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BackgroundThe prognostic implications of tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are poorly studied in hematologic malignancies.ObjectivesThis study aimed to better understand the characteristics and prognostic value of TMB and PD-1/PD-L1 in hematologic malignancies.DesignThis 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).MethodsTMB was measured by NGS. PD-L1 expression (tumor proportion score, TPS) was measured by immunohistochemistry (classified as high (⩾50%), low (1-49%), and negative (

IntroductionAllogeneic 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.MethodsWe 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.ResultsIn 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.ConclusionIn 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. ClinicalTrials.gov Identifier: NCT02478931.

IntroductionOncology media websites such as Oncology Live (OncLive) and Targeted Oncology (TargetedOnc) play an important role in the dissemination of oncology news to patients and clinicians; however, the quality of the content on these websites has not been assessed. Our study aimed to analyze content from these websites and assess financial conflicts of interest (FCOI) amongst speakers interviewed on these websites.MethodsArticles published on OncLive and TargetedOnc during October 2021, were prospectively captured and analyzed. The primary outcome of our study was the quality of oncology news reporting in OncLive and TargetedOnc. We assessed the FCOI amongst speakers using data from Open Payments.ResultsWe examined 196 articles (OncLive 108, TargetedOnc 88). Limitations of cited research were reported in 7% (7/105) of OncLive and zero TargetedOnc articles. Benefit and risks in absolute numbers were reported in 28% (28/99) of OncLive and 16% (7/45) of TargetedOnc articles. Independent experts were quoted in 47% (51/108) and 51% (44/86) of the OncLive and TargetedOnc articles, respectively (Table 3). Pharmaceutical executives were quoted in 18% (20/108) and 11% (10/88) of OncLive and TargetedOnc articles, respectively. No FCOI disclosures were listed or reported for any articles. The mean general payment received from industry by United States physicians was $63,861 in 2019 and $39,639 in 2020.ConclusionOur study demonstrates low quality and potentially biased reporting of oncology news on OncLive and TargetedOnc. Careful safeguards, oversight and reporting of relevant FCOI are needed to maintain the quality and transparency of content being provided.

BackgroundAs the landscape of haematological malignancies dramatically changes due to diagnostic and therapeutic advances, it is important to evaluate trends in clinical trial designs. The objective of our study was to describe the design of clinical trials for five common haematological malignancies with respect to randomisation and end-points. We also aimed to assess trends over time and examine the relationships of funding source and country of origin to proportions of randomisation and utilisation of clinical end-points.MethodsThis systematic review identified haematological malignancy clinical trials starting in 2015-2020 registered at ClinicalTrials.gov as of 20th February 2021. Trial-related variables including randomisation status, type of primary end-point, and both projected and actual enrolment numbers were captured. Clinical end-points were defined as overall survival and quality of life, while surrogate end-points included all other end-points.ResultsOf 2609 relevant trials included in this analysis, only one-fifth were randomised (538, 21%), with a significant decrease in the proportion of randomised clinical trials from 26% of trials in 2015 to 19% in 2020 (p

BackgroundTumor mutational burden (TMB) may be a predictive biomarker of immune checkpoint inhibitor (ICI) responsiveness. Genomic landscape heterogeneity is a well-established cancer feature. Molecular characteristics may differ even within the same tumor specimen and undoubtedly evolve with time. However, the degree to which TMB differs between tumor biopsies within the same patient has not been established.MethodsWe curated data on 202 patients enrolled in the PREDICT study (NCT02478931), seen at the University of California San Diego (UCSD), who had 404 tissue biopsies for TMB (two per patient, mean of 722 days between biopsies) to assess difference in TMB before and after treatment in a pan-cancer cohort. We also performed an orthogonal analysis of 2872 paired pan-solid tumor biopsies in the Foundation Medicine database to examine difference in TMB between first and last biopsies.ResultsThe mean (95% CI) TMB difference between samples was 0.583 [- 0.900-2.064] (p = 0.15). Pearson correlation showed a flat line for time elapsed between biopsies versus TMB change indicating no correlation (R2 = 0.0001; p = 0.8778). However, in 55 patients who received ICIs, there was an increase in TMB (before versus after mean mutations/megabase [range] 12.50 [range, 0.00-98.31] versus 14.14 [range, 0.00-100.0], p = 0.025). Analysis of 2872 paired pan-solid tumor biopsies in the Foundation Medicine database also indicated largely stable TMB patterns; TMB increases were only observed in specific tumors (e.g., breast, colorectal, glioma) within certain time intervals.ConclusionsOverall, our results suggest that tissue TMB remains stable with time, though specific therapies such as immunotherapy may correlate with an increase in TMB.Trial registrationNCT02478931 , registered June 23, 2015.

IntroductionChimeric antigen receptor T-cell therapy (CART) has revolutionised treatment of haematological malignancies; however, current reporting uses a modified intention-to-treat analysis (mITT) which over-estimates efficacy. We assessed what proportion of CD19 and B-cell maturation antigen (BCMA) CART trials report the number of patients not receiving CART after being enrolled by performing meta-analysis of the mITT and intention-to-treat (iTT) overall response rate (ORR).MethodsPubMed/MEDLINE, EMBASE and Cochrane databases were searched. All prospective clinical trials of CD19 and BCMA-targeting CART enrolling two or greater patients from 1st January 2013 to 1st November 2020 were included.ResultsA total of 28 BCMA CART and 74 CD19 CART trials were identified. These included 10 BCMA CART (35.7%) and 52 (70.2%) CD19 CART trials reporting total number of patients enrolled and number of patients treated with CART. For this cohort of trials, the mITT ORR for BCMA CART was 78.0% (95% confidence interval (CI) = 67.0-89.0%), and the iTT ORR was 70.0% (95% CI = 59.0-80.0%). For CD19 leukaemia CART, the mITT ORR was 87.2% (95% CI = 83.1-91.2), and the iTT ORR was 74.9 (95% CI = 64.8-85.0). For CD19 lymphoma CART, the mITT ORR was 70.7% (95% CI = 63.9-77.5), and the iTT ORR was 58.7% (95% CI = 49.7-67.7).ConclusionAcross BCMA and CD19 CART trials, there is a difference of up to 8-12% in the ORR between modified and iTT analyses and a paucity of information regarding reasons why patients did not receive the intended study treatment.

ImportanceA thorough understanding of the optimal role and sequence of agents for treatment of multiple myeloma (MM) requires knowledge of the use and rate of postprotocol therapies in randomized clinical trials (RCTs).ObjectivesTo examine the proportion of MM RCTs that reported postprotocol therapies and, among those, the percentage of patients who received no further therapy and how treatments differed between the control and intervention arms.Evidence reviewThe reporting of postprotocol therapies was systematically assessed in published MM RCTs using 3 databases (PubMed, Embase, and Cochrane Registry of Controlled Trials) for MM RCTs from January 1, 2005, to December 30, 2019. All MM RCTs were included, and all other studies, such as editorials, nonrandomized studies, and review articles, were excluded.FindingsA total of 103 RCTs were identified (47 251 patients); of these, 45 (43.7%) reported subsequent treatments in that publication or in any subsequent publication. Trials funded by pharmaceutical companies (26 of 47 [55.3%]) were more likely to report subsequent treatments than cooperative group studies (19 of 56 [33.9%]) (χ21,103 = 4.8; P = .03). Differences were found in the treatments received between the intervention and control arms of RCTs. When data were reported, 5150 of 9351 patients (54.9%) in RCTs of newly diagnosed MM and 2197 of 4501 patients (48.8%) in RCTs of relapsed/refractory MM received any subsequent therapy.Conclusions and relevancePostprotocol therapies in MM RCTs are often not reported and, when they are, many patients receive no further therapy. Reporting guidelines for postprotocol therapies are needed.

To our knowledge, no study has evaluated the quality of control groups in randomised controlled trials of multiple myeloma. We aimed to do a systematic review of randomised controlled trials of multiple myeloma to ascertain the quality of the control groups used. PubMed (MEDLINE), Embase, Cochrane Controlled Register of Trials, and CinicalTrials.gov were searched for articles of randomised controlled trials of multiple myeloma based in the USA that initiated participant enrolment between Jan 1, 2010, and June 30, 2020. A control group regimen was considered to be inferior if a previous randomised controlled trial had shown an improved progression-free survival versus the control group before enrolment. Of 49 identified randomised controlled trials, seven (14%) began enrolling patients into inferior control groups after an existing superior regimen to the control had already been published. Nine (18%) of the 49 trials continued enrolment on substandard control groups after data emerged during the study enrolment period. The median time that newer data emerged regarding inferiority of the control group from the time a trial first enrolled a patient was 13 months (IQR 8-29 months). 12 (75%) of these 16 randomised controlled trials are published, and nine (75%) of the 12 published trials had overlapping investigators with trials that had previously shown the inferiority of the control group being used. Greater scrutiny on the quality of control groups in randomised controlled trials of multiple myeloma is needed.

Over the past decade, 2 strategies have advanced the treatment of patients with multiple myeloma and its precursor diseases. First, the definition has changed to include patients without end organ damage, who previously would not have been treated. Second, there is widespread enthusiasm for treating high-risk, smoldering multiple myeloma. In this commentary, we explore the evidence supporting these therapeutic expansions. Although early treatment adds cost and therapeutic burden, it remains unknown whether survival and health-related quality of life are improved by early treatment. Herein, we consider the implications of diagnostic expansion in multiple myeloma.

BackgroundImmune checkpoint blockade (ICB) with antibodies inhibiting cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) (or its ligand (PD-L1)) can stimulate immune responses against cancer and have revolutionized the treatment of tumors. The influence of host germline genetics and its interaction with tumor neoantigens remains poorly defined. We sought to determine the interaction between tumor mutational burden (TMB) and the ability of a patient's major histocompatibility complex class I (MHC-I) to efficiently present mutated driver neoantigens in predicting response ICB.MethodsComprehensive genomic profiling was performed on 83 patients with diverse cancers treated with ICB to determine TMB and human leukocyte antigen-I (HLA-I) genotype. The ability of a patient's MHC-I to efficiently present mutated driver neoantigens (defined by the Patient Harmonic-mean Best Rank (PHBR) score (with lower PHBR indicating more efficient presentation)) was calculated for each patient.ResultsThe median progression-free survival (PFS) for PHBR score  6 months/partial response/complete response rate, median PFS, and median overall survival (OS) of TMB high/PHBR high vs. TMB high/PHBR low were 43% vs. 78% (P = 0.049), 5.8 vs. 26.8 months (P = 0.03), and 17.2 months vs. not reached (P = 0.23), respectively. These findings were confirmed in an independent validation cohort of 32 patients.ConclusionsPoor presentation of driver mutation neoantigens by MHC-I may explain why some tumors (even with a high TMB) do not respond to ICB.

BACKGROUND:Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis. The BRAF inhibitor vemurafenib is approved by the U.S. Food and Drug Administration (FDA) for patients with ECD harboring a BRAF V600E mutation. Successful treatment has also been reported with MEK-targeted therapies, likely because of the fact that BRAF mutant-negative patients harbor MEK pathway alterations. In our Rare Tumor Clinic, we noted that these patients have frequent drug-related toxicity, consistent with previous reports indicating the need to markedly lower doses of interferon-alpha when that agent is used in these patients. PATIENTS AND METHODS:We performed a review of ten patients with ECD seen at the Rare Tumor Clinic at University of California San Diego receiving 16 regimens of targeted BRAF, MEK, or combined therapies. RESULTS:The median age of the ten patients with ECD was 53 years (range, 29-77); seven were men. The median dose percentage (percent of FDA-approved dose) tolerated was 25% (range, 25%-50%). The most common clinically significant adverse effects resulting in dose adjustments of targeted therapies were rash, arthralgias, and uveitis. Renal toxicity and congestive heart failure were seen in one patient each. In spite of these issues, eight of ten patients (80%) achieved a partial remission on therapy. DISCUSSION:Patients with ECD appear to require substantially reduced doses of BRAF and MEK inhibitors but are responsive to these lower doses.

Programmed death receptor-1/ligand 1 (PD-1/L1) antibodies can induce durable remissions in malignancies. However, response rates are only approximately 10% to 20% in unselected patients versus approximately 50% in microsatellite instability-high (MSI-high) tumors, probably related to high tumor mutational burden (TMB). Pembrolizumab is approved for MSI-high or deficient mismatch repair tumors. However, outside of colorectal and endometrial carcinoma, only a small subset of tumors were MSI-high, making this treatment option unavailable to most patients. It is not known if MS-stable tumors with high TMB respond to PD-1/PD-L1 blockade. Next-generation sequencing (NGS) was performed on 60 patients (14 different histologies) treated with checkpoint blockade using the FoundationOne assay to determine TMB and MSI status. TMB was dichotomized into two groups: low-to-intermediate (0-19 mutations/mb) versus high (≥20 mutations/mb). Benefit rate (stable disease for ≥6 months and partial or complete response) was determined: 2,179 of 148,803 samples (1.5%) were MSI-high and 9,762 (6.6%) TMB-high (7,972, MS-stable/TMB-high). The majority (82.1%) of MSI-H tumors were TMB-high; however, only 18.3% of TMB-high tumors were MSI-H. Median progression-free survival for MS-stable/TMB-high versus MS-stable/TMB-low/TMB-intermediate tumors was 26.8 versus 4.3 months (P = 0.0173). Thus, our data demonstrate that MS-stable/TMB-high tumors are more common than MSI-high cancers and may benefit from immunotherapy.

The BRAF V600E mutation and BRAF inhibitor responsiveness characterize ∼50% of patients with the non-Langerhans cell histiocytosis (non-LCH) Erdheim-Chester disease (ECD). We interrogated the non-LCH molecular landscape [ECD, n = 35; Rosai-Dorfman disease (RDD), n = 3; mixed ECD/RDD, n = 1] using BRAF V600E PCR and/or next-generation sequencing [tissue and cell-free DNA (cfDNA) of plasma and/or urine]. Of 34 evaluable patients, 17 (50%) had the BRAF V600E mutation. Of 31 patients evaluable for non-BRAF V600E alterations, 18 (58%) had ≥1 alteration and 12 putative non-BRAF V600E MAPK pathway alterations: atypical BRAF mutation; GNAS, MAP2K1, MAP2K2, NF1, and RAS mutations; RAF1 or ERBB2 amplifications; LMNA-NTRK1 (TRK inhibitor-sensitive) and CAPZA2-BRAF fusions. Four patients had JAK2, MPL ASXL1, U2AF1 alterations, which can correlate with myeloid neoplasms, a known ECD predisposition, and one developed myelofibrosis 13 months after cfDNA testing. Therefore, our multimodal comprehensive genomics reveals clinically relevant alterations and suggests that MAPK activation is a hallmark of non-LCH.

Advanced and metastatic squamous cell carcinomas (SCC) are common and difficult-to-treat malignancies. We assessed 75 immunotherapy-treated patients with SCC from a clinically annotated database of 2,651 patients, as well as 9,407 patients from a deidentified database for molecular features that might influence checkpoint blockade response. SCCs had higher tumor mutational burdens (TMB) than non-SCCs (P < 0.0001). Cutaneous SCCs had the highest TMB (P < 0.0001), with 41.3% demonstrating a very high TMB (≥50 mutations/Mb). In immunotherapy-treated patients with SCC, higher TMB (≥12 mutations/Mb) correlated with a trend to higher clinical benefit rate [stable disease ≥ 6 months or partial/complete remission; 60% vs. 29%; (high vs. low TMB); P = 0.06] and significantly longer median time-to-treatment failure (TTF; 9.9 vs. 4.4 months; P = 0.0058). Cutaneous SCCs had the highest clinical benefit [11/15 patients (73%) vs. 20/60 (33%) non-cutaneous (P = 0.008)], TTF (P = 0.0015), and overall survival (P = 0.06) with immunotherapy treatment. In conclusion, among a diverse set of SCCs, higher TMB and cutaneous disease associated with better immunotherapy outcome.

Metastatic basal cell cancer (BCC) is an ultra-rare malignancy with no approved therapies beyond Hedgehog inhibitors. We characterized the genomics, tumor mutational burden (TMB), and anti-PD-1 therapy responses in patients with locally advanced or metastatic BCC. Overall, 2,039 diverse cancer samples that had undergone comprehensive genomic profiling (CGP) were reviewed. Eight patients with locally advanced/metastatic BCC were identified (two had two CGP analyses; total, 10 biopsies). Two tumors demonstrated PD-L1 amplification. Seven patients had >1 actionable alteration. The TMB (mutations/mb) (median (range)) was 90 (3-103) for the BCCs versus 4 (1-860) for 1637 cancers other than BCC (P < 0.0001). Median progression-free survival (PFS) for all four patients treated with PD-1 blockade was 10.7 months (range, 3.8 to 17.6+ months); three patients had an objective response. In conclusion, advanced/metastatic BCC often has biological features (high TMB; PD-L1 amplification) predictive of immunotherapy benefit, and patients frequently respond to PD-1 blockade.

Immunotherapy induces durable responses in a subset of patients with cancer. High tumor mutational burden (TMB) may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free survival (PFS), and overall survival (OS). Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥20 mutations/mb) versus low to intermediate TMB was 22/38 (58%) versus 23/113 (20%; P = 0.0001); median PFS, 12.8 months vs. 3.3 months (P ≤ 0.0001); median OS, not reached versus 16.3 months (P = 0.0036). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders versus nonresponders treated with anti-PD-1/PD-L1 monotherapy was 18.0 versus 5.0 mutations/mb (P < 0.0001). Interestingly, anti-CTLA4/anti-PD-1/PD-L1 combinations versus anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%; P = 0.004) and PFS (P = 0.024). Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB. Mol Cancer Ther; 16(11); 2598-608. ©2017 AACR.

Purpose: Tumor mutational burden detected by tissue next-generation sequencing (NGS) correlates with checkpoint inhibitor response. However, tissue biopsy may be costly and invasive. We sought to investigate the association between hypermutated blood-derived circulating tumor DNA (ctDNA) and checkpoint inhibitor response.Experimental Design: We assessed 69 patients with diverse malignancies who received checkpoint inhibitor-based immunotherapy and blood-derived ctDNA NGS testing (54-70 genes). Rates of stable disease (SD) ≥6 months, partial and complete response (PR, CR), progression-free survival (PFS), and overall survival (OS) were assessed based on total and VUS alterations.Results: Statistically significant improvement in PFS was associated with high versus low alteration number in variants of unknown significance (VUS, >3 alterations versus VUS ≤3 alterations), SD ≥6 months/PR/CR 45% versus 15%, respectively; P = 0.014. Similar results were seen with high versus low total alteration number (characterized plus VUS, ≥6 vs. 3 had a median PFS of 23 versus 2.3 months (P = 0.0004).Conclusions: Given the association of alteration number on liquid biopsy and checkpoint inhibitor-based immunotherapy outcomes, further investigation of hypermutated ctDNA as a predictive biomarker is warranted. Clin Cancer Res; 23(19); 5729-36. ©2017 AACR.

Metastatic basal cell carcinoma may be treated with hedgehog pathway inhibitors, including vismodegib and sonidegib. However, patients can demonstrate resistance to these agents. We describe a man with metastatic basal cell carcinoma who did not respond well to vismodegib and sonidegib. Next generation sequencing of his metastatic liver tumor demonstrated a high tumor mutational burden (103 mutations per megabase) and the genomic amplification of PD-L1, both of which are features that predict response to anti-PD1/PD-L1 immunotherapy. Treatment with nivolumab, an anti-PD1 checkpoint inhibitor, resulted in near complete remission. Yet, he developed new primary cutaneous basal cell carcinomas while receiving immunotherapy and while his metastatic disease showed an ongoing response. His new superficial skin cancer had a lower tumor mutational burden (45 mutations per megabase) than the metastatic disease. Since immunotherapy response rates are higher in patients with more genomically complex tumors, our observations suggest that, in contrast with the premise of earlier treatment is better, which holds true for targeted and cytotoxic therapies, immunotherapy may be better suited to more advanced disease.

Metastatic basal cell carcinomas are rare malignancies harbouring Hedgehog pathway alterations targetable by SMO antagonists (vismodegib/sonidegib). We describe, for the first time, the molecular genetics and response of a patient with Hedgehog inhibitor-resistant metastatic basal cell carcinoma who achieved rapid tumour regression (ongoing near complete remission at 4 months) with nivolumab (anti-PD1 antibody). He had multiple hallmarks of anti-PD1 responsiveness including high mutational burden (> 50 mutations per megabase; 19 functional alterations in tissue next-generation sequencing (NGS; 315 genes)) as well as PDL1/PDL2/JAK2 amplification (as determined by both tissue NGS and by analysis of plasma-derived cell-free DNA). The latter was performed using technology originally developed for the genome-wide detection of sub-chromosomal copy-number alterations (CNAs) in noninvasive prenatal testing and showed numerous CNAs including amplification of the 9p24.3-9p22.2 region containing PD-L1, PD-L2 and JAK2. Of interest, PD-L1, PD-L2 and JAK2 amplification is a characteristic of Hodgkin lymphoma, which is exquisitely sensitive to nivolumab. In conclusion, selected SMO antagonist-resistant metastatic basal cell carcinomas may respond to nivolumab based on underlying molecular genetic mechanisms that include PD-L1 amplification and high tumour mutational burden.