Clinical utility of molecular testing to select therapy in relapsed/refractory non-Hodgkin lymphoma: Mayo Clinic Center for Individualized Medicine experience.

11571 Background: Relapsed/refractory (R/R) non-Hodgkin lymphomas (NHL) have a poor prognosis with limited treatment options. Our expanding knowledge of molecular alterations seen in R/R NHL allows identification of patients that potentially may benefit from a precision medicine approach. However, experience in routine clinical implementation of precision medicine has been limited. Here, we summarize our clinical experience in molecular characterization of RR NHL targeted therapy (TT) using next-generation sequencing (NGS), and selection of targeted therapy (TT) based on molecular profile. Methods: We conducted a prospective study in RR NHL through the Center for Individualized Medicine at Mayo Clinic. Consenting patients underwent NGS using FoundationOne Heme panel from biopsies done at time of relapse. Results of NGS were discussed at the Genomic Tumor Board and recommendations for TT were given based on matching specific molecular alteration(s) with potential agent(s) predicted to be active based on NGS. The agents could include FDA-approved, off-label use and clinical trial therapies. Results: 28 cases were enrolled: 18 aggressive NHL, 10 follicular lymphoma (FL). Molecular alterations were present in all cases. In aggressive B-cell NHL, CDKN2A/B gene cluster alterations were seen in 73% (8/11), while seen in only 1/7 T-cell lymphomas (TCL), and 1/10 FL. TP53 deletions were second most common genomic alterations in DLBCL (57%) and seen in 40% FL. JAK-STAT and ERBB pathways were altered in TCL (2/7 each). IGH-BCl-2 gene rearrangement were common in FL (70%), followed by MLL gene alterations (50%). Targetable mutations were present in 86% (24/28) of cases. A TT was recommended in all 24 cases, but received by 2 patients only. Remaining patients did not due to benefit from current therapy (10/24), ineligibility or lack of clinical trial (7/24) or interim clinical deterioration (5/24). Conclusions: Targetable mutations were identified in most cases of RR NHL with TT recommended for all cases. However, access to TT limits potential clinical benefit of molecular-based matching strategy. More studies are needed to assess impact on clinical outcomes.

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Can pediatric and adolescent patients with recurrent tumors benefit from a precision medicine program? The European MAPPYACTS experience.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.10018 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 10018-10018 ◽

Cited By ~ 1

Author(s):

Pablo Berlanga ◽

Gaëlle Pierron ◽

Ludovic Lacroix ◽

Tiphaine Adam de Beaumais ◽

Virginie Bernard ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Precision Medicine ◽

Tumor Board ◽

Molecular Profile ◽

Proof Of Concept ◽

Tumor Biopsy ◽

Rapid Disease Progression ◽

Targeted Agent

10018 Background: The international prospective precision medicine trial MAPPYACTS (NCT02613962) aims to define the molecular profile in recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. Methods: Patients < 18 years-old at the time of initial diagnosis underwent on-purpose tumor biopsy/surgery of their recurrent/refractory malignancy for molecular characterization by WES and whole RNA sequencing. Results were reviewed in a dedicated weekly molecular tumor board (MTB), followed by discussion with the treating physician in a clinical MTB (CMTB). Whenever possible, patients were enrolled subsequently in clinical trials based on CMTB recommendations. Results: From February 2016 to October 2018, 500 patients have been included in 17 centers in France, Italy and Ireland. Median age at inclusion was 13 years. 38% had sarcomas, 28% brain tumors, 22% other solid tumors, 12% hematological malignancies with a median of one prior relapse/progression. Eleven patients did not undergo intervention procedure (10 screening failures, 1 consent withdrawal). Molecular profiling was performed on samples in 433 patients and was contributive for 390 patients. For 271/390 patients (70%), there was at least one genetic alteration that could represent a potential therapeutic target and 8% had alterations considered as “ready for use” for treatment at relapse. Among them, 19 (7%) died before the CMTB. With follow-up censored in January 2019, 72 patients (27%) were treated with at least one matched targeted agent, 57 of them in a clinical trial, mostly the proof-of concept AcSé-ESMART trial (NCT02813135). Of the 166 patients (61%) that did not receive the matched treatment recommended by CMTB (80 still on follow-up), main reasons were: response/stable disease under previous therapy (50), another treatment (48), rapid disease progression/death (30) and legal representative refusal (12). Conclusions: MAPPYACTS profiling allowed tailored targeted treatment, mainly through early clinical trials, in patients with recurrent pediatric cancer. Since most detected molecular findings are within the investigational or hypothetical evidence level, therapeutic proof-of-concept trials that are exploring targeted therapies in molecularly enriched patient populations are crucial to improve knowledge and potentially outcome. Clinical trial information: NCT02613962.

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Outcome of Targeted Therapy Recommendations for Metastatic and Recurrent Head and Neck Cancers

Cancers ◽

10.3390/cancers12113381 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3381

Author(s):

Hossein Taghizadeh ◽

Robert M. Mader ◽

Leonhard Müllauer ◽

Thorsten Fuereder ◽

Alexandra Kautzky-Willer ◽

...

Keyword(s):

Targeted Therapy ◽

Head And Neck ◽

Precision Medicine ◽

Head And Neck Cancers ◽

Molecular Profile ◽

Therapy Recommendations ◽

Advanced Therapy ◽

Cancer Tumor ◽

Generation Sequencing ◽

Recurrent Head

Recurrent/metastatic (R/M) head and neck cancers bear a poor prognosis. In this analysis, we examined the efficacy and the outcome of targeted therapy recommendations based on the patients’ molecular tumor portrait after failure of all standard therapy options. In this single-center, real-world retrospective analysis of our platform for precision medicine, we analyzed the molecular profile of 50 patients diagnosed with R/M head and neck cancer. Tumor samples of the patients were examined using next-generation sequencing panels of mutation hotspots, microsatellite instability (MSI) testing, and immunohistochemistry (IHC). In 31 cases (62.0% of all patients), a molecular-driven targeted therapy approach was recommended. Eventually, 14 patients (28%) received the suggested targeted therapy. Six of fourteen patients (43%) achieved stable disease conditions and four patients (29%) experienced a progressive disease. The median time to treatment failure was 2.8 months. Therapy recommendations were significantly more often issued for men (p = 0.037) than for women. This analysis demonstrated that precision medicine provided the basis for molecular-driven therapy recommendations in over half of the patients with advanced therapy refractory head and neck cancers, with significantly more therapy recommendations for men. Our analysis showed that although precision medicine approaches are implementable and feasible for the management of recurrent/metastatic head and neck cancers in daily clinical routine, there are major limitations and challenges that have to be overcome.

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A virtual molecular tumor board to improve efficiency and scalability of delivering precision oncology to physicians and their patients

JAMIA Open ◽

10.1093/jamiaopen/ooz045 ◽

2019 ◽

Vol 2 (4) ◽

pp. 505-515 ◽

Cited By ~ 11

Author(s):

Michael J Pishvaian ◽

Edik M Blais ◽

R Joseph Bender ◽

Shruti Rao ◽

Simina M Boca ◽

...

Keyword(s):

Treatment Plan ◽

Critical Role ◽

Tumor Board ◽

Care Process ◽

Molecular Profile ◽

Molecular Testing ◽

Precision Oncology ◽

Therapy Options ◽

Scoring Model ◽

Molecular Tumor Board

Abstract Objectives Scalable informatics solutions that provide molecularly tailored treatment recommendations to clinicians are needed to streamline precision oncology in care settings. Materials and Methods We developed a cloud-based virtual molecular tumor board (VMTB) platform that included a knowledgebase, scoring model, rules engine, an asynchronous virtual chat room and a reporting tool that generated a treatment plan for each of the 1725 patients based on their molecular profile, previous treatment history, structured trial eligibility criteria, clinically relevant cancer gene-variant assertions, biomarker-treatment associations, and current treatment guidelines. The VMTB systematically allows clinician users to combine expert-curated data and structured data from clinical charts along with molecular testing data to develop consensus on treatments, especially those that require off-label and clinical trial considerations. Results The VMTB was used as part of the cancer care process for a focused subset of 1725 patients referred by advocacy organizations wherein resultant personalized reports were successfully delivered to treating oncologists. Median turnaround time from data receipt to report delivery decreased from 14 days to 4 days over 4 years while the volume of cases increased nearly 2-fold each year. Using a novel scoring model for ranking therapy options, oncologists chose to implement the VMTB-derived therapies over others, except when pursuing immunotherapy options without molecular support. Discussion VMTBs will play an increasingly critical role in precision oncology as the compendium of biomarkers and associated therapy options available to a patient continues to expand. Conclusion Further development of such clinical augmentation tools that systematically combine patient-derived molecular data, real-world evidence from electronic health records and expert curated knowledgebases on biomarkers with computational tools for ranking best treatments can support care pathways at point of care.

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Personalized medicine in a phase I clinical trials program: The M. D. Anderson Cancer Center Initiative.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.18_suppl.cra2500 ◽

2011 ◽

Vol 29 (18_suppl) ◽

pp. CRA2500-CRA2500 ◽

Cited By ~ 12

Author(s):

A. M. Tsimberidou ◽

N. G. Iskander ◽

D. S. Hong ◽

J. J. Wheler ◽

S. Fu ◽

...

Keyword(s):

Clinical Trials ◽

Targeted Therapy ◽

Personalized Medicine ◽

Phase I ◽

Molecular Analysis ◽

Pik3ca Mutation ◽

Molecular Profile ◽

Cancer Center ◽

Molecular Testing ◽

Phase I Clinical Trials

CRA2500 Background: We initiated a personalized medicine program hypothesizing that tumor molecular analysis and use of targeted therapy to counteract the effects of specific aberrations would improve the outcomes of affected patients. Methods: Molecular analysis was performed in the M. D. Anderson CLIA-certified pathology laboratory. Patients whose tumors had an aberration were treated in the Phase I Program with a matched targeted agent, when available. Results: Tumor molecular analysis was feasible in 852 (89%) of 955 consecutive patients with advanced cancer. Of 852 patients (median, age 56 yrs; prior therapies 4), 354 (41.5%) had ≥ 1 aberration: 10% of patients had a PIK3CA mutation; 19% KRAS; 8% NRAS; 19% BRAF; 3% EGFR; and 2% had a CKIT mutation; 21% had PTEN loss. Results are shown in the table. Median time to treatment failure (TTF) in 161 patients with 1 aberration treated with matched targeted therapy was 5.3 months (95%CI: 4.1, 6.6) vs 3.2 months (95%CI: 2.9 – 4.0) for their prior systemic antitumor therapy (prior to referral to phase I) (p= .0003). For patients with 1 aberration, the CR+PR rate was 29% with matched targeted therapy vs. 8% without matching (p = .0001). The CR+PR rate was 6% in 438 patients without molecular testing treated on the same studies. Conclusions: Preliminary results suggest that in early clinical trials matching patients with targeted drugs based on their molecular profile results in (a) longer TTF compared to their prior therapy and (b) higher rates of response, survival and TTF compared to those seen in patients treated without molecular matching. Support: 3UL1 RR024148 04 S1 and IPCT. [Table: see text]

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Targeted therapy for gastrointestinaI (GI) tumors based on molecular profiles: Early results from MyPathway, an open-label phase IIa basket study in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.653 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 653-653 ◽

Cited By ~ 16

Author(s):

Herbert Hurwitz ◽

John D. Hainsworth ◽

Charles Swanton ◽

Edith A. Perez ◽

Christopher Sweeney ◽

...

Keyword(s):

Targeted Therapy ◽

Early Response ◽

Molecular Testing ◽

Her2 Positive ◽

Open Label ◽

Molecular Alterations ◽

Response Data ◽

Early Results ◽

Best Response ◽

Open Label Phase

653 Background: Next-generation sequencing often reveals potentially actionable molecular alterations; however, data on approved targeted therapies in non-indicated tumors are limited. MyPathway (NCT02091141) evaluates agents targeting the HER2, EGFR, BRAF, or Hedgehog (Hh) pathways in tumors for which these therapies are not currently indicated. Here, we present early response data for patients with GI tumors. Methods: Eligible patients had metastatic tumors with potentially actionable genomic alterations, identified by a CLIA-certified lab, and progression on standard therapy. Based on the identified alteration, patients received standard doses of trastuzumab + pertuzumab (HER2), erlotinib (EGFR), vemurafenib (BRAF), or vismodegib (Hh). Response was evaluated by the investigator using RECIST v1.1. Results: As of Aug 21, 2015, 96 patients had enrolled, 36 of whom (38%) had GI tumors with the following alterations: HER2 (n=28 [22 amplifications, 5 activating mutations, 1 both]), BRAF (n=4), Hh (n=2 [2 PTCH-1 mutations]), and EGFR (n=2). Patients had a median of 4 (range, 1–8) prior lines of therapy. Tumor types and interim best response data are shown below. Among all evaluable patients with GI tumors (n=26), 5 have had a PR to targeted therapy (duration 3–10+ months). Conclusions: Targetable molecular alterations were found in a variety of GI tumors, resulting in clinical benefit from targeted treatments that would not have otherwise been realized. These early results support this molecular testing strategy. Accrual to the trial continues; based on activity observed, the HER2-positive colorectal cancer cohort will be expanded to ≥30 patients. Additional data will be presented at the meeting. Clinical trial information: NCT02091141. [Table: see text]

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Molecular profiling (MP) for malignancies: Knowledge gaps and variable practice patterns among United States oncologists (Onc).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.10510 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 10510-10510 ◽

Cited By ~ 1

Author(s):

Bhavana Pendurthi Singh ◽

Susan Lynne Britton ◽

Petra Prins ◽

Chao Yin ◽

Maria L. Lankford ◽

...

Keyword(s):

Targeted Therapy ◽

Standard Of Care ◽

Molecular Testing ◽

Audience Response ◽

Tumor Type ◽

Community Based ◽

Molecular Alteration ◽

Molecular Alterations ◽

The Us ◽

Academic Practices

10510 Background: Clinically impactful therapies for malignancies require the identification of specific molecular alterations. Onc must be aware of these targets and how to interpret them to provide optimum care. The use of MP has become the standard of care for many cancers, and is recently FDA approved. Using 2 data sets, we assessed the current awareness and incorporation of MP in the treatment of cancer; comparing data from community based Onc (C) to academic Onc (A). Methods: C consisted of 292 physicians polled using an audience response system during 6 case-based research events across the US. Questions focused on various aspects of molecular testing. Data for A was obtained from a chart review focused on timing and extent of MP in disease specific academic practices (lung, breast, GI) (N = 59). Results: Within C, 257 (88%) were Onc from community-based practices. The frequency at which Onc ordered MP significantly varied depending on tumor type; 33% in lung cancer (LC), 18% in colorectal cancer (CRC) and less commonly in breast cancer (BC) (8%). In A, MP was ordered more frequently; 74% in LC, 27% in CRC and 0% in BC. These results reflect a gap in practice among community versus academic Onc, as C had lower utilization of MP for both LC and CRC. In C, Onc were also asked to match the molecular alteration with the appropriate targeted therapy. Onc incorrectly matched the molecular alteration to the targeted therapy or marked unknown in up to 69%. This reflects a large knowledge gap among community Onc with regards to the correct application of MP to currently FDA approved targeted therapies. Conclusions: Given the significant knowledge and practice gap, we conclude there is an urgent need for focused educational activities that facilitate improved knowledge of MP and corresponding personalized therapeutic strategies for Onc in the US.

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Oncology precision medicine for hepatobiliary and pancreatic cancer: An institutional review.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14626 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14626-e14626

Author(s):

Geoffrey Bellini ◽

Jennifer Jo Godden ◽

James L. Weese ◽

Aaron Chevinsky ◽

Wesley Allan Papenfuss ◽

...

Keyword(s):

Precision Medicine ◽

Genetic Alterations ◽

Molecular Testing ◽

Cancer Type ◽

Extrahepatic Cholangiocarcinoma ◽

Term Outcome ◽

Primary Tumors ◽

Long Term Outcome ◽

Molecular Alterations ◽

Number Of Patients

e14626 Background: Hepatobiliary cancers - hepatocellular carcinoma (HCC), intra or extrahepatic cholangiocarcinoma (I/EC), and gallbladder carcinoma (GB) - and pancreatic adenocarcinoma (PC) remain a leading cause of death with little improvement in long-term outcome. Recent studies have suggested that these cancers harbor actionable mutations to varying degrees. The aim of our study was to examine the number of patients (Pts) with these primary tumors who underwent molecular testing in a large vertically integrated health system. Subsequently, we analyzed the percentage of that population who may be candidates for oncology precision medicine (OPM) directed therapy. Methods: We identified Pts with HCC, IC, EC, GB in an IRB reviewed OPM database of our system over a one year period. Pts who underwent molecular panel testing were selected out, and their molecular alterations were identified and stratified by cancer type. Results: 304 total Pts were identified. 61 (20%) underwent molecular testing broken down as follows: 17/132 (13%) I/EC and HCC, 3/11 (27%) GB, and 41/161 (25%) PC. Quantity not sufficient for testing was in 10/61 (16%), of which 5/10 (50%) were resubmitted and tested successfully. 6/61 (10%) were cancelled or deemed not appropriate. Test recommended potential actionability was 8/17 (47%) of I/EC and HCC, 2/3 (67%) of GB, and 25/41 (61%) of PC. Conclusions: OPM is a dynamic area of increasing testing and learning. We found 13-27% of hepatobiliary and pancreatic Pts had molecular testing, which suggests the potential to increase molecular screening for this difficult group of tumors. Total genetic alterations (TGA) and clinically relevant genomic alterations (CRGA) per patient are similar to Ross et al. ( http://ow.ly/k52a30nBMnU ) for GB. Final interpretation regarding pragmatic actionability (patient on drug) and clinical outcomes are still under investigation.[Table: see text]

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Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT2): Challenges and Opportunities in Conducting an MD Anderson Randomized Study in Precision Oncology.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3140 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3140-3140

Author(s):

Henry Hiep Vo ◽

Siqing Fu ◽

David S. Hong ◽

Daniel D. Karp ◽

Sarina Anne Anne Piha-Paul ◽

...

Keyword(s):

Clinical Trial ◽

Advanced Cancer ◽

Patient Preference ◽

Randomized Study ◽

Tumor Board ◽

Molecular Testing ◽

Precision Oncology ◽

Phase I Clinical Trials ◽

Metastatic Setting ◽

Patient Resources

3140 Background: Precision oncology is associated with favorable outcomes in selected patients with cancer. Our first IMPACT trial (IMPACT1) demonstrated that in sequential patients with advanced cancer who had tumor molecular testing and participated in phase I clinical trials, matched targeted therapy (MTT) was associated with superior rates of response, progression-free survival (PFS) and overall survival compared with those of patients who received non-MTT. Despite the statistical significance for these outcomes, the study was non-randomized. Recognizing that it would be difficult to randomize patients we nonetheless undertook IMPACT2, a phase 2 randomized study to determine whether patients treated on the basis of tumor genomic alterations have longer PFS compared to those whose treatment is not selected on the basis of molecular alteration analysis. Methods: Patients with metastatic cancer undergo a tumor biopsy and genomic profiling. Patients are presented at tumor board and are offered to be randomized between two arms: MTT or non-MTT, when criteria (biomarker present, available clinical trial, eligibility criteria met, insurance approval) are met. In April 2019, we amended the trial to include a “patient-preference” cohort for each arm. Patients who decline randomization are offered choice of arm (ClinicalTrials.gov: NCT02152254). The primary analysis will use both randomized and patient-preference cohorts based on a Bayesian hierarchical model that “borrows” from the patient-preference cohorts to the extent to which its PFS agrees with that in the randomization cohort. Results: The key barriers randomizing patients with actionable molecular alterations are patient-related (advanced, metastatic setting requiring immediate intervening therapy; decline in performance status, organ function; or death); drug-related (FDA-approved drug available; or unavailable MTT against key driver biomarker) or financial (no insurance coverage of MTT; lack of patient resources to participate in trials). As the study spans over a few years, some investigational agents that were considered non-MTT at the time of treatment assignment were later proven to be MTT (e.g., immunotherapeutic agents targeting high tumor mutational burden); and/or were approved by the FDA. Conclusions: Although randomized trials have been considered the gold standard in drug development, such studies in the advanced metastatic setting are complicated. The benefit of Precision Oncology has been exemplified in individual patients who were treated with biomarker-selected therapy. The adaptive design of IMPACT2 enables patient randomization despite the evolving tumor biomarkers and the plethora of investigational drugs. IMPACT2 provides insights for the development of cancer genome-based medicine. Outcomesfor randomized patients are awaited. Clinical trial information: NCT02152254.

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Targeted Therapy Recommendations for Therapy Refractory Solid Tumors—Data from the Real-World Precision Medicine Platform MONDTI

Journal of Personalized Medicine ◽

10.3390/jpm10040188 ◽

2020 ◽

Vol 10 (4) ◽

pp. 188

Author(s):

Hossein Taghizadeh ◽

Matthias Unseld ◽

Martina Spalt ◽

Robert M. Mader ◽

Leonhard Müllauer ◽

...

Keyword(s):

Targeted Therapy ◽

Precision Medicine ◽

Solid Tumors ◽

Real World ◽

Molecular Profile ◽

Tumor Type ◽

Therapy Recommendations ◽

Dismal Prognosis ◽

Advanced Therapy ◽

Therapy Recommendation

Advanced therapy-refractory solid tumors bear a dismal prognosis and constitute a major challenge in offering effective treatment strategies. In this real-world retrospective analysis of our precision medicine platform MONDTI, we describe the molecular profile of 554 patients diagnosed with 17 different types of advanced solid tumors after failure of all standard treatment options. In 304 cases (54.9% of all patients), a molecular-driven targeted therapy approach could be recommended, with a recommendation rate above 50% in 12 tumor entities. The three highest rates for therapy recommendation per tumor classification were observed in urologic malignancies (90.0%), mesothelioma (78.6%), and male reproductive cancers (71.4%). Tumor type (p = 0.46), expression of p-mTOR (p = 0.011), expression of EGFR (p = 0.046), and expression of PD-L1 (p = 0.023) had a significant impact on the targeted therapy recommendation rate. Therapy recommendations were significantly more often issued for men (p = 0.015) due to gender-specific differences in the molecular profiles of patients with head and neck cancer and malignant mesothelioma. This analysis demonstrates that precision medicine was feasible and provided the basis for molecular-driven therapy recommendations in patients with advanced therapy refractory solid tumors.

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