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Clear cell renal cell carcinoma (RCC) is commonly associated with alterations in the VHL tumor suppressor gene, resulting in upregulation of hypoxia-inducible factor pathways. Immune checkpoint inhibitors and vascular endothelial growth factor inhibitors are the mainstays of systemic treatment for metastatic RCC; however, most patients encounter disease progression after the initial response. The phase 3 clinical trial LITESPARK-005–belzutifan (HIF-2α inhibitor) demonstrated improvement in progression-free survival compared with everolimus in heavily pretreated patients unselected for somatic/germline VHL alterations (an objective response rate of 23% and a median time on therapy of 7.6 months in the belzutifan cohort), resulting in U.S. FDA approval for patients with advanced RCC. Herein, we present two cases of refractory metastatic RCC (including one with brain metastases) with somatic VHL mutations who received belzutifan after discussion in the institutional Molecular Tumor Board. Both patients had an excellent clinical response (partial remissions ongoing at >12 and >20 months). Future studies should assess the merits of biomarker selection for belzutifan treatment.

Abstract Background Kinase-impaired class III BRAF mutations have recently received attention as a possible prognostic factor and therapeutic target. Class III BRAF variants differ from class I and class II mutations in terms of mechanism of pathway activation and therapeutic vulnerabilities. Genomic landscape analyses of tumors in large real-world cohorts represent a great opportunity to further characterize tumor-related molecular events and treatment vulnerabilities, however, such data is not yet available for tumors with BRAF class III mutations. Methods We investigated the pan-cancer genomic landscape of BRAF class III mutations in 376,302 patients. Patients had comprehensive genomic profiling either by FoundationOne® or FoundationOne®CDx from formalin-fixed, paraffin embedded tissue biopsies. 2 patient cases that harbored BRAF class III mutations who demonstrated dramatic response to anti-EGFR treatment were presented. Results BRAF class III mutations are likely to co-occur with RAF1, NRAS and HRAS alterations, while concomitant KRAS alterations were rare. Moreover, we found that alterations that predict resistance to anti-EGFR agents were significantly less common in tumors harboring BRAF class III mutations, which is of great importance as anti-EGFR therapies are a potential targeted treatment option in these tumors. Discussion Our findings suggest a heterogenous interplay of oncogenic alterations in BRAF class III mutated tumors and have important implications for the molecular mechanisms of carcinogenesis while revealing potential therapeutic vulnerabilities. Highlights Tumors harboring BRAF class III (BRAF vIII) mutations comprise a novel subset with distinct genomic heterogeneity. BRAF vIII mutations may sensitize tumors to anti-EGFR treatments. BRAF vIII alterations show significantly less co-occurrence with alterations that predict resistance to anti-EGFR agents. Rare tumors with limited therapy options should be screened for BRAF vIII mutations as they may benefit from anti-EGFR agents.

A 62-year-old man presented with a slowly growing, painless lesion on his face. This eventually led to a progressive left-eye vision lesion, and the patient was subsequently diagnosed with advanced basal cell carcinoma (BCC). Of note, BCC involving cranial nerves is extremely rare, making this case unique and important to highlight. Standard treatment options for BCC involve surgery, radiation, or platinum-based chemotherapy. However, targeted therapies such as sonidegib and vismodegib – sonic hedgehog pathway inhibitors – have emerged that have been approved for treating BCC, as have anti-PD1 immunotherapies, such as cemiplimab, with their success likely based on the high tumor mutational burden seen in some of these tumors. Epidermal growth factor receptor (EGFR) inhibitors also serve a role in treating this condition as well. Molecular studies on metastatic/advanced BCC and other rare malignancies may inform treatment therapeutic decisions.

Background: Anti-programmed death-1 (PD-1)/cytotoxic T lymphocyte antigen-4 antibodies are efficacious in various malignancies. Objectives: This study presents the first results of ipilimumab–nivolumab in invasive mucinous or non-mucinous lepidic adenocarcinoma (invasive mucinous adenocarcinoma (IMA) or invasive non-mucinous lepidic adenocarcinomas (INLA), respectively) of the lung. Design: Dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) is a prospective, open-label, multicenter (1016 US sites), multi-cohort phase II trial of ipilimumab (1 mg/kg intravenously (IV) every 6 weeks) plus nivolumab (240 mg IV every 2 weeks). Methods: Participants histologically diagnosed with advanced IMA or INLA, who had not responded to at least one line of therapy, were included in the bronchioloalveolar carcinoma cohort. The primary endpoint was the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (confirmed complete and partial responses (CR and PR)). Secondary endpoints were progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR; stable disease (SD) ⩾ 6 months plus ORR), and toxicity. Results: Eight evaluable patients (median age: 77 years; the number of prior therapies ranged from 0 to 4; one patient with prior exposure to a PD-1 inhibitor; comprising six IMA and two INLA) were treated. One IMA had a 40% regression (PFS 45.2+ months, PD-L1 0%, KRAS G12C mutated, tumor mutational burden [TMB] 13 mut/Mb). One INLA had 66% regression (PFS 23.8 months, PD-L1 unknown, no actionable mutations, TMB 3 mut/Mb). Overall ORR was 25.0% (2/8) and CBR, 62.5% (5/8); PFS for the patients with SD > 6 months was 43.4+, 11.7+, and 8.3 months. The median PFS was 16 months (5.3–not reached) and the median OS was 32.2 months (14.6–not reached). The toxicity profile was similar to previous reports. Conclusion: Ipilimumab plus nivolumab in the bronchioloalveolar carcinoma cohort (IMA, INLA) resulted in a durable ORR of 25.0% and CBR of 62.5% (PFS, 8.3 11.7+. 23.8 (PR), 43.4+ and 45.2+ (PR) months). Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies are warranted. Trial registration: ClinicalTrials.gov registry: NCT02834013.

Background: Dysregulated pathways in cancer may be hub addicted. Identifying these dysregulated networks for targeting might lead to novel therapeutic options. Objective: Considering the hypothesis that central hubs are associated with increased lethality, identifying key hub targets within central networks could lead to the development of novel drugs with improved efficacy in advanced metastatic solid tumors. Design: Exploring transcriptomic data (22,000 gene products) from the WINTHER trial ( N = 101 patients with various metastatic cancers), in which both tumor and normal organ-matched tissue were available. Methods: A retrospective in silico analysis of all genes in the transcriptome was conducted to identify genes different in expression between tumor and normal tissues (paired t -test) and to determine their association with survival outcomes using survival analysis (Cox proportional hazard regression algorithm). Based on the biological relevance of the identified genes, hub targets of interest within central networks were then pinpointed. Patients were grouped based on the expression level of these genes ( K -mean clustering), and the association of these groups with survival was examined (Cox proportional hazard regression algorithm, Forest plot, and Kaplan–Meier plot). Results: We identified four key central hub genes— PLOD3, ARHGAP11A, RNF216 , and CDCA8 , for which high expression in tumor tissue compared to analogous normal tissue had the most significant correlation with worse outcomes. The correlation was independent of tumor or treatment type. The combination of the four genes showed the highest significance and correlation with the poorer outcome: overall survival (hazard ratio (95% confidence interval (CI)) = 10.5 (3.43–31.9) p = 9.12E−07 log-rank test in a Cox proportional hazard regression model). Findings were validated in independent cohorts. Conclusion: The expression of PLOD3, ARHGAP11A, RNF216 , and CDCA8 constitute, when combined, a prognostic tool, agnostic of tumor type and previous treatments. These genes represent potential targets for intercepting central hub networks in various cancers, offering avenues for novel therapeutic interventions.

ABSTRACT: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that primarily causes the growth of tumors alongnerves. Additionally, the germline mutations involved in NF1 predispose patients to develop further malignancies. The mainstay initial treatment for these malignancies is surgical removal at diagnosis, although targeted therapies are under evaluation in the relapsed setting. We report a case of malignant peripheral nerve sheath tumor (MPNST), gastrointestinal stromal tumor (GIST), and pheochromocytoma in a patient with NF1 who presented with an infected right shoulder lesion that was confirmed to be spindle cell sarcoma via biopsy. She was treated with antibiotics; however, she rapidly deteriorated and opted for hospice care. NF1 germline mutations increase the risk of patients developing various types of cancer. Recent studies have shown that there is a rolefor using MEK inhibitors such as selumetinib for treating patients with NF1.

Carcinoma of unknown primary (CUP) is a difficult‐to‐manage malignancy. Multi‐omic profiles and treatment outcome vs. degree of precision matching were assessed. Tumours underwent next‐generation sequencing (NGS) [tissue and/or blood‐derived cell‐free DNA (cfDNA)]. Selected patients had transcriptome‐based immune profiling and/or programmed cell death 1 ligand 1 (PD‐L1) immunohistochemistry analysis. Patients could be reviewed by a Molecular Tumor Board, but physicians chose the therapy. Of 6497 patients in the precision database, 97 had CUP. The median number of pathogenic tissue genomic alterations was 4 (range, 0–25), and for cfDNA, was 2 (range, 0–9). Each patient had a distinct molecular landscape. Food and Drug Administration (FDA)‐approved biomarkers included the following: PD‐L1+ ≥ 1%, 30.9% of CUPs tested; microsatellite instability, 3.6%; tumour mutational burden ≥ 10 mutations·Mb−1, 23%; and neurotrophic receptor tyrosine kinase (NTRK) fusions, 0%. RNA‐based immunograms showed theoretically druggable targets: lymphocyte activation gene 3 protein (LAG‐3), macrophage colony‐stimulating factor 1 receptor (CSF1R), adenosine receptor A2 (ADORA2) and indoleamine 2,3‐dioxygenase 1 (IDO1). Overall, 56% of patients had ≥ 1 actionable biomarker (OncoKB database). To quantify the degree of matching (tumours to drugs), a Matching Score (MS; roughly equivalent to number of alterations targeted/total number of deleterious alterations) was calculated post hoc. Comparing evaluable treated patients [MS high, > 50% (N = 15) vs. low ≤ 50% (N = 47)], median progression‐free survival was 10.4 vs. 2.8 months (95% CI 0.11–0.64; HR 0.27; P = 0.002); survival, 15.8 vs. 6.9 months (95% CI 0.17–1.16; HR 0.45; P = 0.09); and clinical benefit rate (stable disease ≥ 6 months/partial/complete response), 71% vs. 24% (P = 0.003). Higher MS was the only factor that predicted improvement in outcome variables after multivariate analysis. In conclusion, CUPs are molecularly complex. Treatments with high degrees of matching to molecular alterations (generally achieved by individualized combinations) correlated with improved outcomes.

Background Dual inhibition using anti-programmed death-1 (PD-1) and anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) checkpoint inhibitors has proven effective in many cancers. However, its efficacy in rare solid cancers remains unclear. Desmoid tumors are ultrarare soft-tissue tumors, traditionally treated with surgery. This study reviews the first results of using ipilimumab and nivolumab in the desmoid tumor cohort of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial.Methods DART is a prospective/open-label/multicenter (1,016 US sites)/multicohort phase II trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) that opened at 1,016 US sites. The primary endpoint included overall response rate (ORR) defined as confirmed complete (CR) and partial responses (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1. Secondary endpoints include progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR; stable disease (SD) ≥6 months plus CR and PR) and toxicity.Results Sixteen evaluable patients (median age: 37) with desmoid tumors and a median of 1.5 prior therapies (with no prior exposure to immunotherapy) were analyzed. The tumors varied in location (eight abdomen, three lower limb, two upper limb, two pelvis, and one neck). ORR was 18.8% (3/16; 3 confirmed PR): 40% regression (PFS 30+ months), 83% regression (PFS 16 months) and 71% regression (PFS 8.4 months). Seven additional patients (43.8%) had prolonged SD over 6 months (PFS: 16.5, 22.4+, 22.6, 30.1, 38.2+, 48.3+ and 60.7+ months). Overall CBR was 62.5% (10/16). Median PFS was 19.4 months, with 6-month PFS of 73% and 1-year PFS of 67%. All patients were alive at 1 year; median OS was not assessable, as 13 patients were alive at analysis. Common adverse events included fatigue, nausea and hypothyroidism, with 50% experiencing grade 3–4 events. There were no grade 5 events.Conclusion Treatment with ipilimumab and nivolumab in desmoid tumors yielded an ORR of 18.8% and a CBR of 62.5% with durable responses seen. This is the first prospective study exploring the efficacy of this combination in this rare disease. Ongoing studies aim to identify markers for response and resistance. Expanded trials are necessary.Trial registration number NCT02834013.

Background: The prognostic implications of tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are poorly studied in hematologic malignancies. Objectives: This study aimed to better understand the characteristics and prognostic value of TMB and PD-1/PD-L1 in hematologic malignancies. Design: This real-world study was conducted among patients with hematologic malignancies who had next-generation sequencing (NGS) (Foundation Medicine) at the University of California San Diego Moores Cancer Center (2014–2018). Methods: TMB was measured by NGS. PD-L1 expression (tumor proportion score, TPS) was measured by immunohistochemistry (classified as high (⩾50%), low (1–49%), and negative (

Summary: Treatment of rare/ultra-rare tumors is an unmet need due to a lack of standardized therapies and clinical trials. We developed the Molecular Tumor Board (MTB), a multidisciplinary team that integrates molecular profiling to generate personalized, N-of-One treatments for advanced cancers. This study evaluates 112 patients with rare/ultra-rare tumors who presented to the MTB and were evaluable for clinical therapeutic outcome. Overall, 46/112 patients (41%) received a treatment regimen with a high degree of matching between tumor molecular alterations and drugs given (reflected by a high Matching Score (≥50%)). Patients with a high versus low Matching Score experienced significantly longer progression-free survival (p = 0.005) and overall survival (p = 0.047), and higher rates of clinical benefit (stable disease ≥6 months, partial response, or complete response) (54% vs. 32% p = 0.027). The MTB facilitated personalized N-of-One matching of drugs to tumor molecular alterations, which was associated with improved clinical outcomes in patients with rare/ultra-rare cancers.

Objectives Multiple common cancers benefit from immunotherapy; however, less is known about efficacy in rare tumors. We report the results of the adrenocortical carcinoma cohort of NCI/SWOG S1609 Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors.Design/setting A prospective, phase 2 clinical trial of ipilimumab plus nivolumab was conducted by the SWOG Early Therapeutics and Rare Cancers Committee for multiple rare tumor cohorts across >1,000 National Clinical Trial Network sites.Participants 21 eligible patients were registered. Median age was 53 years (range 26–69); 16 (76%) were women.Interventions Ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks was administered until disease progression, symptomatic deterioration, treatment delay for any reason >56 days, unacceptable or immune-related toxicity with inability to decrease prednisone to 6 months), progression-free survival (PFS), overall survival (OS), and toxicity. Immune-related outcomes included immune ORR (iORR), immune CBR (iCBR), and immune PFS (iPFS). A two-stage design was used assuming: null=5% alternative=30%, n=6 in the first stage, 16 max, one-sided alpha=13%.Results The median number of prior therapy lines was 2 (range: 1–9). 3 of 21 patients attained confirmed partial response (PR) (ORR=14%). In addition, one patient had an unconfirmed PR; one, stable disease (SD)>6 months; one, immune-related RECIST (iRECIST) PR (iPR); and one patient attained iSD>6 months: clinical benefit rate (response or SD>6 months)=5/21 (24%), iORR=4/21 (19%), iCBR=7/21 (33%). The 6-month PFS was 24%; 6-month iPFS, 33%. The PFS for patients (N=7) with iRECIST clinical benefit were 57, 52, 18, 15, 13, 7, and 7 months. The 6-month OS was 76%; the median OS, was 15.8 months. The most common toxicities were fatigue (62%) and rash (38%), and the most common grade 3/4 immune-related adverse events were hepatic dysfunction (9.5%) and adrenal insufficiency (9.5%). Treatment-related adverse events leading to discontinuation of therapy in four patients (21%). There were no grade 5 adverse events.Conclusions Ipilimumab plus nivolumab is active in refractory metastatic adrenocortical cancer meeting the primary endpoint of the study, with a 19% iORR and 33% iCBR (includes SD/iSD>6 months) and with the longest PFS/iPFS of 52 and 57 months.Trial registration number NCT02834013 (registered 15 July, 2016; https://clinicaltrials.gov/ct2/show/NCT02834013).

Abstract Identifying sex differences in outcomes and toxicity between males and females in oncology clinical trials is important and has also been mandated by National Institutes of Health policies. Here we analyze the Trialtrove database, finding that, strikingly, only 472/89,221 oncology clinical trials (0.5%) had curated post-treatment sex comparisons. Among 288 trials with comparisons of survival, outcome, or response, 16% report males having statistically significant better survival outcome or response, while 42% reported significantly better survival outcome or response for females. The strongest differences are in trials of EGFR inhibitors in lung cancer and rituximab in non-Hodgkin’s lymphoma (both favoring females). Among 44 trials with side effect comparisons, more trials report significantly lesser side effects in males (N = 22) than in females (N = 13). Thus, while statistical comparisons between sexes in oncology trials are rarely reported, important differences in outcome and toxicity exist. These considerable outcome and toxicity differences highlight the need for reporting sex differences more thoroughly going forward.

Abstract Background Neuregulin-1 (NRG1) is implicated in both cancer and neurologic diseases such as amyotrophic lateral sclerosis (ALS); however, to date, there has been little cross-field discussion between neurology and oncology in regard to these genes and their functions. Main body Approximately 0.15–0.5% of cancers harbor NRG1 fusions that upregulate NRG1 activity and hence that of the cognate ERBB3/ERBB4 (HER3/HER4) receptors; abrogating this activity with small molecule inhibitors/antibodies shows preliminary tissue-agnostic anti-cancer activity. Notably, ERBB/HER pharmacologic suppression is devoid of neurologic toxicity. Even so, in ALS, attenuated ERBB4/HER4 receptor activity (due to loss-of-function germline mutations or other mechanisms in sporadic disease) is implicated; indeed, ERBB4/HER4 is designated ALS19. Further, secreted-type NRG1 isoforms may be upregulated (perhaps via a feedback loop) and could contribute to ALS pathogenesis through aberrant glial cell stimulation via enhanced activity of other (e.g., ERBB1-3/HER1-3) receptors and downstream pathways. Hence, pan-ERBB inhibitors, already in use for cancer, may be agents worthy of testing in ALS. Conclusion Common signaling cascades between cancer and ALS may represent novel therapeutic targets for both diseases.

Background: KRAS wild-type (WT) pancreatic ductal adenocarcinoma (PDAC) represents a distinct entity with unique biology. The therapeutic impact of matched targeted therapy in these patients in a real-world setting, to date, is less established. Objectives: The aim of our study was to review our institutional database to identify the prevalence of actionable genomic alterations in patients with KRAS -WT tumors and to evaluate the therapeutic impact of matched targeted therapy in these patients. Design: We reviewed electronic medical records of patients with KRAS-WT PDAC and advanced disease ( n = 14) who underwent clinical-grade tissue ± liquid next-generation sequencing (315–648 genes for tissue) between years 2015 and 2021. Methods: Demographic and disease characteristics were summarized using descriptive parameters. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Results: Of 236 PDAC patients, 14 had advanced/metastatic disease with KRAS-WT tumors. Median age at diagnosis was 66 years. There was a high frequency of potentially actionable genomic alterations, including three (21%) with BRAF alterations, two (14%) with fusions [ RET-PCM1 and FGFR2-POC1B ( N = 1 each)]; and one with a druggable EGFR ( EGFR E746_A755delISERD) variant; two other patients had an STK11 and a MUTYH alteration. Five patients were treated with matched targeted therapy, with three having durable benefit: (i) erlotinib for EGFR -altered tumor, followed by osimertinib/capmatinib when MET amplification emerged (first-line therapy); (ii) pralsetinib for RET fusion (fifth line); and (iii) dabrafenib/trametinib for BRAF N486_P490del (third line). Duration of time on chemotherapy-free matched targeted therapy for these patients was 17+, 11, and 18+ months, respectively. Conclusion: Sustained therapeutic benefit can be achieved in a real-world setting in a subset of patients with advanced/metastatic KRAS-WT PDAC treated with chemotherapy-free matched targeted agents. Prospective studies are warranted.

Despite multiple recent advances in systemic therapy for metastatic breast cancer, cases which display suboptimal response to guideline-driven treatment are frequently seen in the clinic. Effective options for such patients are limited, particularly in later line of therapy, and selection of optimal treatment options is essentially empirical and based largely on considerations of previous regimens received. Comprehensive cancer profiling includes detection of genetic alterations in tissue and circulating tumor DNA (ctDNA), immunohistochemistry (IHC) from re-biopsied metastatic disease, circulating tumor cells (CTCs), gene expression analysis and pharmacogenomics. The advent of this methodology and application to metastatic breast cancer, facilitates a more scientifically informed approach to identification of optimal systemic therapy approaches independent of the restrictions implied by clinical guidelines. Here we describe a case of metastatic breast cancer where consecutive comprehensive tumor profiling reveals ongoing tumor evolution, guiding the identification of novel effective therapeutic strategies.

This paper presents a patient with a novel Ig-like-III domain fibroblast growth factor receptor (FGFR2) alteration (W290_P307>C) along with CDKN2A/B alterations and a cadherin 1 (CDH1) alteration. Initial responsiveness to pazopanib monotherapy was encouraging, yet progression occurred after 7.5 months. Following progression, the molecular tumor board recommended a combination therapy approach comprising pazopanib, crizotinib, and palbociclib to target all of the changed pathways at the same time. Pazopanib was chosen to specifically target the FGFR2 alteration, while crizotinib was selected due to its potential synthetic lethality with the CDH1 alteration. In addition, the CDK4/6 inhibitor palbociclib was administered to address the CDKN2A/B alterations. The patient exhibited a remarkable and sustained response to this innovative combination. This case not only underscores the potential of tyrosine kinase inhibitors, exemplified by pazopanib, as a viable alternative for patients without access to pan-FGFR inhibitors, but it also emphasizes their efficacy beyond commonly detected point mutations and rearrangements. Notably, the outstanding response to combination therapy, including crizotinib, in a patient with a CDH1 alteration, further substantiates the preclinical evidence of synthetic lethality between crizotinib and CDH1 alterations. To our knowledge, this represents the first clinical evidence demonstrating the efficacy of crizotinib in a patient with a CDH1 alteration. Through careful dosage adjustments and consideration of individualized genomic information, this case exemplifies the power of personalized medicine in achieving favorable treatment outcomes.

Summary: Indoleamine 2,3-dioxygenase 1 (IDO1), which catabolizes tryptophan, is a potential target to unlock the immunosuppressive tumor microenvironment. Correlations between IDO1 and immune checkpoint inhibitor (ICI) efficacy remain unclear. Herein, we investigated IDO1 transcript expression across cancers and clinical outcome correlations. High IDO1 transcripts were more frequent in uterine (54.2%) and ovarian cancer (37.2%) but varied between and within malignancies. High IDO1 RNA expression was associated with high expression of PD-L1 (immune checkpoint ligand), CXCL10 (an effector T cell recruitment chemokine), and STAT1 (a component of the JAK-STAT pathway) (all multivariable p

Abstract In oncology clinical trials, many patients spend their final months at a central clinical trial facility far from home for “mandatory” protocol visits/diagnostic testing. Studies suggest that the travel strain may be greatest among patients living in low‐income areas and/or participating in early-phase studies. In this regard, rare cancers constitute a special unmet need with limited therapeutic options and few trials. Though individually uncommon, rare cancers as a group constitute ~22% of the cancer burden; the portion of cancer burden may even be greater if biomarker-defined rare subsets of either a single cancer type or a tissue-agnostic subgroup are included. Exacerbating the access issue is the fact that, in addition to the paucity of trials, many centers will not activate existing single-arm trials, often due to accrual concerns, which may further disadvantage this patient group and also jeopardize trial completion. Decentralized clinical trials may resolve some of these challenges by allowing patients to participate from close to home. Decentralized clinical trials can take the form of being site-less, with the coordinating body working remotely and care provided by the home oncologist, or by taking the tack of National Cancer Institute/cooperative groups (e.g., NCI-MATCH genomics matching trial or SWOG1609 [NCI] DART immunotherapy rare cancer trial) using a platform design with multiple cohorts and opening at >1000 sites. Decentralized trials now also have supportive FDA guidance. Importantly, home-run trials permit clinical trial access to underserved groups, including those in rural areas and patients financially unable to travel to a central facility.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) has an overall 5-year survival rate of just 12.5% and thus is among the leading causes of cancer deaths. When detected at early stages, PDAC survival rates improve substantially. Testing high-risk patients can increase early-stage cancer detection; however, currently available liquid biopsy approaches lack high sensitivity and may not be easily accessible. Methods Extracellular vesicles (EVs) were isolated from blood plasma that was collected from a training set of 650 patients (105 PDAC stages I and II, 545 controls). EV proteins were analyzed using a machine learning approach to determine which were the most informative to develop a classifier for early-stage PDAC. The classifier was tested on a validation cohort of 113 patients (30 PDAC stages I and II, 83 controls). Results The training set demonstrates an AUC of 0.971 (95% CI = 0.953–0.986) with 93.3% sensitivity (95% CI: 86.9–96.7) at 91.0% specificity (95% CI: 88.3–93.1). The trained classifier is validated using an independent cohort (30 stage I and II cases, 83 controls) and achieves a sensitivity of 90.0% and a specificity of 92.8%. Conclusions Liquid biopsy using EVs may provide unique or complementary information that improves early PDAC and other cancer detection. EV protein determinations herein demonstrate that the AC Electrokinetics (ACE) method of EV enrichment provides early-stage detection of cancer distinct from normal or pancreatitis controls.

Abstract Anaplastic lymphoma kinase (ALK) alterations (activating mutations, amplifications, and fusions/rearrangements) occur in ~3.3% of cancers. ALK fusions/rearrangements are discerned in >50% of inflammatory myofibroblastic tumors (IMTs) and anaplastic large cell lymphomas (ALCLs), but only in ~0.2% of other cancers outside of non-small cell lung cancer (NSCLC), a rate that may be below the viability threshold of even large-scale treatment trials. Five ALK inhibitors –alectinib, brigatinib, ceritinb, crizotinib, and lorlatinib—are FDA approved for ALK-aberrant NSCLCs, and crizotinib is also approved for ALK-aberrant IMTs and ALCL, including in children. Herein, we review the pharmacologic tractability of ALK alterations, focusing beyond NSCLC. Importantly, the hallmark of approved indications is the presence of ALK fusions/rearrangements, and response rates of ~50–85%. Moreover, there are numerous reports of ALK inhibitor activity in multiple solid and hematologic tumors (e.g., histiocytosis, leiomyosarcoma, lymphoma, myeloma, and colorectal, neuroendocrine, ovarian, pancreatic, renal, and thyroid cancer) bearing ALK fusions/rearrangements. Many reports used crizotinib or alectinib, but each of the approved ALK inhibitors have shown activity. ALK inhibitor activity is also seen in neuroblastoma, which bear ALK mutations (rather than fusions/rearrangements), but response rates are lower (~10–20%). Current data suggests that ALK inhibitors have tissue-agnostic activity in neoplasms bearing ALK fusions/rearrangements.

Genomic analysis, performed on tumoral tissue DNA and on circulating tumor DNA (ctDNA) from blood, is the cornerstone of precision cancer medicine. Herein, we characterized the clinical prognostic implications of the concordance of alterations in major cancer genes between tissue‐ and blood‐derived DNA in a pan‐cancer cohort. The molecular profiles of both liquid (Guardant Health) and tissue (Foundation Medicine) biopsies from 433 patients were analyzed. Mutations and amplifications of cancer genes scored by these two tests were assessed. In 184 (42.5%) patients, there was at least one mutual gene alteration. The mean number of mutual gene‐level alterations in the samples was 0.67 per patient (range: 0–5). A higher mutual gene‐level alteration number correlated with shorter overall survival (OS). As confirmed in multivariable analysis, patients with ≥2 mutual gene‐level alterations in blood and tissue had a hazard ratio (HR) of death of 1.49 (95% confidence interval [CI]=1–2.2; P=0.047), whereas patients with ≥3 mutual gene‐level alterations had an HR of death 2.38 (95% CI=1.47–3.87; P=0.0005). Together, our results show that gene‐level concordance between tissue DNA and ctDNA analysis is prevalent and is an independent factor predicting significantly shorter patient survival.

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can cure patients with high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, many patients relapse or develop debilitating graft-versus-host disease. Transplant restores T-cell reactivity against tumor cells, implicating patient human leukocyte antigen (HLA)-dependent antigen presentation via the major histocompatibility complex as a determinant of response. We sought to identify characteristics of the HLA genotype that influence response in allo-HSCT patients. Methods: We collected HLA genotype and panel-based somatic mutation profiles for 55 patients with AML and MDS and available data treated at the University of California San Diego Moores Cancer Center between May 2012 and January 2019. We evaluated characteristics of the HLA genotype relative to relapse-free time and overall survival (OS) post-allo-HSCT using univariable and multivariable regression. Results: In multivariable regression, the presence of an autoimmune allele was significantly associated with relapse-free time (hazard ratio [HR], 0.25; p = 0.01) and OS (HR, 0.16; p < 0.005). The better potential of the donor HLA type to present peptides harboring driver mutations trended toward better relapse-free survival (HR, 0.45; p = 0.07) and significantly correlated with longer OS (HR, 0.33; p = 0.01) though only a minority of cases had an HLA mismatch. Conclusion: In this single institution retrospective study of patients receiving allo-HSCT for relapsed AML/MDS, characteristics of an individual's HLA genotype (presence of an autoimmune allele and potential of the donor HLA to better present peptides representing driver mutations) were significantly associated with better outcomes. These findings suggest that HLA type may guide the optimal application of allo-HSCT and merit evaluation in larger cohorts.

Abstract Immune checkpoint blockade is effective for only a subset of cancers. Targeting T-cell priming markers (TPMs) may enhance activity, but proper application of these agents in the clinic is challenging due to immune complexity and heterogeneity. We interrogated transcriptomics of 15 TPMs (CD137, CD27, CD28, CD80, CD86, CD40, CD40LG, GITR, ICOS, ICOSLG, OX40, OX40LG, GZMB, IFNG, and TBX21) in a pan-cancer cohort (N = 514 patients, 30 types of cancer). TPM expression was analyzed for correlation with histological type, microsatellite instability high (MSI-H), tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) expression. Among 514 patients, the most common histological types were colorectal (27%), pancreatic (11%), and breast cancer (10%). No statistically significant association between histological type and TPM expression was seen. In contrast, expression of GZMB (granzyme B, a serine protease stored in activated T and NK cells that induces cancer cell apoptosis) and IFNG (activates cytotoxic T cells) were significantly higher in tumors with MSI-H, TMB ≥ 10 mutations/mb and PD-L1 ≥ 1%. PD-L1 ≥ 1% was also associated with significantly higher CD137, GITR, and ICOS expression. Patients’ tumors were classified into “Hot”, “Mixed”, or “Cold” clusters based on TPM expression using hierarchical clustering. The cold cluster showed a significantly lower proportion of tumors with PD-L1 ≥ 1%. Overall, 502 patients (98%) had individually distinct patterns of TPM expression. Diverse expression patterns of TPMs independent of histological type but correlating with other immunotherapy biomarkers (PD-L1 ≥ 1%, MSI-H and TMB ≥ 10 mutations/mb) were observed. Individualized selection of patients based on TPM immunomic profiles may potentially help with immunotherapy optimization.

Background: CTLA-4 impedes the immune system’s antitumor response. There are two Food and Drug Administration-approved anti-CTLA-4 agents – ipilimumab and tremelimumab – both used together with anti-PD-1/PD-L1 agents. Objective: To assess the prognostic implications and immunologic correlates of high CTLA-4 in tumors of patients on immunotherapy and those on non-immunotherapy treatments. Design/methods: We evaluated RNA expression levels in a clinical-grade laboratory and clinical correlates of CTLA-4 and other immune checkpoints in 514 tumors, including 489 patients with advanced/metastatic cancers and full outcome annotation. A reference population (735 tumors; 35 histologies) was used to normalize and rank transcript abundance (0–100 percentile) to internal housekeeping gene profiles. Results: The most common tumor types were colorectal (140/514, 27%), pancreatic (55/514, 11%), breast (49/514, 10%), and ovarian cancers (43/514, 8%). Overall, 87 of 514 tumors (16.9%) had high CTLA-4 transcript expression (⩾75th percentile rank). Cancers with the largest proportion of high CTLA-4 transcripts were cervical cancer (80% of patients), small intestine cancer (33.3%), and melanoma (33.3%). High CTLA-4 RNA independently/significantly correlated with high PD-1, PD- L2, and LAG3 RNA levels (and with high PD-L1 in univariate analysis). High CTLA-4 RNA expression was not correlated with survival from the time of metastatic disease [ N = 272 patients who never received immune checkpoint inhibitors (ICIs)]. However, in 217 patients treated with ICIs (mostly anti-PD-1/anti-PD- L1), progression-free survival (PFS) and overall survival (OS) were significantly longer among patients with high versus non-high CTLA-4 expression [hazard ratio, 95% confidence interval: 0.6 (0.4–0.9) p = 0.008; and 0.5 (0.3–0.8) p = 0.002, respectively]; results were unchanged when 18 patients who received anti-CTLA-4 were omitted. Patients whose tumors had high CTLA-4 and high PD-L1 did best; those with high PD-L1 but non-high CTLA-4 and/or other expression patterns had poorer outcomes for PFS ( p = 0.004) and OS ( p = 0.009) after immunotherapy. Conclusion: High CTLA-4, especially when combined with high PD-L1 transcript expression, was a significant positive predictive biomarker for better outcomes (PFS and OS) in patients on immunotherapy.

Abstract Background T‐cell immunoglobulin and mucin domain‐containing protein 3 (TIM‐3), an immune checkpoint receptor, dampens immune function. TIM‐3 antagonists have entered the clinic. Methods We analyzed TIM‐3 transcriptomic expression in 514 diverse cancers. Transcript abundance was normalized to internal housekeeping genes and ranked (0–100 percentile) to a reference population (735 tumors; 35 histologies [high≥75 percentile rank]). Ninety tumors (17.5%) demonstrated high TIM‐3 expression. Results TIM‐3 expression varied between and within tumor types. However, high TIM‐3 expression was more common in pancreatic cancer (20/55 tumors, 36.4%; odds ratio, 95% confidence interval (pancreatic vs. other tumors) = 3.176 (1.733–5.818; p

Abstract Background Lymphocyte activation gene 3 (LAG‐3) or CD223 is a transmembrane protein that serves as an immune checkpoint which attenuates T‐cell activation. Many clinical trials of LAG‐3 inhibitors have had modest effects, but recent data indicate that the LAG‐3 antibody relatlimab, together with nivolumab (anti‐PD‐1), provided greater benefit than nivolumab alone in patients with melanoma. Methods In this study, the RNA expression levels of 397 genes were assessed in 514 diverse cancers at a clinical‐grade laboratory (OmniSeq: https://www.omniseq.com/). Transcript abundance was normalized to internal housekeeping gene profiles and ranked (0–100 percentile) using a reference population (735 tumors; 35 histologies). Results A total of 116 of 514 tumors (22.6%) had high LAG‐3 transcript expression (≥75 percentile rank). Cancers with the greatest proportion of high LAG‐3 transcripts were neuroendocrine (47% of patients) and uterine (42%); colorectal had among the lowest proportion of high LAG‐3 expression (15% of patients) (all p

We performed a literature search in PubMed to identify phase I/II clinical trials with immunotherapy drugs approved by the Food and Drug Administration (labeled, off-label, and/or combined with investigational immune checkpoint inhibitors or other treatment modalities) from 2018 to 2020. We used the following key words: clinical trials, phase 1, Phase 2; and the following filters: cancer, humans; and selected the checkpoint inhibitors that had been approved by the FDA by March 2021, i.e., “pembrolizumab”, “nivolumab”, “atezolizumab”, “durvalumab”, “cemiplimab”, “avelumab”, and “ipilimumab. Clinical trials with their checkpoint inhibitors as in their labeled indications, off-label use or their combinations with investigational immune checkpoint inhibitors or other treatment modalities were included. Studies describing supportive care or locoregional treatments; cellular, viral, or vaccine therapy; studies in the adjuvant or neoadjuvant setting; and pediatric studies were excluded. Overall, 173 articles reporting on relevant studies were identified. Using these articles, we compiled a data file of study-specific covariates for each study. We recorded the immunotherapeutic agent, tumor type and biomarker, and clinical outcomes (objective response rate and median values [point estimate] and confidence intervals for progression-free survival and overall survival. Using these data, we carried out meta-analyses for the three outcomes and meta-regression on study-specific covariates. The same data could be used for any alternative implementation of meta-analysis and meta-regression, using more structured inference models reflecting different levels of dependence based on the available study-specific covariates.

Abstract Despite progress, 2-year pancreatic cancer survival remains dismal. We evaluated a biomarker-driven, combination/N-of-one strategy in 18 patients (advanced/metastatic pancreatic cancer) (from Molecular Tumor Board). Targeted agents administered/patient = 2.5 (median) (range, 1–4); first-line therapy (N = 5); second line, (N = 13). Comparing patients (high versus low degrees of matching) (matching score ≥50% versus

Next-generation sequencing data is fundamentally changing the clinical management of patients with cancer. The most frequent genomic alterations in malignancy are mutations and amplifications, with a subset of tumors having multiple amplifications – “amplificators”. We sought to understand the molecular correlates of high tumor amplification burden in a pan-cancer context. Using both national registries and a single-institution dataset, our results demonstrate that cancers with TP53 mutations (as compared to those with wild-type TP53) exhibited significantly higher tumor amplification burden across all datasets. Amplifications, generally associated with overexpression, may be potentially actionable secondary consequences of TP53 mutations.

Introduction: Many studies have focused on the role of programmed death receptor ligand 1 (PD-L1) expression in predicting immunotherapy outcomes. Limited clinical data are available regarding the role of programmed death receptor 1 (PD-1; the PD-L1 receptor) expressing tumor-infiltrating lymphocytes (TILs) in PD-1/PD-L1 antibody responsiveness. However, preclinical studies demonstrate that TILs expressing PD-1 contribute to tumor immune evasion. Methods: This study analyzed the association between TIL-PD-1 status and outcome after immune checkpoint blockade (ICB) therapy. We evaluated 123 patients with various solid tumors treated with monoclonal antibodies targeting the PD-1/PD-L1 signaling axis. Additionally, 8706 solid tumor specimens were assessed for TIL-PD-1 and tumor mutational burden (TMB) status. Results: The presence of PD-1-expressing TILs in tumors was associated with increased median progression-free survival (7.0 vs 1.9 months; p = 0.006) and overall survival (18.1 vs 8.0 months; p = 0.04) after treatment with ICB. TIL-PD-1–positive patients had an objective response rate (ORR) of 41% (95% CI, 24–61; N = 12/29) compared with 17% (95% CI, 4–43; N = 3/17) for TIL-PD-1–negative patients (p = 0.18). Analyzed as continuous variables, TIL-PD-1 and TMB showed a weak correlation in 8706 solid tumor samples (Pearson r = 0.074); when analyzed as categorical variables (cutoffs: TIL-PD-1 ≥ 1% and TMB ≥ 10 mutations/Mb), the two variables are correlated (p < 0.0001). TIL-PD-1–positive status is also associated with enrichment of pathologic variants within several genes, most notably TP53 (adjusted p < 0.05). Conclusion: TIL-PD-1 positivity in tumors (≥ 1%) is associated with significantly longer progression-free and overall survival after ICB. ClinicalTrials.gov ID: NCT02478931

Primary splenic or hepatic angiosarcomas are ultra-rare and aggressive malignancies associated with poor prognosis. The mainstay treatments are surgical resection and chemotherapy. We report a case of angiosarcoma in a 50-year-old woman who presented with bruising, fatigue, ecchymosis, and hepatosplenomegaly. She was treated with the multi-kinase inhibitor sunitinib for 4 weeks before developing a splenic hemorrhage and succumbing. Recent studies have demonstrated the clinical benefit of immunotherapies in angiosarcomas. Additionally, sequencing techniques have showcased the diverse molecular aberrations involved in angiosarcomas, which offer opportunities for precision-matched targeted therapies such as inhibitors of the VEGF/VEGFR axis and PI3K/Akt/mTor pathway.

Abstract Liquid biopsies are increasingly used for cancer molecular profiling that enables a precision oncology approach. Circulating extracellular nucleic acids (cell-free DNA; cfDNA), circulating tumor DNA (ctDNA), and circulating tumor cells (CTCs) can be isolated from the blood and other body fluids. This review will focus on current technologies and clinical applications for liquid biopsies. ctDNA/cfDNA has been isolated and analyzed using many techniques, e.g., droplet digital polymerase chain reaction, beads, emulsion, amplification, and magnetics (BEAMing), tagged-amplicon deep sequencing (TAm-Seq), cancer personalized profiling by deep sequencing (CAPP-Seq), whole genome bisulfite sequencing (WGBS-Seq), whole exome sequencing (WES), and whole genome sequencing (WGS). CTCs have been isolated using biomarker-based cell capture, and positive or negative enrichment based on biophysical and other properties. ctDNA/cfDNA and CTCs are being exploited in a variety of clinical applications: differentiating unique immune checkpoint blockade response patterns using serial samples; predicting immune checkpoint blockade response based on baseline liquid biopsy characteristics; predicting response and resistance to targeted therapy and chemotherapy as well as immunotherapy, including CAR-T cells, based on serial sampling; assessing shed DNA from multiple metastatic sites; assessing potentially actionable alterations; analyzing prognosis and tumor burden, including after surgery; interrogating difficult-to biopsy tumors; and detecting cancer at early stages. The latter can be limited by the small amounts of tumor-derived components shed into the circulation; furthermore, cfDNA assessment in all cancers can be confounded by clonal hematopoeisis of indeterminate potential, especially in the elderly. CTCs can be technically more difficult to isolate that cfDNA, but permit functional assays, as well as evaluation of CTC-derived DNA, RNA and proteins, including single-cell analysis. Blood biopsies are less invasive than tissue biopsies and hence amenable to serial collection, which can provide critical molecular information in real time. In conclusion, liquid biopsy is a powerful tool, and remarkable advances in this technology have impacted multiple aspects of precision oncology, from early diagnosis to management of refractory metastatic disease. Future research may focus on fluids beyond blood, such as ascites, effusions, urine, and cerebrospinal fluid, as well as methylation patterns and elements such as exosomes.

Abstract Despite remarkable responses to immune checkpoint blockade (ICB) in some advanced cancers, most patients do not benefit, perhaps due to the complexity of tumor/immune/genome interactions. We implemented a multidisciplinary Molecular Tumor Board (MTB) that reviewed multi-omic cancer characteristics to develop N-of-One therapies for patients in the pan-cancer, advanced, refractory setting. This study evaluates the experience of 80 patients who were presented to the MTB and received a treatment regimen that included ICB. Overall, 60/80 patients (75%) who received ICB following MTB discussion had a high degree of matching between tumor molecular characteristics, including ICB biomarkers (reflected by a high Matching Score (≥50%)) and therapy administered. Patients with high versus low Matching Score experienced significantly longer median progression-free survival (6.4 vs. 3.0 months; p = 0.011) and median overall survival (15.3 vs. 4.7 months; p = 0.014) and higher clinical benefit rates (stable disease ≥6 months/partial response/complete response) (53% vs. 21%, p = 0.019). Although most patients (52/80 (65%)) received a personalized combination therapy (e.g., targeted, hormonal, chemotherapy, or a second immunotherapy agent), administering >1 drug was not associated with outcome. Only degree of matching and age, but no other variables, including individual biomarkers (e.g., microsatellite status, tumor mutational burden, or PD-L1 status), were independently correlated with outcome. In the pan-cancer setting, the MTB facilitated a precision medicine strategy to match therapeutic regimens that included ICB alone or combined with matched targeted drugs to patients with advanced malignancy, which was associated with improved clinical outcomes.

Abstract There is a paucity of information about molecularly driven therapy in osteosarcomas. We report a 31-year-old woman with chemotherapy–refractory metastatic osteosarcoma who was successfully treated with the combination of palbociclib (CDK4/6 inhibitor) and lenvatinib (multikinase FGFR inhibitor), selected based on next generation sequencing that showed CDK4 and CCND2 amplifications (upregulates CDK4/6), and FGF6 (ligand for FGFR1,2 and 4), FGF23 (ligand for FGFR1,2,3, and 4) and FRS2 (adaptor protein for FGFR signaling) amplifications. The patient’s tumor showed 68% reduction in positron emission tomography (PET) avidity, lasting 31 months after therapy initiation, when a solitary recurrence occurred, was resected, and treatment continued. The patient remains on matched targeted therapy at 51 + months from the start of the combination. Treatment was given at reduced dosing (lenvatinib 10 mg oral daily (approved dose = 24 mg daily)) and palbociclib 75 mg oral daily, one week on and one week off (approved dose = 125 mg oral daily, three weeks on/one week off) and is tolerated well. Therefore, co-targeting the aberrant cyclin and FGFR pathways resulted in long-term exceptional response in a patient with refractory advanced osteosarcoma.

Abstract Recent rapid biotechnological breakthroughs have led to the identification of complex and unique molecular features that drive malignancies. Precision medicine has exploited next-generation sequencing and matched targeted therapy/immunotherapy deployment to successfully transform the outlook for several fatal cancers. Tumor and liquid biopsy genomic profiling and transcriptomic, immunomic, and proteomic interrogation can now all be leveraged to optimize therapy. Multiple new trial designs, including basket and umbrella trials, master platform trials, and N-of-1 patient-centric studies, are beginning to supplant standard phase I, II, and III protocols, allowing for accelerated drug evaluation and approval and molecular-based individualized treatment. Furthermore, real-world data, as well as exploitation of digital apps and structured observational registries, and the utilization of machine learning and/or artificial intelligence, may further accelerate knowledge acquisition. Overall, clinical trials have evolved, shifting from tumor type-centered to gene-directed and histology-agnostic trials, with innovative adaptive designs and personalized combination treatment strategies tailored to individual biomarker profiles. Some, but not all, novel trials now demonstrate that matched therapy correlates with superior outcomes compared to non-matched therapy across tumor types and in specific cancers. To further improve the precision medicine paradigm, the strategy of matching drugs to patients based on molecular features should be implemented earlier in the disease course, and cancers should have comprehensive multi-omic (genomics, transcriptomics, proteomics, immunomic) tumor profiling. To overcome cancer complexity, moving from drug-centric to patient-centric individualized combination therapy is critical. This review focuses on the design, advantages, limitations, and challenges of a spectrum of clinical trial designs in the era of precision oncology.

Abstract Background The Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) to better define the cancer molecular milieu based on genomics/transcriptomics from tumor and analogous normal tissue biopsies. SPRING is the first trial to assess a SIMS‐based tri‐therapy regimen in advanced non‐small cell lung cancer (NSCLC). Methods Patients with advanced NSCLC (no EGFR, ALK, or ROS1 alterations; PD‐L1 unrestricted; ≤2 prior therapy lines) received avelumab, axitinib, and palbociclib (3 + 3 dose escalation design). Results Fifteen patients were treated (five centers, four countries): six at each of dose levels 1 (DL1) and DL2; three at DL3. The most common ≥Grade 3 adverse events were neutropenia, hypertension, and fatigue. The recommended Phase II dose (RP2D) was DL1: avelumab 10 mg/kg IV q2weeks, axitinib 3 mg po bid, and palbociclib 75 mg po daily (7 days off/21 days on). Four patients (27%) achieved a partial response (PR) (progression‐free survival [PFS]: 14, 24, 25 and 144+ weeks), including two after progression on pembrolizumab. Four patients attained stable disease (SD) that lasted ≥24 weeks: 24, 27, 29, and 64 weeks. At DL1 (RP2D), four of six patients (66%) achieved stable disease (SD) ≥6 months/PR (2 each). Responders included patients with no detectable PD‐L1 expression and low tumor mutational burden. Conclusions Overall, eight of 15 patients (53%) achieved clinical benefit (SD ≥ 24 weeks/PR) on the avelumab, axitinib, and palbociclib combination. This triplet showed antitumor activity in NSCLC, including in tumors post‐pembrolizumab progression, and was active at the RP2D, which was well tolerated. NCT03386929 clinicaltrial.gov

Treatment for advanced colorectal cancer is often limited by complex molecular profiles, which promote resistance to systemic agents and targeted monotherapies. Recent studies suggest that a personalized, combinatorial approach of matching drugs to tumor alterations may be more effective. We implemented a precision medicine strategy by forming a Molecular Tumor Board (MTB), a multidisciplinary team of clinicians, scientists, bioinformaticians and geneticists. The MTB integrated molecular profiling information and patient characteristics to develop N‐of‐One treatments for 51 patients with advanced colorectal cancer. All patients had metastatic disease and 63% had received ≥ 3 prior therapy lines. Overall, 34/51 patients (67%) were matched to ≥ 1 drug recommended by the MTB based on individual tumor characteristics, whereas 17/51 (33%) patients received unmatched therapies. Patients who received matched therapy demonstrated significantly longer progression‐free survival (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.21–0.81; P = 0.01) and a trend towards higher clinical benefit rates (41% vs. 18%, P = 0.058) (all multivariate) compared to patients receiving unmatched therapy. The MTB facilitated personalized matching of drugs to tumor characteristics, which was associated with improved progression‐free survival in patients with advanced colorectal cancer.

BackgroundThe detection of pancreatic ductal adenocarcinoma (PDAC) lesions at pre-cancerous or early-stages is critical to improving patient survival. We have developed a liquid biopsy test (ExoVita®) based on the measurement of protein biomarkers in cancer-derived exosomes. The high sensitivity and specificity of the test for early-stage PDAC has the potential to improve a patient’s diagnostic journey in hopes to impact patient outcomes.MethodsExosome isolation was performed using alternating current electric (ACE) field applied to the patient plasma sample. Following a wash to eliminate unbound particles, the exosomes were eluted from the cartridge. A downstream multiplex immunoassay was performed to measure proteins of interest on the exosomes, and a proprietary algorithm provided a score for probability of PDAC.ResultsWe describe the case of a 60-year-old healthy non-Hispanic white male with acute pancreatitis who underwent numerous invasive diagnostic procedures that failed to detect radiographic evidence of pancreatic lesions. Following the results of our exosome-based liquid biopsy test showing "High Likelihood of PDAC", in addition to KRAS and TP53 mutations, the patient decided to undergo a robotic pancreaticoduodenectomy (Whipple) procedure. Surgical pathology confirmed the diagnosis of high-grade intraductal papillary mucinous neoplasm (IPMN), which was consistent with the results of our ExoVita® test. The patient’s post-operative course was unremarkable. At five-month follow-up, the patient continued to recover well without complications, in addition to a repeat ExoVita test which demonstrated “Low Likelihood of PDAC”.ConclusionThis case report highlights how a novel liquid biopsy diagnostic test based on the detection of exosome protein biomarkers allowed early diagnosis of a high-grade precancerous lesion for PDAC and improved patient outcome.

PurposeGene fusions involving receptor tyrosine kinases (RTKs) define an important class of genomic alterations with many successful targeted therapies now approved for ALK, ROS1, RET and NTRK gene fusions. Fusions involving the ERBB family of RTKs have been sporadically reported, but their frequency has not yet been comprehensively analyzed and functional characterization is lacking on many types of ERBB fusions.Materials and methodsWe analyzed tumor samples submitted to Caris Life Sciences (n=64,354), as well as the TCGA (n=10,967), MSK IMPACT (n=10,945) and AACR GENIE (n=96,324) databases for evidence of EGFR, ERBB2 and ERBB4 gene fusions. We also expressed several novel fusions in cancer cell lines and analyzed their response to EGFR and HER2 tyrosine kinase inhibitors (TKIs).ResultsIn total, we identified 1,251 ERBB family fusions, representing an incidence of approximately 0.7% across all cancer types. EGFR, ERBB2, and ERBB4 fusions were most frequently found in glioblastoma, breast cancer and ovarian cancer, respectively. We modeled two novel types of EGFR and ERBB2 fusions, one with a tethered kinase domain and the other with a tethered adapter protein. Specifically, we expressed EGFR-ERBB4, EGFR-SHC1, ERBB2-GRB7 and ERBB2-SHC1, in cancer cell lines and demonstrated that they are oncogenic, regulate downstream signaling and are sensitive to small molecule inhibition with EGFR and HER2 TKIs.ConclusionsWe found that ERBB fusions are recurrent mutations that occur across multiple cancer types. We also establish that adapter-tethered and kinase-tethered fusions are oncogenic and can be inhibited with EGFR or HER2 inhibitors. We further propose a nomenclature system to categorize these fusions into several functional classes.

Hinestrosa et al. describe the early-stage detection of cancer using biomarkers present in circulating extracellular vesicles purified via an alternating current electrokinetics platform. They show, in a case-control study, that 95.7% of pancreatic, 75.0% of ovarian and 43.8% of bladder stage I and II cancers can be detected.

Abstract Though advanced cancers generally display complex molecular portfolios, there is a subset of patients whose malignancies possess only one genomic alteration or alterations in one oncogenic pathway. We assess how N-of-One therapeutic strategies impact outcomes in these patients. From 12/2012 to 9/2018, 429 therapy-evaluable patients with diverse treatment-refractory cancers were presented at Molecular Tumor Boards at Moores Cancer Center at UC San Diego. The clinical benefit rate, defined by RECIST1.1, was assessed for patients with solid tumors who underwent next-generation sequencing (NGS) profiling revealing one genomic or pathway alteration, subsequently managed with N-of-One therapies. Nine of 429 patients (2.1%) met evaluation criteria. Using matched therapy indicated by NGS, the clinical benefit rate (stable disease ≥ 6 months/partial/complete response) was 66.7%. Median progression-free survival was 11.3 months (95% CI: 3.4–not evaluable). Thus, a small subset of diverse cancers has single pathway alterations on NGS testing. These patients may benefit from customized therapeutic matching.

Abstract Background CDK12 inactivation leading to increased neoantigen burden has been hypothesized to sensitize tumors to immune checkpoint inhibition. Pan‐cancer data regarding the frequency of CDK12 alterations are limited. We aimed to characterize CDK12 alterations across all cancer types through real‐world clinical‐grade sequencing. Methods This was a single‐center retrospective analysis of 4994 cancer patients who underwent tissue or blood genomic profiling, including CDK12 assessment, conducted as part of routine care from December 2012 to January 2020. Prevalence, clinical characteristics, and treatment outcomes of patients with tumors with pathogenic CDK12 alterations were described. Results In all, 39 (0.78%, n = 39/4994) patients had pathogenic CDK12 alterations. Among CDK12‐altered tumors, the most common organ site was prostate (n = 9, 23.1%) followed by colorectal (n = 5, 12.8%). Adenocarcinoma was the most common histology (n = 26, 66.7%). Median follow‐up from time of diagnosis was 4.02 years. Median overall survival from time of metastasis was 4.43 years (95% CI: 3.11–5.74). Ten patients with CDK12‐altered tumors received at least one immune checkpoint inhibitor‐containing regimen. The majority of patients (n = 6/10, 60%) experienced an objective response. Progression‐free survival for patients who had metastatic disease and received a checkpoint inhibitor‐containing regimen was 1.16 years (95% CI: 0.32–2.00). Conclusion CDK12 alterations are rare events across hematologic and solid tumor malignancies. They represent a clinically distinct molecular cancer subtype which may have increased responsiveness to checkpoint inhibition. Prospective studies are warranted to investigate checkpoint inhibition in CDK12‐altered tumors.

Background: The current model of clinical drug development in oncology displays major limitations due to a high attrition rate in patient enrollment in early phase trials and a high failure rate of drugs in phase III studies. Objective: Integrating transcriptomics for selection of patients has the potential to achieve enhanced speed and efficacy of precision oncology trials for any targeted therapies or immunotherapies. Methods: Relative gene expression level in the metastasis and normal organ-matched tissues from the WINTHER database was used to estimate in silico the potential clinical benefit of specific treatments in a variety of metastatic solid tumors. Results: As example, high mRNA expression in tumor tissue compared to analogous normal tissue of c-MET and its ligand HGF correlated in silico with shorter overall survival (OS; p

PD-L1 (CD274) amplification occurs in a small subset of malignancies and may predict anti-PD-1/PD-L1 immunotherapy responsiveness. We hypothesized that both copy number (CN) and focality of cancer-related PD-L1 amplifications impact protein expression, and, thus, analyzed solid tumors that underwent comprehensive genomic profiling between March 2016 and February 2022 at Foundation Medicine. PD-L1 CN alterations were detected using a comparative genomic hybridization-like method. PD-L1 CN changes were correlated with PD-L1 protein expression (DAKO 22C3 antibody) by immunohistochemistry (IHC). Overall, 60,793 samples were analyzed (most frequent histologies: lung adenocarcinoma (20%), colon adenocarcinoma (12%), lung squamous carcinoma (8%)). Using a definition of CD274 CN ≥ specimen ploidy +4 (6 copies), 1.21% of tumors (738/60,793) were PD-L1 amplified. Focality category distribution was as follows:

Abstract Amplifications of oncogenic genes are often considered actionable. However, not all patients respond. Questions have therefore arisen regarding the degree to which amplifications, especially non-focal ones, mediate overexpression. We found that a subset of high-level gene amplifications (≥ 6 copies) (from The Cancer Genome Atlas database) was not over-expressed at the RNA level. Unexpectedly, focal amplifications were more frequently silenced than non-focal amplifications. Most non-focal amplifications were not silenced; therefore, non-focal amplifications, if over-expressed, may be therapeutically tractable. Furthermore, specific silencing of high-level focal or non-focal gene amplifications may explain resistance to drugs that target the relevant gene product.