On May 29, 2020 EORTC reported that the long-term results of the MINDACT (EORTC 10041/BIG3-04) study were presented today in the ASCO (Free ASCO Whitepaper) virtual meeting (Press release, EORTC, MAY 29, 2020, View Source [SID1234558776]). MINDACT tests the 70-gene signature MammaPrint to help identifying breast cancer patients who would do not need adjuvant chemotherapy . In 2016, the results of the primary endpoint (distant metastasis free survival (DMFS)) at 5 years median follow up were presented . Dr Fatima Cardoso, the principle investigator of the study, presented the updated results with 8.7 years of median follow-up, with more than 90% of patients followed for at least 5 years. 6693 patients were enrolled in the randomised MINDACT study between 2007-2011. The DMFS was assessed at 5 years for 644 clinical high and genomic low risk patients who were randomised to follow the genomic risk assessment and received no chemotherapy. In addition, a secondary analysis was conducted to evaluate DMFS and overall survival in the same population of clinical high and genomic low population depending on whether chemotherapy was administered or not.

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The present analysis confirms that MINDACT is a positive de-escalation study, as the primary DMFS endpoint at 5 years is continually met in clinical high and genomic low risk patients who receive no chemotherapy. The outcome of the "intention to treat" population are shown in the table below.

At 8 years, the estimated DMFS gain for chemotherapy administration in Clinical-High/Genomic-Low is 2.6% and must be balanced with the treatment’s harmful side effects.

A subgroup analyses was performed regarding the effect of chemotherapy per age group. This analysis showed that: a) omitting chemotherapy in Clinical-High/Genomic-Low postmenopausal women continues to be safe, (DMFS gain 0.2% ± 2.3%), and a fully preserved performance of MammaPrint to forego adjuvant chemotherapy is demonstrated; b) in premenopausal women the difference seen might be clinically relevant (DMFS gain 5% ± 2.8%); importantly, this effect may possibly be related to chemotherapy-induced ovarian function suppression.

"The present analysis clearly proves that chemotherapy can safely be avoided for postmenopausal women, classified as high risk of relapse by traditional clinico-pathological factors, but with a MammaPrint test of low risk, confirming the clinical utility of this genomic test, " said Dr Fatima Cardoso, Principal Investigator of the Study and Director of the Breast Unit at the Champalimaud Clinical Centre, Lisbon, Portugal.

Research Funding:
MINDACT was supported by grants from the European Commission Framework Programme VI (FP6-LSHC-CT-2004-503426, "TRANSBIG Network of Excellence"), the Breast Cancer Research Foundation, the U.S. National Cancer Institute, the European Breast Cancer Council-, Pharmaceutical/Biotech Company, U.S. National Institutes of Health

Session Type: Oral Abstract Session
Session Title: Breast Cancer—Local/Regional/Adjuvant
Track: Breast Cancer—Local/Regional/Adjuvant
Subtrack: Adjuvant Therapy
Abstract #: 506
Clinical Trial Registry Number: NCT00433589
Citation: J Clin Oncol 38: 2020 (suppl; abstr 506)
DOI: 10.1200/JCO.2020.38.15_suppl.506
Research support: Funding

MINDACT was supported by grants from the European Commission Framework Programme VI (FP6-LSHC-CT-2004-503426, "TRANSBIG Network of Excellence"), the Breast Cancer Research Foundation, Novartis, F. Hoffman La Roche, Sanofi-Aventis, Eli Lilly, Veridex, the U.S. National Cancer Institute, the European Breast Cancer Council-Breast Cancer Working Group (BCWG grant for the MINDACT biobank), the Jacqueline Seroussi Memorial Foundation (2006 JSMF award), Prix Mois du Cancer du Sein (2004 award), Susan G. Komen for the Cure (SG05-0922-02), Fondation Belge Contre le Cancer (SCIE 2005-27), Dutch Cancer Society (KWF), The Netherlands Genomics Initiative – Cancer Genomics Centre (2008-2012), Association Le Cancer du Sein, Parlons-en!, the Brussels Breast Cancer Walk-Run and the American Women’s Club of Brussels, NIF Trust, German Cancer Aid, the Grant Simpson Trust and Cancer Research UK, La Ligue Nationale Contre Le Cancer. This trial was also supported by the EORTC Cancer Research Fund. Whole genome analysis was provided in kind by Agendia.

Role of the funding sources

The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Acknowledgments

We are grateful to all patients and families who participated in this study.

We are grateful to the European Commission Sixth Framework Programme (FP6-LSHC-CT-2004-503426), the European Community Seventh Framework Programme (HEALTH-F2-2009-223175 to the Collaborative Oncological Gene-environment Study), the Breast International Group (BIG) AISBL, F. Hoffmann-La Roche, Novartis, Sanofi-Aventis, for supporting this independent EORTC Study.

On May 29, 2020, Blueprint Medicines Corporation Presented the Corporate Presentation (Press release, Blueprint Medicines, MAY 29, 2020, View Source [SID1234558775]).

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On May 29, 2020 The University of Texas MD Anderson Cancer Center reported that results from a Phase I clinical trial led by researchers the adoptive T-cell therapy ADP-A2M4, which is engineered to express a T-cell receptor (TCR) directed against the MAGE-A4 cancer antigen, achieved responses in patients with multiple solid tumor types, including #102synovial sarcoma, head and neck cancer and lung cancer (Press release, MD Anderson, MAY 29, 2020, View Source [SID1234558773]).

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Among 38 patients treated on the trial, the ADP-A2M4 T cells resulted in overall response (OR), or tumor shrinkage, in 9 patients (23.7%) and stable disease in 18 patients (47.4%). Trial data were shared in an oral presentation at the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting by principal investigator David Hong, M.D., professor of Investigational Cancer Therapeutics.

"Thus far, we haven’t seen strong responses in treating solid tumors with available cellular therapies, in large part because antigens expressed are not restricted to the tumors," said Hong. "In this trial, I’ve been encouraged to see durable responses in several patients, and the results suggest there is potential for this emerging TCR-based technology for treating solid tumors."

Adoptive cellular therapy is a form of immunotherapy that modifies immune cells to be more effective in mounting an immune response against cancer. For ADP-A2M4, T cells are isolated from patients and engineered to express a TCR targeting MAGE-A4, a protein normally expressed only in the testis but present in certain cancers.

Unlike chimeric antigen receptor (CAR)-modified T cells, which target surface proteins on cancer cells, TCR T-cell therapies are able to target proteins normally found inside the cell by recognizing protein fragments bound to immune-related proteins on the cell surface.

The Phase I trial was designed as a dose-escalation study to assess the safety, tolerability and antitumor activity of ADP-A2M4 in patients with advanced solid tumors with expression of the MAGE-A4 protein. Patients on the trial included those with synovial sarcoma, ovarian cancer, head and neck cancer, gastric cancer, myxoid/round cell liposarcoma, non-small cell lung cancer, bladder cancer, esophageal cancer and melanoma. Participants had a median of three prior lines of systemic therapy.

The therapy achieved strong responses in particular groups of patients in the trial. Patients with synovial sarcoma saw a 43.8% OR rate and a disease control rate of more than 90%. There also was an additional patient with an unconfirmed response after the data cut-off. Median duration of response in these patients was 28 weeks and median progression-free survival was 20 weeks. Confirmed responses were also seen in patients with lung cancer and head and neck cancer.

Most patients (97.4%) experienced some treatment-related adverse events, with the most common being low blood cell counts (lymphopenia, leukopenia, neutropenia, anemia and thrombocytopenia). Half of patients experienced cytokine release syndrome. Two patients had trial-related deaths, which led to modification of the lymphodepletion regimen and eligibility criteria.

"The side effects seen on the trial were largely consistent with those typically experienced by cancer patients undergoing lymphodepleting chemotherapy and cellular therapy," said Hong. "This study is a nice proof of concept for treating solid tumors and suggests there could be a role for cellular therapies in these indications going forward."

This research is part of an ongoing strategic alliance between MD Anderson and Adaptimmune, designed to expedite the development of novel T-cell therapies for multiple cancer types. Translational research and analyses of related biomarkers continues. Results from this study led to a low-dose radiation sub-study, a Phase II trial of ADP-A2M4 in sarcoma and a Phase I trial of Adaptimmune’s next-generation T-cell therapy targeting MAGE-A4, ADP-A2M4CD8.

On May 29, 2020 NRG Oncology reported that Results of the phase III clinical trial NRG-GY004 indicated that the addition of the investigational agent cediranib to olaparib and standard platinum-based chemotherapy did not improve progression-free survival (PFS) outcomes for women with platinum-sensitive ovarian cancer;, however, activity between the treatments were similar in patients (Press release, NRG Oncology, MAY 29, 2020, https://www.nrgoncology.org/Home/News/Post/combined-cediranib-and-olaparib-presents-similar-activity-to-standard-of-care-treatment-for-platinum-sensitive-ovarian-cancer [SID1234558772]). These results were recently presented at the virtual Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper).

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NRG-GY004 was designed to expand upon the findings of a phase II trial that indicated a combination of cediranib and olaparib improved PFS outcomes compared to olaparib alone for women with platinum-sensitive, high-grade serous/endometrioid ovarian cancer, regardless if they had a BRCA mutation. On NRG-GY004, women were randomly assigned to one of three treatment regimens. Participants randomly assigned to the first treatment arm received the standard of care chemotherapy chemotherapy with either carboplatin and paclitaxel, carboplatin and gemcitabine, or carboplatin and pegylated lipsomal doxorubicin. The participants on the experimental treatment arms either received olaparib at 300mg twice a day or olaparib at 200mg twice a day with cediranib at 30mg twice a day. The primary endpoint of this study was to assess PFS of cediranib and olaparib treatment compared to chemotherapy for women with platinum-sensitive ovarian cancer.

Between March 2016 and June 2018, 565 patients had enrolled in NRG-GY004 and, of those patients, 528 initiated treatment: 23.7% of the patients had a germline BRCA mutation. At a median follow-up of 29.1 months, the hazard ratio for PFS was 0.856 (95% CI 0.66-1.11, p = 0.08, 1-tail) for the combination of cediranib and olaparib compared to chemotherapy treatment. The hazard ratio for PFS was 1.20 (95% CI 0.93-1.54) for olaparib alone compared to chemotherapy treatment. Median PFS for patients was 10.3 months for the standard of care chemotherapy, 8.2 months for olaparib alone, and 10.4 months for patients receiving combination cediranib and olaparib. In a predefined biomarker subset analysis of women with a germline BRCA mutation, the PFS hazard ratio was 0.55 (95% CI 0.73-1.30) for combined cediranib and olaparib compared to chemotherapy and 0.63 (95% CI 0.37-1.07) for olaparib alone versus the standard chemotherapy. In women without a germline BRCA mutation, the PFS hazard ratio was 0.97 (95% CI 0.73-1.30) for combined cediranib and olaparib compared to chemotherapy and 1.41 (1.07-1.86) for olaparib alone versus standard chemotherapy.

"This is the first Phase 3 trial comparing a completely oral non platinum-based therapy regimen to standard of care platinum-based chemotherapy in platinum-sensitive ovarian cancer. While the combination of cediranib and olaparib was not found to improve PFS compared to standard of care chemotherapy, the findings of this study suggest that non-platinum based alternatives have potential in this setting, especially in appropriate biomarker subgroups such as patients with BRCA mutations," stated Joyce Liu, MD, MPH, of the Dana-Farber Cancer Institute and the lead author of the NRG-GY004 abstract.

There were no overall survival differences between the treatment arms. Patients who received cediranib and olaparib in addition to the standard of care did experience a higher frequency of grade 3 or higher gastrointestinal, hypertension, and fatigue adverse events.

This study was supported by the National Cancer Institute grants U10CA180822 (NRG Oncology SDMC), U10CA180868 (NRG Oncology Operations), U24CA180803 (IROC), U24CA196067 (NRG Specimen Bank). , NRG-GY004 was sponsored by National Cancer Institute (NCI), part of the National Institutes of Health. AstraZeneca provided cediranib and olaparib to support the study through a Collaborative Research and Development Agreement with NCI. Olaparib is jointly developed and commercialized by AstraZeneca and Merck & Co. (Merck: known as MSD outside the US and Canada).

Citation

Liu JF, Brady MF, Matulonis UA, Miller A, Kohn EC, Swisher E, Tew WP, Cloven NG, Muller C, Bender D, Moore RG, Michelin D, Waggoner SE, Geller MA, Fujiwara K, D’ Andre SD,Carney M, Secord AA, Moxley KM, Bookman MA. A Phase III Study Comparing Single-Agent Olaparib or the Combination of Cediranib and Olaparib to Standard Platinum-Based Chemotherapy in Recurrent Platinum Sensitive Ovarian Cancer. Abstract presented at the virtual Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper).

On May 29, 2020 Caris Life Sciences, a leading innovator in molecular science focused on fulfilling the promise of precision medicine, reported that it will present results from a study today that characterize KRAS mutations in patients with non-small cell lung cancer (NSCLC) (Press release, Caris Life Sciences, MAY 29, 2020, View Source [SID1234558771]). In this study, the molecular profiles of more than 17,000 patients with NSCLC were evaluated using the Caris Molecular Intelligence platform, which were then classified based on specific types of KRAS mutations using a 592-gene DNA sequencing panel. The study found that KRAS mutations are relatively common in NSCLC and that differences between KRAS mutation subtypes warrant further investigation in how they could guide treatment decisions, including the use of targeted and immuno-oncology drugs.

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Across 17,113 NSCLC patients, KRAS mutations were present in 27% of samples (n=4,706), with KRAS G12C being the most common variant and present in 40% of samples that exhibited a mutation. KRAS G12C was associated with the highest rate of PD-L1 expression. The rate of high tumor mutational burden (TMB) (>10 mutations/MB) was significantly different across KRAS mutation subtypes and was most frequently seen in KRAS G13X (68.3%) and least frequently in G12D (43.2%). KRAS mutations were more commonly seen in adenocarcinoma versus squamous subtype (37.2% vs. 4.4%)

The full results will be presented today during a poster session (Abstract 9544/Poster 310) as part of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 (ASCO20) Virtual Scientific Program. The poster is titled, "Characterization of KRAS mutations (mt) in non-small cell lung cancer (NSCLC)."

In a second study, the molecular profiles of a large cohort of KRAS wild-type (WT) pancreatic tumors were evaluated using DNA sequencing and whole transcriptome sequencing (WTS), which were then classified based on specific types of KRAS mutations using a 592-gene DNA sequencing panel. The study looked to assess the prevalence of alterations that could represent targets for personalized treatment. Researchers found that the use of WTS, in combination with DNA sequencing, identified activated molecular pathways in the majority of KRAS WT tumors, and that these tumors are significantly more enriched with targetable alterations (e.g., BRAF, ALK, ROS1, NRG1, MSI-H) compared to KRAS mutant tumors. These findings suggest a potential benefit of using targeted therapies to treat patients with KRAS WT tumors.

"While KRAS mutations in pancreatic cancer are found in the majority of cases, we used comprehensive molecular profiling to generate crucial information on mutations and transcriptional programs found in KRAS wild-type pancreatic cancer that provide additional opportunities for therapeutic intervention in this cancer type that has a low survival rate and few treatment options," said Philip A. Philip, M.D., Ph.D., FRCP., lead investigator of the study and an oncologist with Barbara Ann Karmanos Cancer Institute at Wayne State University, a member of the Caris Precision Oncology Alliance.

The full results will be presented today during a poster session (Abstract 4629/Poster 237). The poster is titled, "Alterations in targetable molecular pathways are enriched in KRAS wild-type (WT) pancreatic cancer (PC)."

"Our data at ASCO (Free ASCO Whitepaper)20 continue to reinforce the power of molecular profiling and precision medicine technologies in changing the face of cancer treatment," said W. Michael Korn, M.D., Chief Medical Officer at Caris Life Sciences. "The combination of Next-Generation DNA Sequencing and whole transcriptome sequencing is giving clinicians new insights and clearer direction in how they approach non-small cell lung cancer and pancreatic cancer, two particularly difficult-to-treat cancers."

Additional Presentations Provide Key Insight Into The Genetic Profile of Cancer
Caris will present additional data from studies highlighting the distinct molecular landscapes of patients across several cancer types, including mesothelioma and gastroesophageal cancers. Better understanding of a tumor’s genomic landscape and distribution of immune biomarkers has the potential to enable the development of new, novel therapies and can help physicians prescribe the optimal treatment to each patient.

A study, "Genomic Landscape and Immune Phenotype of Malignant Pleural Mesothelioma" (Abstract 9056/Poster 249), found that the majority of mesothelioma tumors harbor at least one alteration in key cellular pathways, with homologous recombination (HR) pathway mutations the most common.
"Molecular correlates of PD-L1 expression in patients (pts) with gastroesophageal (GE) cancers" (Abstract 4558/Poster 166) is the largest study to investigate the distinct molecular landscape of patients with different PD-L1 expression levels in GE cancers. These data can be used by oncologists to bring the right treatment to the right patient and by researchers to develop new combination immunotherapy regiments in GE cancers.
"As we continue to learn more about the molecular landscape of cancer, it is important to study all cancers, including those that are more uncommon and those that have an established treatment paradigm," said Chadi Nabhan, M.D., MBA, FACP, Chairman of the Caris Precision Oncology Alliance. "At Caris, our goal is to work with leading institutions to bring precision medicine to all people living with a cancer diagnosis, so that each patient can receive the best possible therapy for their own distinct cancer."

About the Caris Precision Oncology Alliance
A collaborative and growing network of leading cancer centers that demonstrate a commitment to precision medicine. The Alliance currently comprises 38 academic, hospital and community-based cancer institutions, including 12 NCI-designated Comprehensive Cancer Centers and now includes over 2,200 physicians, spanning more than 440 locations, who provide services for over 350,000 people with cancer each year.