India: Conference Briefs From American Association For Cancer Research (AACR) Annual Meeting 2018

The American Association for Cancer Research (AACR) Annual Meeting 2018, was held from 14th -18th April 2018, at Chicago, Illinois, USA. This year's theme, "Driving Innovative Cancer Science to Patient Care", was evident throughout the meeting as the latest and most exciting discoveries were showcased from every region of cancer research. A number of presentations included exciting new data from cutting-edge clinical trials as well as companion presentations that spotlighted the science behind the trials and implications for delivering improved care to patients. New exciting presentations from AACR 2018 are discussed below:

1. Successful CAR T-Cell Treatment Needs Good T Cells to Begin With - CAR T-Cell therapy, a type of immunotherapy based on the principle of adoptive T-Cell transfer, has revolutionized treatments for blood cancers, particularly in children. This therapy has yielded striking responses in some patients with cancers deemed incurable and in those who had stopped responding to chemotherapies and even resulted in complete remission rates of up to 90 percent in clinical trials.

Last year, the U.S. Food and Drug Administration approved two CAR T-Cell therapies - tisagenlecleucel (Kymriah, Novartis) was approved for treating certain pediatric and young adult patients with acute lymphoblastic leukemia (ALL) and; axicabtagene ciloleucel (Yescarta, Gilead) was approved for treating adults with certain types of non- Hodgkin lymphoma.

According to a research presented in the AACR Annual Meeting 2018 by David M. Barrett, MD, PhD, Assistant Professor of Pediatrics at Children's Hospital of Philadelphia, one of the approaches to improve CART-Cell therapy and potentially making it effective against solid tumors involves going back to the drawing board and looking at the starting material. . In this study, co-sponsored by a Stand up To Cancer (SU2C) Innovative Research Grant (the AACR is the Scientific Partner of SU2C), Barrett and colleagues found that a lot can be learned by closely examining the patient T cells which are an essential starting material for the process of CAR T-Cell manufacture.

An important criterion for modifying T-Cells into CAR-T cells is that the T-Cells from the patient must be healthy enough to survive during the complex endeavor of making them express a CAR, and then have enough energy left, once reintroduced in to the patient, to efficiently attack the cancer cells.

The metabolism of normal T-Cells changes when they are stimulated to convert into a CAR-T Cell, Barrett explained. Normal T Cells rely heavily on the fuel sources in the environment. They use one of the two fuel sources, the glycolysis or the glutamine and fatty acid pathway, to build their energy. The researchers learned that while T Cells that use glutamine and fatty acid pathways as fuel sources had great CAR T-Cell potential, those that depended on glycolysis were poorly suited to the process of CAR T-cell manufacture35.

2. Pembrolizumab Plus Chemotherapy: According to data from the phase III clinical trial KEYNOTE-189, presented at the AACR Annual Meeting 2018, Practice-Changing for mNSCLC - Patients with nonsquamous metastatic non-small cell lung carcinoma (NSCLC) lived significantly longer and had a 48% reduced risk for disease progression if they received pembrolizumab (Keytruda, Merck) in addition to chemotherapy compared with those who received standard chemotherapy alone.

"The long-term survival of patients with advanced NSCLC remains poor and the standard of care for most patients is chemotherapy, which affords a survival benefit measured in months," said Leena Gandhi, MD, PhD, Associate Professor in the Department of Medicine and Director of Thoracic Medical Oncology Program, Perlmutter Cancer Center at NYU Langone Health.

In May 2017, the U.S. Food and Drug Administration approved pembrolizumab plus pemetrexed and carboplatin- based chemotherapy as first-line treatment for patients with advanced nonsquamous NSCLC based on data from the phase II cohort G of the KEYNOTE-021 study, but it was not widely adopted in the absence of positive results from a phase III study, Gandhi explained36.

3. Adjuvant Pembrolizumab for Melanoma According to the data presented at the AACR 2018 Annual Meeting and simultaneously published online in the New England Journal of Medicine, patients with stage III melanoma may soon have access to yet another immunotherapeutic agent after they undergo surgery. New data from a pivotal phase 3 trial show that 1,019 patients with stage 3 melanoma who were at high risk of recurrence after complete resection of their tumors in the KEYNOTE-054/EORTC 1325-MG. Patients were randomized 1:1 to a flat dose of 200 milligrams of pembrolizumab or placebo every three weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity. Patients receiving Pembrolizumab (Keytruda, Merck) were at a 43% reduced risk for recurrence compared to patients who received placebo. These data are expected to lead to approval for this new indication. The FDA approved ipilumumab (Yervoy) and nivolumab (Opdivo), for use as an adjuvant treatment for patients with high-risk stage 3 melanoma that has been completely resected respectively in October 2015 and December 2017. The benefits of pembrolizumab were similar when patients with PD-L1- positive and PD-L1-negative tumors were analyzed separately. This study was conducted by the European Organisation for Research and Treatment of Cancer (EORTC) and sponsored by Merck37.

4. Children with Non-chromosomal Birth Defects Face Higher Risk of Several Childhood Cancers - According to a study presented at the AACR Annual Meeting 2018, a retrospective analysis of registry data on more than 10 million live births, the risk for childhood cancers was 2.6-fold higher in children born with non-chromosomal abnormalities than in children born without any defects. In addition, some cancers were linked with specific birth defects.

"Approximately one in 33 children is born with a birth defect,"said the study's lead author, Jeremy M. Schraw, PhD, a postdoctoral fellow at Texas Children's Cancer Center, Texas Children's Hospital. Some birth defects, including the fairly common cleft palate and cleft lip, had no association with childhood cancer. Childhood cancer is rare and, therefore, the risk that a child with a non-chromosomal birth defect will develop cancer during childhood is low, Schraw said.

In this study, the researchers pooled statewide registry data from Texas, Michigan, North Carolina, and Arkansas for the period 1992-2013, and linked information from birth certificates, birth defects registries, and cancer registries. They used Cox proportional hazard models to evaluate associations between 60 birth defects and 31 childhood cancers38.

4. Tumor Mutational Burden (TMB) as New Biomarker in NSCLC - According to data from the phase III clinical trial CheckMate -227, presented at the AACR Annual Meeting 2018, a new biomarker has emerged in lung cancer. Patients with newly diagnosed advanced non–small cell lung cancer (NSCLC) who were found to have a high TMB >10 mutations/Mb, fared better with immunotherapy than with standard-of-care chemotherapy (CT). These patients were at a significantly 42% reduced risk for disease progression if they received the immunotherapy combination of nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb) compared with patients who received standard-of-care chemotherapy (CT).

"The results show that in TMB-high NSCLC patients, nivolumab plus ipilimumab provides improved benefit compared to chemotherapy, increases benefit compared to anti-PD-1 monotherapy, yields durable responses, spares the use of chemotherapy in the first-line setting, and could preserve an effective option in the second line of therapy, if needed," said Matthew Hellmann, MD, attending at Memorial Sloan Kettering Cancer Center.

"These practice-changing data establish the combination of nivolumab plus ipilimumab as a first-line treatment option for patients with high-TMB NSCLC," Hellmann said. This work also identifies TMB as an important and reliable biomarker that should be tested in patients with newly diagnosed NSCLC, Hellmann added.

Nivolumab plus ipilimumab was well tolerated and the safety profile was similar to the previous experience with this regimen. The rate of treatment-related grade 3-4 toxicities was 31%, versus 36% with chemotherapy. This study was supported by Bristol Myers Squibb (BMS) and Ono Pharmaceutical39.

5. Olaparib in Breast Cancer - PFS is significant but OS is not - According to the final analysis of OlympiAD trial A few months ago, olaparib (Lynparza, AstraZeneca) became the first drug approved to treat women with advanced breast cancer with germline mutations in BRCA. The approval was based on a significant improvement in progression-free survival (PFS) compared with standard chemotherapy. Now, however, a final analysis of OlympiAD trial results presented at the AACR Annual Meeting 2018 show that overall survival (OS) did not significantly improve.

At the final analysis, of the 302 patients randomly assigned, 205 received olaparib and 91 received chemotherapy (investigator's choice of capecitabine [Xeloda, Hoffmann-La Roche]), eribulin [Halaven, Eisai], or vinorelbine [Navelbine, Pierre Fabre]). With a hazard ratio (HR) of 0.90, patients receiving olaparib had a 10% reduced risk for death compared with those receiving chemotherapy, but these data did not reach statistical significance.

Benefit with olaparib was greatest for patients who received olaparib as first-line therapy - 22.6 months with olaparib vs 14.7 months with chemotherapy (HR, 0.51; 95% confidence intervals, 0.29 - 0.90; P = .02). OS was not significant for patients who received olaparib as a later line of therapy (median OS, 18.8 months vs 17.2 months for chemotherapy).40








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