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Introduction: Immune checkpoint inhibitors (ICIs) have substantially advanced the treatment of patients with malignant melanoma. However, improving therapeutic efficacy requires identifying drug combinations that elicit durable responses without inducing intolerable toxicity. Within that context, selinexor emerges as a possible combination option that has been shown in preclinical studies to enhance the efficacy of ICI therapy. Methods: In this phase 1b study, we investigated selinexor in combination with pembrolizumab in 25 patients with advanced non-uveal melanoma. Patients received selinexor at a dosage of 60 mg taken orally twice weekly, and pembrolizumab intravenously at a dosage of 200 mg every 3 weeks. Results: Despite the high incidence of adverse events (96%), most treatment-related toxicities were manageable with supportive care and dose reductions. The most common adverse events of any grade were nausea (n = 20; 80%), decreased white blood cell count (n = 15; 60%), vomiting (n = 14; 56%), anemia (n = 12; 48%), fatigue (n = 12; 48%), and decreased platelet count (n = 12; 48%). The 10 patients with treatment-naïve evaluable disease had an objective response rate (ORR) of 70% (n = 7, including three patients with complete response), which was significantly higher than that of the 14 patients with prior anti–programmed cell death protein 1 (anti-PD-1) therapy, whose ORR was 7% (n = 1; p = 0.002). Stable disease was observed in two patients (20%) with treatment-naïve disease and seven patients (50%) with prior anti-PD-1 therapy. Conclusion: Selinexor combined with pembrolizumab showed promising antitumor activity in patients with treatment-naïve metastatic melanoma. The toxicity profile of the combination was consistent with that reported for individual agents, with no additional safety concerns.

Abstract Cancer cells with BRCA1/2 deficiencies are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We evaluated the efficacy of talazoparib in DNA-Damage Repair (DDR)-altered patients. In this phase II trial, patients were enrolled onto one of four cohorts based on molecular alterations: (1) somatic BRCA1/2, (2) other homologous recombination repair pathway, (3) PTEN and (4) germline BRCA1/2. The primary endpoint was a clinical benefit rate (CBR): complete response, partial response or stable disease ≥24 weeks. 79 patients with a median of 4 lines of therapy were enrolled. CBR for cohorts 1–4 were: 32.5%, 19.7%, 9.4% and 30.6%, respectively. PTEN mutations correlated with reduced survival and a trend towards shorter time to progression.Talazoparib demonstrated clinical benefit in selected DDR-altered patients. PTEN mutations/loss patients derived limited clinical benefit. Further study is needed to determine whether PTEN is prognostic or predictive of response to PARP inhibitors.

Abstract Previous studies have shown the clinical benefit of rechallenging the RAF pathway in melanoma patients previously treated with BRAF inhibitors. 44 patients with multiple tumors harboring RAF alterations were rechallenged with a second RAF inhibitor, either as monotherapy or in combination with other therapies, after prior therapy with a first RAF inhibitor. This retrospective observational study results showed that rechallenging with RAFi(s) led to an overall response rate of 18.1% [PR in thyroid (1 anaplastic; 3 papillary), 1 ovarian, 2 melanoma, 1 cholangiocarcinoma, and 1 anaplastic astrocytoma]. The clinical benefit rate was 54.5%; more than 30% of patients had durable responses with PR and SD lasting > 6 months. The median progression-free survival on therapy with second RAF inhibitor in the rechallenge setting either as monotherapy or combination was shorter at 2.7 months (0.9-30.1 m) compared to 8.6 months (6.5-11.5 m) with RAF-1i. However, the median PFS with RAF-2i responders (PFS-2) improved at 12.8 months compared to 11.4 months with RAF-1i responders. The median OS from retreatment with RAF-2i was 15.5 months (11.1-30.8 m). Further prospective studies are needed to validate these results and expand targeted therapy options for RAF-aberrant cancers.

Abstract Patients treated with RET protein tyrosine kinase inhibitors (TKIs) selpercatinib or pralsetinib develop RET TKI resistance by secondary RET mutations or alterative oncogenes, of which alterative oncogenes pose a greater challenge for disease management because of multiple potential mechanisms and the unclear tolerability of drug combinations. A patient with metastatic medullary thyroid carcinoma (MTC) harboring a RET activation loop D898_E901del mutation was treated with selpercatinib. Molecular alterations were monitored with tissue biopsies and cfDNA during the treatment. The selpercatinib-responsive MTC progressed with an acquired ETV6::NTRK3 fusion, which was controlled by selpercatinib plus the NTRK inhibitor larotrectinib. Subsequently, tumor progressed with an acquired EML4::ALK fusion. Combination of selpercatinib with the dual NTRK/ALK inhibitor entrectinib reduced the tumor burden, which was followed by appearance of NTRK3 solvent-front G623R mutation. Preclinical experiments validated selpercatinib plus larotrectinib or entrectinib inhibited RET/NTRK3 dependent cells, whereas selpercatinib plus entrectinib was necessary to inhibit cells with RET/NTRK3/ALK triple alterations or a mixture of cell population carrying these genetic alterations. Thus, RET-altered MTC adapted to selpercatinib and larotrectinib with acquisition of ETV6::NTRK3 and EML4::ALK oncogenes can be managed by combination of selpercatinib and entrectinib providing proof-of-concept of urgency of incorporating molecular profiling in real-time and personalized N-of-1 care transcending one-size-fits-all approach.

Introduction Genomic profiling is performed in patients with advanced or metastatic cancer, in order to direct cancer treatment, often sequencing tumor-only, without a matched germline comparator. However, because many of the genes analyzed on tumor profiling overlap with those known to be associated with hereditary cancer predisposition syndromes (HCPS), tumor-only profiling can unknowingly uncover germline pathogenic (P) and likely pathogenic variants (LPV). In this study, we evaluated the number of patients with P/LPVs identified in BRCA1 and BRCA2 (BRCA1/2) via tumor-only profiling, then determined the germline testing outcomes for those patients. Methods A retrospective chart review was performed to identify patients with BRCA1/2 variants on tumor-only genomic profiling, and whether they had germline testing. Results This study found that of 2923 patients with 36 tumor types who underwent tumor-only testing, 554 had a variant in BRCA1/2 (19.0%); 119 of the 554 patients (21.5%) had a P/LP BRCA1/2 variant, representing 4.1% of the overall population who underwent genomic profiling. Seventy-three (61.3%) of 119 patients with BRCA1/2 P/LPV on tumor-only testing did not undergo germline testing, 34 (28.6%) had already had germline testing before tumor-only testing, and 12 (10.1%) underwent germline testing after tumor-only testing. Twenty-eight germline BRCA1/2 P/LPVs were detected, 24 in those who had prior germline testing, and 4 among the 12 patients who had germline testing after tumor-only testing. Conclusion Tumor-only testing is likely to identify P/LPVs in BRCA1/2. Efforts to improve follow-up germline testing is needed to improve identification of germline BRCA1/2 alterations.

Abstract Several alterations in fibroblast growth factor receptor (FGFR) genes have been found in breast cancer; however, they have not been well characterized as therapeutic targets. Futibatinib (TAS-120; Taiho) is a novel, selective, pan-FGFR inhibitor that inhibits FGFR1-4 at nanomolar concentrations. We sought to determine futibatinib’s efficacy in breast cancer models. Nine breast cancer patient–derived xenografts (PDXs) with various FGFR1-4 alterations and expression levels were treated with futibatinib. Antitumor efficacy was evaluated by change in tumor volume and time to tumor doubling. Alterations indicating sensitization to futibatinib in vivo were further characterized in vitro. FGFR gene expression between patient tumors and matching PDXs was significantly correlated; however, overall PDXs had higher FGFR3-4 expression. Futibatinib inhibited tumor growth in 3 of 9 PDXs, with tumor stabilization in an FGFR2-amplified model and prolonged regression (> 110 days) in an FGFR2 Y375C mutant/amplified model. FGFR2 overexpression and, to a greater extent, FGFR2 Y375C expression in MCF10A cells enhanced cell growth and sensitivity to futibatinib. Per institutional and public databases, FGFR2 mutations and amplifications had a population frequency of 1.1%–2.6% and 1.5%–2.5%, respectively, in breast cancer patients. FGFR2 alterations in breast cancer may represent infrequent but highly promising targets for futibatinib.

Poly (adenosine diphosphate-ribose) polymerase inhibitors (PARP)i are emerging as standard oncology treatments in various tumor types. The indications will expand as PARPi are being investigated in various breast cancer subtypes. Currently, except for BRCA1/2 mutation carriers with human epidermal growth factor receptor 2 (HER2)-negative breast cancer, there is inadequate identification of predictive biomarkers of response. We present a 57-year-old woman with metastatic breast cancer, hormone-receptor-positive, HER2 negative with a germline ataxia-telangiectasia mutation with a large brain metastasis with clinical benefit to talazoparib. This case report exemplifies the importance of the multidisciplinary management of patients with brain metastases and personalized biomarker selected treatment.

Abstract TROP2 antibody drug conjugates (ADCs) are under active development. We seek to determine whether we can enhance activity of TROP2 ADCs by increasing TROP2 expression. In metaplastic breast cancers (MpBC), there is limited expression of TROP2, and downregulating transcription factor ZEB1 upregulates E-cad and TROP2, thus sensitizing cancers to TROP2 ADC sacituzumab govitecan (SG). Demethylating agent decitabine decreases DNA methyltransferase expression and TROP2 promoter methylation and subsequently increases TROP2 expression. Decitabine treatment as well as overexpression of TROP2 significantly enhance SG antitumor activity. Decitabine also increases SLFN11, a biomarker of topoisomerase 1 inhibitor (TOP1) sensitivity and is synergistic with SG which has a TOP1 payload, in TROP2-expressing SLFN11-low BC cells. In conclusion, TROP2 and SLFN11 expression can be epigenetically modulated and the combination of demethylating agent decitabine with TROP2 ADCs may represent a novel therapeutic approach for tumors with low TROP2 or SLFN11 expression.

Abstract Genomically-informed therapy requires consideration of the functional impact of genomic alterations on protein expression and/or function. However, a substantial number of variants are of unknown significance (VUS). The MD Anderson Precision Oncology Decision Support (PODS) team developed an actionability classification scheme that categorizes VUS as either “Unknown” or “Potentially” actionable based on their location within functional domains and/or proximity to known oncogenic variants. We then compared PODS VUS actionability classification with results from a functional genomics platform consisting of mutant generation and cell viability assays. 106 (24%) of 438 VUS in 20 actionable genes were classified as oncogenic in functional assays. Variants categorized by PODS as Potentially actionable (N = 204) were more likely to be oncogenic than those categorized as Unknown (N = 230) (37% vs 13%, p = 4.08e-09). Our results demonstrate that rule-based actionability classification of VUS can identify patients more likely to have actionable variants for consideration with genomically-matched therapy.

Abstract Background Sapanisertib is a potent ATP‐competitive, dual inhibitor of mTORC1/2. Ziv‐aflibercept is a recombinant fusion protein comprising human VEGF receptor extracellular domains fused to human immunoglobulin G1. HIF‐1α inhibition in combination with anti‐angiogenic therapy is a promising anti‐tumor strategy. This Phase 1 dose‐escalation/expansion study assessed safety/ tolerability of sapanisertib in combination with ziv‐aflibercept in advanced solid tumors. Methods Fifty‐five patients with heavily pre‐treated advanced metastatic solid tumors resistant or refractory to standard treatment received treatment on a range of dose levels. Results Fifty‐five patients were enrolled and treated across a range of dose levels. Forty were female (73%), median age was 62 (range: 21–79), and ECOG PS was 0 (9, 16%) or 1 (46, 84%). Most common tumor types included ovarian (8), colorectal (8), sarcoma (8), breast (3), cervical (4), and endometrial (4). Median number of prior lines of therapy was 4 (range 2–11). Sapanisertib 4 mg orally 3 days on and 4 days off plus 3 mg/kg ziv‐aflibercept IV every 2 weeks on a 28‐day cycle was defined as the maximum tolerated dose. Most frequent treatment‐related grade ≥2 adverse events included hypertension, fatigue, anorexia, hypertriglyceridemia, diarrhea, nausea, mucositis, and serum lipase increase. There were no grade 5 events. In patients with evaluable disease (n = 50), 37 patients (74%) achieved stable disease (SD) as best response, two patients (4%) achieved a confirmed partial response (PR); disease control rate (DCR) (CR + SD + PR) was 78%. Conclusion The combination of sapanisertib and ziv‐aflibercept was generally tolerable and demonstrated anti‐tumor activity in heavily pre‐treated patients with advanced malignancies.

Abstract Pre-clinically, the mTORC1/2 inhibitor sapanisertib restored sensitivity to platinums and enhanced paclitaxel-induced cancer cell killing. NCT03430882 enrolled patients with mTOR pathway aberrant tumors to receive sapanisertib, carboplatin and paclitaxel. Primary objective was safety and secondary objectives were clinical response and survival. One patient had a dose-limiting toxicity at dose level 4. There were no unanticipated toxicities. Grade 3–4 treatment-related adverse events included anemia (21%), neutropenia (21%), thrombocytopenia (10.5%), and transaminitis (5%). Of 17 patients evaluable for response, 2 and 11 patients achieved partial response and stable disease, respectively. Responders included a patient with unclassified renal cell carcinoma harboring EWSR1-POU5F1 fusion and a patient with castrate resistant prostate cancer harboring PTEN loss. Median progression free survival was 3.84 months. Sapanisertib in combination with carboplatin plus paclitaxel demonstrated a manageable safety profile, with preliminary antitumor activity observed in advanced malignancies harboring mTOR pathway alterations.

Abstract Combined BRAF + MEK inhibition is FDA approved for BRAF V600E-mutant solid tumors except for colorectal cancer. However, beyond MAPK mediated resistance several other mechanisms of resistance such as activation of CRAF, ARAF, MET, P13K/AKT/mTOR pathway exist among other complex pathways. In the VEM-PLUS study, we performed a pooled analysis of four phase one studies evaluating the safety and efficacy of vemurafenib monotherapy and vemurafenib combined with targeted therapies (sorafenib, crizotinib, or everolimus) or carboplatin plus paclitaxel in advanced solid tumors harboring BRAF V600 mutations. When vemurafenib monotherapy was compared with the combination regimens, no significant differences in OS or PFS durations were noted, except for inferior OS in the vemurafenib and paclitaxel and carboplatin trial (P = 0.011; HR, 2.4; 95% CI, 1.22–4.7) and in crossover patients (P = 0.0025; HR, 2.089; 95% CI, 1.2–3.4). Patients naïve to prior BRAF inhibitors had statistically significantly improved OS at 12.6 months compared to 10.4 months in the BRAF therapy refractory group (P = 0.024; HR, 1.69; 95% CI 1.07–2.68). The median PFS was statistically significant between both groups, with 7 months in the BRAF therapy naïve group compared to 4.7 months in the BRAF therapy refractory group (P = 0.016; HR, 1.80; 95% CI 1.11–2.91). The confirmed ORR in the vemurafenib monotherapy trial (28%) was higher than that in the combination trials. Our findings suggest that, compared with vemurafenib monotherapy, combinations of vemurafenib with cytotoxic chemotherapy or with RAF- or mTOR-targeting agents do not significantly extend the OS or PFS of patients who have solid tumors with BRAF V600E mutations. Gaining a better understanding of the molecular mechanisms of BRAF inhibitor resistance, balancing toxicity and efficacy with novel trial designs are warranted.

In biliary tract cancer HER2 alterations correlate with poor prognosis. Here, the authors present the results of a phase II clinical trial reporting the efficacy and safety of the tyrosine kinase inhibitor neratinib in patients with HER2-mutation positive advanced biliary tract cancers.

Introduction: We aimed to identify clinical, pathologic, and treatment factors that are predictive of response and survival in patients with cervical cancer referred to phase I clinical trials. Methods: Patients with cervical cancer who received at least one dose of a phase I investigational agent at our institution between 2014 and 2022 were included. The log-rank test was used to analyze differences in progression-free survival (PFS) and overall survival (OS), and multivariable regression analysis was performed. Results: We included 65 patients with a median age of 41 years (range, 20–74), 3 prior therapies (range, 1–7), and 67.7% squamous carcinoma. The rate of distant metastasis at trial entry was 84.6%. The most common molecular alterations included PIK3CA (46.5%), PD-L1+ (46.2%), EPH (30.0%), and CREBBP (23.1%); 23.1% had received a prior checkpoint inhibitor. Phase I trials were for immunotherapy (58.5%) or targeted therapy (41.5%). The rate of biomarker matching was 21.5%. For all patients, median PFS was 3.6 months (95% CI, 2.0–5.2) and OS was 9.3 months (95% CI, 7.0–10.6). Factors at study entry associated with worse survival were presence of bone metastasis (PFS 1.6 vs 4.4 months: hazard ratio [HR], 2.8; p = 0.001; OS 3.8 vs 10.0 months: HR, 3.9; p < 0.0001) and absolute lymphocyte count below 1000/μL (PFS 1.8 vs 5.2 months: HR, 2.9; p = 0.0004; OS 7.0 vs 10.6 months: HR, 3.2; p = 0.0009). Factors associated only with worse OS were absolute neutrophil count above 4700/μL, hemoglobin below 10.5 g/dL, and smoking status. Grade 3+ treatment-related adverse events were seen in 16.9% of cases. Conclusion: Bone metastasis and absolute lymphocyte count below normal range at phase I study entry portend poor survival in patients with recurrent or metastatic cervical cancer.

Abstract Antibody-drug conjugates (ADCs) are one of fastest growing classes of oncology drugs in modern drug development. By harnessing the powers of both cytotoxic chemotherapy and targeted therapy, ADCs are unique in offering the potential to deliver highly potent cytotoxic agents to cancer cells which express a pre-defined cell surface target. In lung cancer, the treatment paradigm has shifted dramatically in recent years, and now ADCs are now joining the list as potential options for lung cancer patients. Since 2020, the first ADC for NSCLC patients has been FDA-approved (trastuzumab deruxtecan) and two ADCs have been granted FDA Breakthrough Therapy Designation, currently under evaluation (patritumab deruxtecan, telisotuzumab vedotin). Furthermore, several early-phase trials are assessing various novel ADCs, either as monotherapy or in combinations with advanced lung cancer, and more selective and potent ADCs are expected to become therapeutic options in clinic soon. In this review, we discuss the structure and mechanism of action of ADCs, including insights from pre-clinical work; we summarize the ADCs’ recent progress in lung cancer, describe toxicity profiles of ADCs, and explore strategies designed to enhance ADC potency and overcome resistance. In addition, we discuss novel ADC strategies of interest in lung cancer, including non-cytotoxic payloads, such as immunomodulatory and anti-apoptotic agents.

Abstract The RxPONDER and TAILORx trials demonstrated benefit from adjuvant chemotherapy in patients age ≤ 50 with node-positive breast cancer and Recurrence Score (RS) 0–26, and in node-negative disease with RS 16–25, respectively, but no benefit in older women with the same clinical features. We analyzed transcriptomic and genomic data of ER+/HER2− breast cancers with in silico RS

Abstract We investigated the challenges of conducting IMPACT2, an ongoing randomized study that evaluates molecular testing and targeted therapy (ClinicalTrials.gov: NCT02152254). Patients with metastatic cancer underwent tumor profiling and were randomized between the two arms when eligibility criteria were met (Part A). In Part B, patients who declined randomization could choose the study arm. In Part A, 69 (21.8%) of 317 patients were randomized; 78.2% were not randomized because of non-targetable alterations (39.8%), unavailability of clinical trial (21.8%), other reasons (12.6%), or availability of US Food and Drug Administration (FDA)-approved drugs for the indication (4.1%). In Part B, 32 (20.4%) of 157 patients were offered randomization; 16 accepted and 16 selected their treatment arm; 79.0% were not randomized (patient’s/physician’s choice, 29.3%; treatment selection prior to genomic reports, 16.6%; worsening performance status/death, 12.7%; unavailability of clinical trials, 6.4%; other, 6.4%; non-targetable alterations, 5.7%; or availability of FDA-approved drugs for the indication, 1.9%). In conclusion, although randomized controlled trials have been considered the gold standard for drug development, the execution of randomized trials in precision oncology in the advanced metastatic setting is complicated. We encountered various challenges conducting the IMPACT2 study, a large precision oncology trial in patients with diverse solid tumor types. The adaptive design of IMPACT2 enables patient randomization despite the continual FDA approval of targeted therapies, the evolving tumor biomarker landscape, and the plethora of investigational drugs. Outcomes for randomized patients are awaited.

Background Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the past.Patients and methods We used a novel method for long-amplicon next generation sequencing of rearranged TCRB chains from peripheral blood total RNA to evaluate the link between TRBV polymorphisms and irAEs in patients treated with immunotherapy for cancer. We employed multiplex PCR to create amplicons spanning the three beta chain complementarity-determining regions (CDR) regions to enable detection of polymorphism within the germline-encoded framework and CDR1 and CDR2 regions in addition to CDR3 profiling. Resultant amplicons were sequenced via the Ion Torrent and TRBV allele profiles constructed for each individual was correlated with irAE annotations to identify haplotypes associated with severe irAEs (≥ grade 3).Results Our study included 81 patients who had irAEs when treated with immunotherapy for cancer. By using principal component analysis of the 81 TRBV allele profiles followed by k-means clustering, we identified six major TRBV haplotypes. Strikingly, we found that one-third of this cohort possessed a TRBV allele haplotype that appeared to be protective against severe irAEs.Conclusion The data suggest that long-amplicon TCRB repertoire sequencing can potentially identify TRBV haplotype groups that correlate with the risk of severe irAEs. Germline-encoded TRBV polymorphisms may serve as a predictive biomarker of severe irAEs.

Abstract Patients with rare solid tumors treated on early phase trials experience toxicities from their tumors and treatments. However, limited data exist to describe the detailed symptom burden suffered by these patients, particularly those with rare solid tumors treated with immunotherapy. We performed a prospective longitudinal study to capture patient-reported symptom burden. Patients completed the validated MD Anderson Symptom Inventory (MDASI)—Immunotherapy with 20 symptoms including 7 immunotherapy-specific items and 6 interference items at baseline and weekly thereafter for up to 9 weeks. Symptoms and interference were rated on 0–10 scales (0 = none or no interference, 10 = worst imaginable or complete interference). Group-based trajectory modelling determined higher and lower symptom groups. A total of 336 MDASI questionnaires were completed by 53 patients (mean age 55.4y, 53% male) with advanced rare cancers receiving pembrolizumab in a Phase II clinical trial. Symptoms reported as most severe over the course of the treatment over 9 weeks were fatigue [mean (M) = 3.8, SD = 2.3], pain (M = 3.7, SD = 2.9), disturbed sleep (M = 2.7, SD = 2.3), drowsiness (M = 2.6, SD = 2.0) and lack of appetite (M = 2.5, SD = 2.1). Pain in the abdomen (M = 2.2, SD = 2.4), rash (M = 1.1, SD = 1.8) and diarrhea (M = 0.9, SD = 1.5) were less severe. Interference with walking was rated the highest (M = 3.4, SD = 2.8) and relations with others was rated the lowest (M = 2.1, SD = 2.6). Using a composite score based on the five most severe symptoms (fatigue, pain, lack of appetite, feeling drowsy and sleep disturbance), 43% were classified into the high symptom burden group. Using a score based on immunotherapy-specific symptoms (e.g., rash, diarrhea) 33% of patients were included in the high symptom group. Symptom burden stayed relatively stable in the high- and low-symptom burden patient groups from baseline through 9 weeks. Some patients with rare malignancies experienced high symptom burden even at baseline. In patients with rare cancers, symptom trajectories stayed relatively stable over nine weeks of treatment with pembrolizumab. Trial registration: ClinicalTrials.gov identifier: NCT02721732.

Abstract Anticancer combination therapy has been developed to increase efficacy by enhancing synergy. Patient-derived xenografts (PDXs) have emerged as reliable preclinical models to develop effective treatments in translational cancer research. However, most PDX combination study designs focus on single dose levels, and dose–response surface models are not appropriate for testing synergism. We propose a comprehensive statistical framework to assess joint action of drug combinations from PDX tumor growth curve data. We provide various metrics and robust statistical inference procedures that locally (at a fixed time) and globally (across time) access combination effects under classical drug interaction models. Integrating genomic and pharmacological profiles in non-small-cell lung cancer (NSCLC), we have shown the utilities of combPDX in discovering effective therapeutic combinations and relevant biological mechanisms. We provide an interactive web server, combPDX ( https://licaih.shinyapps.io/CombPDX/ ), to analyze PDX tumor growth curve data and perform power analyses.

Abstract Cyclin E is frequently encoded by CCNE1 gene amplification in various malignancies. We reviewed the medical records of patients with solid tumors displaying CCNE1 amplification to determine the effect of this amplification for future therapeutic development. We reviewed the medical records of patients with advanced solid tumors harboring CCNE1 amplification who were seen at the phase I clinic between September 1, 2012, and December 31, 2019. Among 79 patients with solid tumors harboring CCNE1 amplification, 56 (71%) received phase 1 clinical trial therapy, 39 (49%) had 3 or more concurrent genomic aberrances, and 52 (66%) had a concurrent TP53 mutation. The median overall survival (OS) after patients’ initial phase I visit was 8.9 months and after their initial metastasis diagnosis was 41.4 months. We identified four factors associated with poor risk: age upper limit of normal. In patients treated with gene aberration-related therapy, anti-angiogenic therapy led to significantly longer OS after their initial phase I trial therapy than those who did not: 26 months versus 7.4 months, respectively (P = 0.04). This study provided preliminary evidence that CCNE1 amplification was associated with frequent TP53 mutation and aggressive clinical outcomes. Survival benefit was observed in patients who received antiangiogenic therapy and gene aberration-related treatment, supporting the future development of a personalized approach to combine gene aberration-related therapy with antiangiogenesis for the treatment of advanced malignancies harboring CCNE1 amplification.

Intrahepatic cholangiocarcinoma is a rare malignancy, which is rich in actionable alterations. Genomic aberrations in the mitogen-activated protein kinase (MAPK) pathway are common, and BRAF exon 15 p.V600E mutations are present in 5–7% of biliary tract cancers (BTC). Dual inhibition of BRAF and MEK has been established for BRAF-mutated melanoma and lung cancer, and recent basket trials have shown efficacy of this combination in BRAF V600E-mutant BTCs. Here, we report on a patient with BRAF exon 15 p.V600E mutant metastatic intrahepatic cholangiocarcinoma who was started on BRAF and MEK inhibition with vemurafenib and combimetinib. Shortly thereafter, he developed debilitating myositis, which was refractory to corticosteroids, requiring therapeutic plasma exchange and intravenous immunoglobulin. We also review BRAF as a target in BTCs, relevant clinical trials, and adverse events associated with BRAF and MEK inhibition.

Abstract Artificial intelligence (AI) is transforming many domains, including finance, agriculture, defense, and biomedicine. In this paper, we focus on the role of AI in clinical and translational research (CTR), including preclinical research (T1), clinical research (T2), clinical implementation (T3), and public (or population) health (T4). Given the rapid evolution of AI in CTR, we present three complementary perspectives: (1) scoping literature review, (2) survey, and (3) analysis of federally funded projects. For each CTR phase, we addressed challenges, successes, failures, and opportunities for AI. We surveyed Clinical and Translational Science Award (CTSA) hubs regarding AI projects at their institutions. Nineteen of 63 CTSA hubs (30%) responded to the survey. The most common funding source (48.5%) was the federal government. The most common translational phase was T2 (clinical research, 40.2%). Clinicians were the intended users in 44.6% of projects and researchers in 32.3% of projects. The most common computational approaches were supervised machine learning (38.6%) and deep learning (34.2%). The number of projects steadily increased from 2012 to 2020. Finally, we analyzed 2604 AI projects at CTSA hubs using the National Institutes of Health Research Portfolio Online Reporting Tools (RePORTER) database for 2011–2019. We mapped available abstracts to medical subject headings and found that nervous system (16.3%) and mental disorders (16.2) were the most common topics addressed. From a computational perspective, big data (32.3%) and deep learning (30.0%) were most common. This work represents a snapshot in time of the role of AI in the CTSA program.

Abstract Background Arginine depletion interferes with pyrimidine metabolism and DNA damage repair pathways. Preclinical data demonstrated that depletion of arginine by PEGylated arginine deiminase (ADI‐PEG 20) enhanced liposomal doxorubicin (PLD) cytotoxicity in cancer cells with argininosuccinate synthase 1 (ASS1) deficiency. The objective of this study was to assess safety and tolerability of ADI‐PEG 20 and PLD in patients with metastatic solid tumors. Methods Patients with advanced ASS1‐deficient solid tumors were enrolled in this phase 1 trial of ADI‐PEG 20 and PLD following a 3 + 3 design. Eligible patients were given intravenous PLD biweekly and intramuscular (IM) ADI‐PEG 20 weekly. Toxicity and efficacy were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0) and Response Evaluation Criteria in Solid Tumors (version 1.1), respectively. Results Of 15 enrolled patients, 9 had metastatic HER2‐negative breast carcinoma. We observed no dose‐limiting toxicities or treatment‐related deaths. One patient safely received 880 mg/m2 PLD in this study and 240 mg/m2 doxorubicin previously. Treatment led to stable disease in 9 patients and was associated with a median progression‐free survival time of 3.95 months in 15 patients. Throughout the duration of treatment, decreased arginine and increased citrulline levels in peripheral blood remained significant in a majority of patients. We detected no induction of anti‐ADI‐PEG 20 antibodies by week 8 in one third of patients. Conclusion Concurrent IM injection of ADI‐PEG 20 at 36 mg/m2 weekly and intravenous infusion of PLD at 20 mg/m2 biweekly had an acceptable safety profile in patients with advanced ASS1‐deficient solid tumors. Further evaluation of this combination is under discussion.

Abstract Most tumors with activating MAPK (mitogen-activated protein kinase) pathway alterations respond poorly to MEK inhibitors alone. Here, we evaluated combination therapy with MEK inhibitor selumetinib and MDM2 inhibitor KRT-232 in TP53 wild-type and MAPK altered colon and thyroid cancer models. In vitro, we showed synergy between selumetinib and KRT-232 on cell proliferation and colony formation assays. Immunoblotting confirmed p53 upregulation and MEK pathway inhibition. The combination was tested in vivo in seven patient-derived xenograft (PDX) models (five colorectal carcinoma and two papillary thyroid carcinoma models) with different KRAS, BRAF, and NRAS mutations. Combination therapy significantly prolonged event-free survival compared with monotherapy in six of seven models tested. Reverse-phase protein arrays and immunohistochemistry, respectively, demonstrated upregulation of the p53 pathway and in two models cleaved caspase 3 with combination therapy. In summary, combined inhibition of MEK and MDM2 upregulated p53 expression, inhibited MAPK signaling and demonstrated greater antitumor efficacy than single drug therapy in both in vitro and in vivo settings. These findings support further clinical testing of the MEK/MDM2 inhibitor combination in tumors of epithelial origin with MAPK pathway alterations.

Summary: Single-cell DNA sequencing (scDNA-seq) methods are powerful tools for profiling mutations in cancer cells; however, most genomic regions sequenced in single cells are non-informative. To overcome this issue, we developed a multi-patient-targeted (MPT) scDNA-seq method. MPT involves first performing bulk exome sequencing across a cohort of cancer patients to identify somatic mutations, which are then pooled together to develop a single custom targeted panel for high-throughput scDNA-seq using a microfluidics platform. We applied MPT to profile 330 mutations across 23,500 cells from 5 patients with triple negative-breast cancer (TNBC), which showed that 3 tumors were monoclonal and 2 tumors were polyclonal. From these data, we reconstructed mutational lineages and identified early mutational and copy-number events, including early TP53 mutations that occurred in all five patients. Collectively, our data suggest that MPT can overcome a major technical obstacle for studying tumor evolution using scDNA-seq by profiling information-rich mutation sites.

Abstract Acquired resistance to molecular targeted therapy is a significant challenge of the precision medicine era. The ability to understand these mechanisms of resistance may improve patient selection and allow for the development of rationally designed next-line or combination treatment strategies and improved patient outcomes. AKT is a critical effector of the phosphoinositide 3-kinase signaling cascade, one of the most commonly activated pathways in human cancer. Deregulation of signaling pathways, such as RAF/MEK/ERK are previously described mechanisms of resistance to AKT/PI3K inhibitors. Mutations in the mTOR gene, however, are exceedingly rare. We present a case of acquired mTOR resistance, following targeted AKT inhibition, and subsequent response to mTOR1/2 inhibitor in a patient with metastatic endometrial cancer, the first documented response to ATP-competitive mTOR inhibition in this setting. This case supports mTOR mutation as a mechanism of resistance, and underscores the importance of tumor molecular profiling, exemplifying precision medicine in action.

Abstract Selinexor, an oral selective inhibitor of nuclear export (SINE), was demonstrated to hinder the DNA damage repair (DDR) system by reducing DDR proteins while enhancing the killing of cancer cells by DDR-based therapeutics in vivo studies. In this single-center, multi-arm phase 1b study, selinexor with carboplatin, doxorubicin and cyclophosphamide (DC), irinotecan with fluorouracil and folinic acid (FOLFIRI), irinotecan, and capecitabine and oxaliplatin (XELOX), were employed as separate parallel arms. Eligible patients have relapsed/ metastatic refractory solid tumors following standard therapy or addition of selinexor to systemic therapy was appropriate. Nineteen patients were treated in the 5 arms. Tumor types included were colorectal (n = 3), breast (n = 3), neuroendocrine (n = 2), ovarian (n = 2), and pancreas cancers (n = 2). All patients developed one treatment-related adverse events (TRAE). The most prevalent TRAE were thrombocytopenia (84%), nausea (68%), leukopenia (68%), neutropenia (63%), and fatigue (58%). The common grade 3/4 TRAE were neutropenia (42%), leukopenia (26%), and hyponatremia (21%). Three patients had dose-limiting toxicities (DLT) in 3 separate arms. Fourteen patients were evaluable for response. Although no patients achieved complete or partial response (CR or PR), seven patients attained stable disease (SD). Disease control rate (DCR) was 14%. The combination of oral selinexor with different standard chemotherapies showed limited clinical activity despite toxicity and DLT prevented further dose escalation. Optimizing supportive care, the utility of growth factors, and aggressive measures on antiemetics strategies remain tangible. Trial registration ClinicalTrials.gov Identifier: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495 ). Sponsor(s): Karyopharm Therapeutics

Patient-derived xenograft models (PDX) have been extensively used to study the molecular and clinical features of cancers. Here the authors present a cohort of 536 PDX models from 25 cancers, as well as their genomic and evolutionary profiles and their suitability for clinical trials.

Introduction: For maximum utility of molecular characterization by next-generation sequencing (NGS) and better understanding of tumor microenvironment with immune correlates analysis, biopsy specimens must yield adequate tumor tissue, and sequential biopsy specimens should sample a consistent site. We developed a web-based lesion selection tool (LST) that enables management and tracking of the biopsy specimen collections. Methods: Of 145 patients, the LST was used for 88 patients; the other 57 served as controls. We evaluated consistency of the lesion biopsied in longitudinal collections, number of cores obtained, and cores with adequate tumor cellularity for NGS. The Fisher exact test and Wilcoxon rank sum test were used to identify differences between the groups. Results: The analysis included 30 of 88 (34%) patients in the LST group and 52 of 57 (91%) in the control group. The LST workflow ensured 100% consistency in the lesions biopsied compared with 75% in the control group in longitudinal collections and increased the proportion of patients in whom at least five cores were collected per biopsy. Conclusions: The novel LST platform facilitates coordination, performance, and management of longitudinal biopsy specimens. Use of the LST enables sampling of the designated lesion consistently, which is likely to accurately inform us the effect of the treatment on tumor microenvironment and evolution of resistant pathways. Such studies are important translational component of any clinical trials and research as they guide the development of next line of therapy, which has significant effect on clinical utility. However, validation of this approach in a larger study is warranted.

Abstract Five to ten percent of ER+ metastatic breast cancer (MBC) tumors harbor somatic PTEN mutations. Loss of function of this tumor-suppressor gene defines a highly aggressive, treatment-refractory disease for which new therapies are urgently needed. This Phase I multipart expansion study assessed oral capivasertib with fulvestrant in patients with PTEN-mutant ER+ MBC. Safety and tolerability were assessed by standard methods. Plasma and tumor were collected for NGS and immunohistochemistry analyses of PTEN protein expression. In 31 eligible patients (12 fulvestrant naive; 19 fulvestrant pretreated), the 24-week clinical benefit rate was 17% in fulvestrant-naive and 42% in fulvestrant-pretreated patients, with objective response rate of 8% and 21%, respectively. Non-functional PTEN was centrally confirmed in all cases by NGS or immunohistochemistry. Co­mutations occurred in PIK3CA (32%), with less ESR1 (10% vs 72%) and more TP53 (40% vs 28%) alterations in fulvestrant-naive versus fulvestrant-pretreated patients, respectively. PTEN was clonally dominant in most patients. Treatment-related grade ≥3 adverse events occurred in 32% of patients, most frequently diarrhea and maculopapular rash (both n = 2). In this clinical study, which selectively targeted the aggressive PTEN-mutant ER+ MBC, capivasertib plus fulvestrant was tolerable and clinically active. Phenotypic and genomic differences were apparent between fulvestrant-naive and -pretreated patients. Trial registration number for the study is NCT01226316.

Abstract Background MDM2/MDMX proteins are frequently elevated in hormone receptor-positive (ER+) breast cancer. We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models. Methods Three hundred two cell lines representing multiple tumor types were screened to confirm the role of TP53 status in ALRN-6924 efficacy. ER+ breast cancer cell lines (MCF-7 and ZR-75-1) were used to investigate the antitumor efficacy of ALRN-6924 combination. In vitro cell proliferation, cell cycle, and apoptosis assays were performed. Xenograft tumor volumes were measured, and reverse-phase protein array (RPPA), immunohistochemistry (IHC), and TUNEL assay of tumor tissues were performed to evaluate the in vivo pharmacodynamic effects of ALRN-6924 with paclitaxel. Results ALRN-6924 was active in wild-type TP53 (WT-TP53) cancer cell lines, but not mutant TP53. On ER+ breast cancer cell lines, it was synergistic in vitro and had enhanced in vivo antitumor activity with both paclitaxel and eribulin. Flow cytometry revealed signs of mitotic crisis in all treatment groups; however, S phase was only decreased in MCF-7 single agent and combinatorial ALRN-6924 arms. RPPA and IHC demonstrated an increase in p21 expression in both combinatorial and single agent ALRN-6924 in vivo treatment groups. Apoptotic assays revealed a significantly enhanced in vivo apoptotic rate in ALRN-6924 combined with paclitaxel treatment arm compared to either single agent. Conclusion The significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.

Abstract Fatigue is the most prevalent symptom of cancer and its treatments. Changes in the intestinal microbiome have been identified in chronic fatigue syndrome and other neuropsychiatric disorders, and cancer patients. However, the association between intestinal microbiome and fatigue in patients with advanced cancers has not been evaluated. Understanding the connection between intestinal microbiome and fatigue will provide interventional and therapeutic opportunities to manipulate the microbiome to improve fatigue and other patients’ reported outcomes. In this project, we aimed to identify associations between microbiome composition and fatigue in advanced cancer patients. In this cross-sectional observational study at a tertiary cancer care center, we included 88 patients with advanced, metastatic, unresectable cancers who were in a washout period from chemotherapy. We measured fatigue using the MD Anderson Symptom Inventory—Immunotherapy fatigue score, and used 16srRNA to analyze intestinal microbiome. Using correlation analysis we found that Eubacterium hallii was negatively associated with fatigue severity scores (r = − 0.30, p = 0.005), whereas Cosenzaea was positively associated with fatigue scores (r = 0.33, p = 0.0002). We identified microbial species that exhibit distinct composition between high-fatigued and low-fatigued cancer patients. Further studies are warranted to investigate whether modulating the microbiome reduces cancer patients’ fatigue severity and improves their quality of life.

Abstract Precision medicine is associated with favorable outcomes in selected patients with cancer. Herein, we report an interim analysis of IMPACT2, an ongoing randomized study evaluating genomic profiling and targeted agents in metastatic cancer. Patients with metastatic cancer underwent tumor genomic profiling (ClinialTrials.gov: NCT02152254), and 69 patients met the criteria for randomization. Tumor board and multidisciplinary review of molecular alterations optimized treatment selection. From 5/2014 to 4/2017, 320 patients (median age, 63 years; men, 47%) had tumor molecular aberrations, and 213 (66.56%) received anticancer therapy. The most frequently mutated genes were TP53 (42%), KRAS (16%), PIK3CA (12%), and CDKN2A (11%). The median OS was 10.9 months (95% CI, 8.8–12.9). OS was shorter in patients with higher tumor mutational burden. Independent factors associated with shorter OS were age ≥60 years, liver metastases, low albumin levels, high LDH levels, and KRAS and TP53 mutations. Outcomes for randomized patients will be reported after completion of the study.

Abstract DNA repair gene aberrations (GAs) occur in several cancers, may be prognostic and are actionable. We investigated the frequency of DNA repair GAs in gallbladder cancer (GBC), association with tumor mutational burden (TMB), microsatellite instability (MSI), programmed cell death protein 1 (PD-1), and its ligand (PD-L1) expression. Comprehensive genomic profiling (CGP) of 760 GBC was performed. We investigated GAs in 19 DNA repair genes including direct DNA repair genes (ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, and RAD50) and caretaker genes (BAP1, CDK12, MLL3, TP53, and BLM) and classified patients into 3 groups based on TMB level: low (

Uterine serous carcinoma (USC) is an uncommon subtype of endometrial cancer with a poor prognosis. USCs have genomic alterations in the PI3K pathway. A prior phase II study of AKT inhibitor MK-2206 (an allosteric AKT inhibitor, primarily affecting AKT1 and AKT2) in endometrial cancers resulted in progression-free survival (PFS) of ≥6 months in five out of seven patients with USC. To further assess the activity of MK-2206 in USC, we designed a phase II, single-stage assessment of MK-2206 in patients with advanced or recurrent high-grade serous endometrial cancer, who had received up to two lines of prior therapy. MK-2206 (135 mg) was administered orally once per week, in continuous 28-day cycles. Fourteen patients received treatment. The most common treatment-related adverse events were diarrhea (36%), acneiform rash (36%), nausea (29%), fatigue (29%), and hyperglycemia (21%); most events were grade 1–2. One confirmed partial response was observed in a patient who was also alive and progression-free at 6 months. One additional patient was alive and progression-free at 6 months. The clinical benefit rate was 14.3% (95% CI: 1.8 to 42.8). Five patients had stable disease (35.7%) and seven had progressive disease (50%); one was unevaluable. Median PFS was 2 months (95% CI: 1.6 to 4.4) and median overall survival was 6.4 months (95% CI: 5.1 to not reached). In summary, MK-2206 had limited activity in USC, although a few patients achieved sustained progression-free intervals in this study and in the previously reported phase II trial of MK-2206. Further investigations are needed to identify features associated with response.

Abstract Background Angiogenesis and activation of the epidermal growth factor (EGFR) pathway play an essential role in tumor proliferation and metastasis. Targeting angiogenesis or EGFR alone does not yield adequate tumor control in most solid tumors. Overcoming intrinsic and/or acquired resistance may need a doublet or triplet therapy strategy. Herein, we report the safety and feasibility of dual EGFR blockade with EGFR monoclonal antibody and EGFR tyrosine kinase inhibitor combined with anti-VEGF antibody in advanced solid tumors. Methods We conducted a phase I study combining erlotinib, cetuximab, and bevacizumab. Patients with advanced or metastatic solid tumors (excluding colorectal and non-small cell lung cancers) were analyzed for safety, toxicity profile, and response. Anti-tumor activity was evaluated per response evaluation criteria in solid tumors (RECIST 1.0). Results Thirty-six patients received treatment on a range of dose-levels. The most frequent tumor types enrolled were cervical (n = 10), head and neck squamous cell (n = 10), and follicular thyroid (n = 4) cancers. The most common treatment-related grade ≥ 2 adverse events were rash (56%), hypomagnesemia (17%), pruritus (11%), diarrhea (8%), and tumor-related bleeding (8%). Seventeen of 19 patients (89%) treated at the maximum tolerated dose did not present treatment-related dose-limiting toxicity. Fifteen (63%) of the 24 evaluable patients achieved a disease control (stable disease ≥ 4 months (n = 14) and partial response (n = 1). The median number of prior lines of therapies was 3 (range 1–10). Conclusions The triplet combination of erlotinib, cetuximab, and bevacizumab was well tolerated, conferring clinical benefit in heavily pretreated patients. Future studies are warranted with second or third-generation EGFR tyrosine kinase triplet combinations in the EGFR pathway aberrant patients. Trial Registration: ClinicalTrials.gov Identifier: NCT00543504. Sponsor(s): National Cancer Institute (NCI), MD Anderson Cancer Center

Background: Polymorphism within the human T-cell receptor beta variable (TRBV) gene has been proposed as a risk factor for autoimmune disease and immune-related adverse events (IRAEs) during immunotherapy. Previous efforts to evaluate TRBV polymorphism by whole genome sequencing have been hampered by the repetitive nature of the T-cell receptor beta (TCRB) locus. We present a novel long-amplicon TCRB repertoire sequencing approach to enable TRBV haplotype analysis from peripheral blood. Methods: Peripheral blood leukocyte total RNA from 81 Caucasians was used for sequencing of TCRB chains via the Oncomine TCRB-LR assay (amplicon spanning CDR1, 2 and 3) and the Ion Gene Studio S5. VDJ rearrangements were annotated by comparison to the IMGT database, then mined to construct TRBV allele profiles for each individual including, where detected, novel alleles not present in the ImMunoGeneTics (IMGT) database. Finally, TRBV allele profiles were subjected to principal component analysis and k-means clustering to identify TRBV allele haplotypes. Results: Clustering analysis revealed the presence of six major sets of coincident TRBV alleles, which we term haplotype groups. Allelic diversity varied markedly across haplotype groups, with approximately one third of the cohort showing limited TRBV allelic diversity and few uncommon alleles compared to members of other groups. Analysis revealed 37 putatively novel TRBV alleles that are absent from the IMGT database. Conclusion: We demonstrate a straightforward and cost-efficient method for TRBV haplotype analysis from long-amplicon TCRB sequencing data.

Abstract Background Adrenocortical carcinoma (ACC) is a rare malignancy without good treatment options. There are limited data about the use of immunotherapy in ACC. We investigated the efficacy and safety of pembrolizumab in patients with metastatic ACC. Methods This is a pre-specified cohort of a single-center, investigator-initiated, phase II clinical trial using pembrolizumab monotherapy in patients with rare malignancies. Patients must have had prior treatment fail in the past 6 months before study enrollment. Patients were enrolled from August 2016 to October 2018. Follow-up data were updated as of March 26, 2019. Patients received 200 mg pembrolizumab intravenously every 3 weeks without concomitant oncologic therapy. The primary endpoint was non-progression rate (NPR) at 27 weeks. Other endpoints included adverse events, tumor responses measured independently by objective radiologic criteria, and select immunological markers. Results Sixteen patients with ACC (including eight women [50%]) were included in this cohort. Ten patients (63%) had evidence of hormonal overproduction (seven had cortisol-producing ACC). Non-progression rate at 27 weeks was evaluable in 14 patients, one patient was lost to follow-up, and one patient left the study because of an adverse event. Five of 14 patients were alive and progression-free at 27 weeks (non-progression rate at 27 weeks was 36, 95% confidence interval 13–65%). Of the 14 patients evaluable for imaging response by immune-related Response Evaluation Criteria in Solid Tumors, two had a partial response (including one with cortisol-producing ACC), seven had stable disease (including three with cortisol-producing ACC), and five had progressive disease, representing an objective response rate of 14% (95% confidence interval 2–43%). Of those who had stable disease, six had disease stabilization that lasted ≥4 months. Severe treatment-related adverse events (≥grade 3) were seen in 2 of 16 patients (13%) and resulted in one patient discontinuing study participation. All studied tumor specimens (14/14) were negative for programmed cell death ligand-1 expression. Thirteen of 14 tumor specimens (93%) were microsatellite-stable. Eight of 14 patients (57%) had a high tumor-infiltrating lymphocyte score on immunohistochemistry staining. Conclusions Single-agent pembrolizumab has modest efficacy as a salvage therapy in ACC regardless of the tumor’s hormonal function, microsatellite instability status, or programmed cell death ligand-1 status. Treatment was well tolerated in most study participants, with a low rate of severe adverse events. Trial registration ClinicalTrials.gov identifier: NCT02721732, Registered March 29, 2016.

Abstract Background The PI3K/AKT pathway is activated through PIK3CA or AKT1 mutations and PTEN loss in breast cancer. We conducted a phase II trial with an allosteric AKT inhibitor MK-2206 in patients with advanced breast cancer who had tumors with PIK3CA/AKT1 mutations and/or PTEN loss/mutation. Methods The primary endpoint was objective response rate (ORR). Secondary endpoints were 6-month progression-free survival (6 m PFS), predictive and pharmacodynamic markers, safety, and tolerability. Patients had pre-treatment and on-treatment biopsies as well as collection of peripheral blood mononuclear cells (PBMC) and platelet-rich plasma (PRP). Next-generation sequencing, immunohistochemistry, and reverse phase protein arrays (RPPA) were performed. Results Twenty-seven patients received MK-2206. Eighteen patients were enrolled into the PIK3CA/AKT1 mutation arm (cohort A): 13 had PIK3CA mutations, four had AKT1 mutations, and one had a PIK3CA mutation as well as PTEN loss. ORR and 6 m PFS were both 5.6% (1/18), with one patient with HR+ breast cancer and a PIK3CA E542K mutation experiencing a partial response (on treatment for 36 weeks). Nine patients were enrolled on the PTEN loss/mutation arm (cohort B). ORR was 0% and 6 m PFS was 11% (1/9), observed in a patient with triple-negative breast cancer and PTEN loss. The study was stopped early due to futility. The most common adverse events were fatigue (48%) and rash (44%). On pre-treatment biopsy, PIK3CA and AKT1 mutation status was concordant with archival tissue testing. However, two patients with PTEN loss based on archival testing had PTEN expression on the pre-treatment biopsy. MK-2206 treatment was associated with a significant decline in pAKT S473 and pAKT T308 and PI3K activation score in PBMC and PRPs, but not in tumor biopsies. By IHC, there was no significant decrease in median pAKT S473 or Ki-67 staining, but a drop was observed in both responders. Conclusions MK-2206 monotherapy had limited clinical activity in advanced breast cancer patients selected for PIK3CA/AKT1 or PTEN mutations or PTEN loss. This may, in part, be due to inadequate target inhibition at tolerable doses in heavily pre-treated patients with pathway activation, as well as tumor heterogeneity and evolution in markers such as PTEN conferring challenges in patient selection. Trial registration ClinicalTrials.gov, NCT01277757. Registered 13 January 2011.

After publication of this supplement [1, 2], it was brought to our attention that due to an error authors were missing in the following abstracts. This has now been included in this correction.

Objective:. A prospective, phase IV study was conducted to assess the effectiveness of Magseed to localize breast lesions requiring surgical excision. Background:. Since Food and Drug Administration approval in 2016, Magseed has been increasingly used to localize nonpalpable lesions due to advantages over wires or radioactive seeds. This is the first prospective, postmarketing trial of Magseed. Methods:. From January 2017 to February 2018, 107 women with lesions requiring localization were enrolled at a single institution. Primary endpoint was Magseed retrieval rate. Secondary endpoints were adverse events, accuracy of placement, surgery duration, and positive margin rate. Clinicians were surveyed for ease of use using a Likert scale. Descriptive statistics and Fisher exact test were performed to assess univariable associations with positive margins. Results:. There were 124 Magseeds placed including 1 marker in 93 subjects, 2 markers in 11, and 3 markers in 3. The majority of lesions were masses (63%) followed by calcifications (24%). All 124 Magseeds were placed within 10 mm of the target lesion and surgically retrieved with median operative time of 15 minutes (range, 4–47). No device-related adverse events occurred. Of the 98 malignant lesions, 9 had positive margins and 7 of them underwent a second surgery for additional margins. On univariable analysis, age ≤50 (25.0% vs 6.4%, P = 0.04), lesion histology (P = 0.03), and pathologic T stage (P = 0.04) were significantly associated with positive margins. Clinicians rated the Magseed very or fairly easy to use in most cases. Conclusions:. The Magseed system for localization of nonpalpable lesions was effective and safe; all markers were successfully retrieved with margin-negative resections in 91%. This study supports use of Magseed for localization of breast lesions.

Purpose The receptor tyrosine kinase rearranged during transfection (RET) can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib and vandetanib have demonstrated activity in RET-dependent malignancies, and selective RET inhibitors (Selpercatinib and Pralsetinib) are in clinical trials. However, the responsiveness of RET-dependent malignancies to immune checkpoint inhibitors (ICIs) is unknown. We compared the time to treatment discontinuation (TTD) for ICI versus non-ICI therapy in patients with malignancies harbouring activating RET mutations or fusions (RET+).Methods A retrospective review of all RET+ patients who were referred to the phase I clinical trials programme at the University of Texas MD Anderson Cancer Center was conducted. TTD was estimated using Kaplan-Meier analysis. Multivariate analysis using the Cox proportional hazard model was performed to identify independent risk factors of treatment discontinuation.Results Of 70 patients who received systemic therapy for RET+ malignancies, 20 (28.6%) received ICI and 50 (71.4%) received non-ICI therapy. Non-ICI therapy was associated with decreased risk for treatment discontinuation compared with ICI in the overall population (HR=0.31; 95% CI 0.16–0.62; p=0.000834) and in patients with RET point mutations (HR=0.13; 95% CI 0.04–0.45; p=0.00134). In patients with RET fusions, non-ICI therapy was associated with a non-statistically significant decreased risk of treatment discontinuation (HR=0.59; 95% CI 0.25–1.4; p=0.24). ICI therapy and a diagnosis other than medullary thyroid cancer (MTC) were independent risk factors for treatment discontinuation.Conclusion Our study supports the prioritisation of non-ICI over ICI therapy in patients with RET+ tumours.

With the advent of immunotherapeutic agents, durable and dramatic responses have been observed in several hard-to-treat malignancies, outlining a roadmap to conquering cancer. Immune checkpoint inhibitors (ICPi) are a class of immunotherapeutic agents that attack the tumor cells by reinvigorating the suppressed immune system. However, the unbridled T-cell activity disrupts the immune homeostasis and induces a unique spectrum of side effects called immune-related adverse events (irAEs) in a significant proportion of patients. These irAEs are distinct from the side effects produced by traditional chemotherapeutic agents. Although majority of irAEs are manageable with corticosteroids and other immunosuppressive agents, life-threatening and fatal events have been reported. In the absence of predictive biomarkers to identify patients at risk for irAEs and standardized approach to detect, report, and treat irAEs, management of irAEs has been challenging to the patients, caregivers and the healthcare providers alike. With increasing use of ICPis for treatment of various cancers, the incidence of irAEs will undoubtedly increase. There is a compelling need to develop measures to effectively manage irAEs, both in the community settings and in cancer centers alike. To this end, in this paper, we propose several strategies, such as providing patient education, harmonizing irAE management guidelines, standardizing reporting of irAEs, optimizing the choice of immunosuppressive agents, conducting preclinical, clinical and translational studies to better understand irAEs, including high-risk patients, incorporating diagnostic tools to personalize irAE management using wireless technology and digital health, providing a platform to hear the missing patient’s voice, and sharing evolving data to improve the management of irAEs.