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Precision Medicine, Targeted Therapy, and ZIP Codes: ASCO GI 2021

Op-Med is a collection of original articles contributed by Doximity members.

The COVID-19 pandemic is still leading to unwarranted fatalities and putting a stop to most social encounters and life as we know it. However, if it is possible to look on the positive side, the pandemic also generated several opportunities. Perhaps one of the most unexpected benefits of the COVID-19 lockdown is the wide use of virtual platforms to enable the sharing and dissemination of knowledge, data, and ideas through large global meetings. 

The ASCO Gastrointestinal (GI) Cancers Symposium has always offered an outstanding opportunity to share the findings from cutting-edge research and a multidisciplinary perspective on ideal GI cancer patient care. This annual meeting is a platform for stakeholders (e.g., medical oncologists, surgical oncologists, radiation oncologists, gastroenterologists, nurses, patients, patient advocates, policymakers, industry representatives, and more) to meet and network face-to-face and exchange ideas and new data to improve outcomes for GI cancer patients. However, because of the COVID-19 pandemic, this meeting's virtual platform allowed it to stretch to all corners of the globe and meet people at their laptops or phones. 

One of the novel aspects of this year was the emphasis on disparity and health equity of patients, as underlined by the keynote lecture, “Old Disparities Are New Again,” on January 17th, given by Professor Robert Winn, director of Virginia Commonwealth University Massey Cancer Center. He spoke rather emotionally and inspirationally about the history of health disparity going back more than 100 years and offered historical context to a pandemic and social unrest occurring simultaneously. Dr. Winn highlighted that research, knowledge, and solutions have existed for a long time, but an implementation plan is still lacking. He concluded his lecture on an optimistic note, pointing out that the COVID-19 pandemic provides an opportunity to do things differently, be different, and make more significant impacts on at-risk communities. His key message was that building trust and engaging the community is of utmost importance to cancer care. He recounted something once said to him: “I don't care how much you know about what you know until I know you care first.” For him, this underlined the importance of establishing trust and taking a patient’s perspectives and beliefs into account. In fact, several studies presented at this 2021 ASCO GI meeting, including our study, entitled “Socioeconomic status and survival outcomes in patients with gastrointestinal cancers: An analysis of 1.4 million patients in the National Cancer Database (NCDB)”(abstract. 458), consistently showed that patients with low socioeconomic status experience worse survival outcomes than patients with high socioeconomic status. Dr. Winn stated that “it appears that your ZIP code is a better prognostic [indicator] than your DNA.”  

One of the major themes of this annual meeting was the emphasis on precision medicine in GI cancer patients, the role of immunotherapy, and targeted therapy in GI cancers. 

Dr. Kai-Keen Shiu of the University College Hospital, NHS Foundation Trust in London presented updated results from the practice-changing, phase III KEYNOTE-177 trial (abstract 6). This trial randomly assigned 307 patients with microsatellite instability-high (MSI-H) and/or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) to pembrolizumab or investigator’s choice of chemotherapy (control arm). The study allowed crossover of patients in the control arm to receive pembrolizumab at the time of disease progression. Initial results from this trial, presented in the 2020 ASCO Virtual Scientific Program, demonstrated a clinically meaningful improvement in median progression-free survival (PFS) compared with standard therapy (16.5 vs. 8.2 months; HR 0.60, 95% CI, 0.45, 0.80; p = 0.0002). These results led to the FDA approval of pembrolizumab as first-line monotherapy for patients with MSI-H/dMMR mCRC. The updated results, after a median follow-up of 32.4 months, were presented at this virtual ASCO GI symposium and not only maintained the vast PFS advantage of first-line pembrolizumab over chemotherapy but also showed that progression-free survival-2 (PFS2), which is the time from randomization to progression on the next line of therapy, was longer when pembrolizumab vs. chemotherapy was administered first (median not reached vs. 23.5 mo; HR 0.63; 95% CI, 0.45-0.88). Final overall survival results from KEYNOTE-177 are pending, expected later this year.

Another aspect of paramount importance is the use of circulating tumor DNA (ctDNA) to detect molecular residual disease (MRD) after surgery and identify patients with stage I-III CRC at high risk for recurrence (abstract 11). Tenna V. Henriksen, a PhD student at Aarhus University in Denmark, presented the results from a prospective study, demonstrating that ctDNA can detect relapse far better than carcinoembryonic antigen (CEA) surveillance. Investigators followed 265 patients who underwent tumor resection and then plasma sampling for ctDNA analysis 30 days and three months after surgery and then every three months thereafter for a total of three years. 

Overall, 63% of patients received adjuvant chemotherapy after surgery based on standard clinical factors. The investigators found that 80% of patients with detectable ctDNA after surgery experienced disease recurrence compared to only 13% of patients with undetectable ctDNA (p < 0.0001). These findings were almost identical to those of ctDNA presence after adjuvant chemotherapy; hence, 83% of patients with detectable ctDNA after completing adjuvant chemotherapy experienced disease recurrence compared to 12.5% of patients with undetectable ctDNA (p < 0.0001).

Furthermore, serial ctDNA monitoring was the most prognostic factor for recurrence, where the recurrence rate reached 89% for patients with detectable ctDNA at any time compared to 3% for patients with consistently undetectable ctDNA (HR 51; 95% CI, 20, 125; p < 0.0001) 

In his excellent remarks as the discussant for this abstract, Dr. Michael J. Overman pointed out that these data show the prognostic ability of ctDNA following surgical resection. However, he added that “… the availability of a test is not the same as the actionability,” meaning that we must investigate the use of ctDNA in therapy guidance to make an impact on patient survival. He encouraged all of us to support patient enrollment into ongoing randomized clinical trials utilizing ctDNA to optimize our use of adjuvant therapy for patients with CRC. 

Updated overall survival (OS) data from the IMbrave150 study of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma (HCC) was presented by primary author Dr. Richard Finn of UCLA in abstract 267. At a median follow-up of 15.6 months, the median OS was 19.2 months compared to 13.4 months with sorafenib (HR, 0.66; 95% CI, 0.52-0.85; P = .0009), and the median PFS was 6.9 months vs 4.3 months (HR, 0.65; 95% CI, 0.53-0.81; P = .0001). Hence, this combination's efficacy and safety remained constant since its approval in the front-line HCC setting in May 2020.

In the era of personalized medicine, the widespread applicability of next-generation sequencing in the clinical setting enables us to discover specific genomic alterations, which can then be targeted using available therapies. Dr. Wainberg of UCLA Medical Center presented results from the phase II FIGHT study (abstract 160), which focused on patients with FGFR2b-positive, HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma. Wainberg’s team examined first-line therapy for these patients using bemarituzumab, a monoclonal antibody targeting the FGFR2b receptor, plus mFOLFOX6, and comparing the efficacy of this combination with placebo plus mFOLFOX6. Results were somewhat encouraging (mPFS, 9.5 months vs. 7.4 months; HR 0.68, 95% CI, 0.44, 1.04; p = 0.0727), introducing another targeted therapy besides trastuzumab as a first-line treatment option for selected patients with advanced gastric or gastroesophageal junction adenocarcinoma. The findings underlined the importance of a tailored therapy in patients with limited effective therapy options and supported the evaluation of bemarituzumab in other FGFR2b-positive tumor types.

Updated results from the POLO phase III trial (abstract 378) deserve a mention. Patients with metastatic germline BRCA-associated pancreatic cancer were randomly assigned in a 3:2 ratio to olaparib or placebo after induction chemotherapy. The primary endpoint was met and reported previously; an improvement in median PFS of patients was seen in patients receiving olaparib compared to placebo (7.4 months vs. 3.8 months; HR 0.53, 95% CI, 0.35, 0.82; p = 0.0038). However, final mature OS data were pending. Nonetheless, the trial results inspired FDA approval of the olaparib as maintenance therapy for patients with germline BRCA-mutated metastatic pancreatic cancer. At the ASCO GI symposium, Dr. Golan presented the study’s OS results after a median follow-up of 31 months; no median OS difference was observed between olaparib and placebo (19.0 vs. 19.2 months; HR 0.83; 95% CI 0.56–1.22; p= 0.3487). The lack of OS superiority sparked significant debate over the use of olaparib in the maintenance setting, which culminated in an agreement that more research into overcoming resistance is needed to improve PARP inhibitor efficacy, particularly in the pancreatic cancer setting.

Another important study was the open label phase 2 study of infigratinib in patients with previously treated advanced cholangiocarcinoma containing FGFR1 to three fusions or rearrangements (abstract 265). Dr. Javle presented results from Cohort 1 of 120 patients with advanced cholangiocarcinoma, specifically with FGFR2 fusions, that had progressed on gemcitabine-based chemotherapy. Infigratinib demonstrated meaningful clinical activity with an ORR of 23%, mPFS of 7.3 months, and mOS of 12.2 months. Infigratinib offers a new therapeutic option in second or later lines for this subset of patients with FGFR2 fusions.

The last topic up for discussion is the still rather mysterious gut microbiome. Dr. Yu Sunakawa and other investigators in the DELIVER observational/translational trial presented preliminary findings from their study of genomic information in the gut microbiome and its possible prediction of advanced gastric cancer patient response to nivolumab (abstract 161). Overall, the microbiome was found to be less diverse in patients with progressive disease. Also, increased invasion of bacteria into epithelial cells explicitly in the KEGG pathway was associated with disease progression and worse clinical outcomes in patients receiving nivolumab. Exploratory analyses found that Odoribacter and Veillonella were associated with tumor response to this PD-1 inhibitor. These findings are novel and further study will hopefully reveal some significant pathway differences that can serve as strong predictors of response to checkpoint and other therapy.

In conclusion, the 2021 ASCO GI Cancers Symposium was held on a large virtual platform, attracting participants from all over the globe and providing exciting new data and novel perspectives for the treatment of GI cancer patients. We expect that future meetings will continue to focus on immunotherapy, precision medicine, and how to increase our ability to better select patients for appropriate therapy by further developing predictive and prognostic biomarkers as well as combination therapies for specific genomic alterations.

Mohamed E. Salem, MD works in the Department of Medical Oncology at the Levine Cancer Institute in Charlotte, North Carolina.

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