcomes for Ipi in atypical cohorts of melanoma (uveal, mucosal) compa...

Patients with melanomas expressing B-RafV600E benefit from treatment with B-Raf-targeted therapeutics, such as vemurafenib. Initial responses to these agents are occasionally profound, but the duration of response is variable from patient to patient, with some tumors recurring within a few weeks and others requiring months before tumors progress. The source of this variability of response is under intense investigation. A number of acquired resistance mechanisms have been described, but it is not known whether they pre-exist or develop after treatment initiation. To address this question, we tracked the cellular response to PLX4720 (the vemurafenib research compound) over 96 hours in the A375 and SK-MEL-5 cell line models of B-RafV600E-expressing melanoma. Both cell lines exhibited a significant early reduction in cell number compared to control, but after 60 hours of treatment cells numbers began to increase even in the presence of 8 μM drug, albeit at a slow rate. This “rebound” proliferation effect was not due to drug decay since re-administration of the drug did not prevent it. We further examined the rebound effect at the single cell level using our newly described Fractional Proliferation assay (Tyson et al., Nat Methods, 2012, 9(9):923-928, doi:10.1038/nmeth.2138). The rebound corresponded to a dividing cell subpopulation whose size and rate of division depend on the concentration of drug. This subpopulation does not represent rare non-responding variants within the cell lines, but rather it arises stochastically as sibling cells do not always exhibit the same phenotypic response. Investigation of the molecular correlates of this dividing subpopulation, which may act as the reservoir from which the resistant cells arise, are ongoing. Citation Format: Darren R. Tyson, Chengwei Peng, Keisha N. Hardeman, Bishal Paudel, Vito Quaranta. A stochastically arising subpopulation of B-RafV600E-expressing melanoma continues division in the presence of vemurafenib. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3403. doi:10.1158/1538-7445.AM2013-3403