The ASCO Gastrointestinal (GI) Cancers Symposium has always been an extraordinary meeting, providing a multidisciplinary perspective on the best treatment for patients with GI cancers. This annual gathering is attended by medical oncologists, surgical oncologists, radiation oncologists, gastroenterologists, nurses, patients, patient advocates, and others who have the opportunity to meet and network face-to-face, exchanging ideas and new data.
One of the novel aspects of this year’s meeting was the emphasis on GI cancer patient advocacy and palliation. The first Keynote Lecture given by Kelly McMasters, MD, PhD of the University of Louisville School of Medicine, for instance, had discussed the differences between palliative treatment and palliative care. Another presentation by patient advocate Melinda Bachini of the Cholangiocarcinoma Foundation offered a rather emotional and inspirational take on the patient perspective on cancer treatment, based on the results from a survey administered to more than 1,000 patients.
These presentations underlined the importance of focusing on patient perspective and beliefs, valorizing quality of life, and endorsing the role of palliative care concurrently with cancer-directed therapy, which reduces the use of potentially aggressive and often unnecessary end-of-life treatment in cancer patients.
The role of immunotherapy in GI cancers was another central aspect of ASCO GI 2019. It was demonstrated many times over that immune-checkpoint inhibitors show impressive clinical activity in patients with microsatellite instability-high (MSI-H) and/or mismatch repair deficient (dMMR) metastatic solid tumors, including gastric and colorectal cancer (CRC), after progression on standard chemotherapy—leading to the FDA-approval of pembrolizumab (an anti-PD-1 monoclonal antibody). In addition, in patients with MSI-H/dMMR metastatic CRC, treatment with nivolumab (anti-PD-1) and with the combination of nivolumab plus ipilimumab (anti-CTLA4) showed striking results and durable clinical responses both in first and later lines of treatment.
However, several trials with immunotherapy failed to prove beneficial to patients with microsatellite-stable (MSS) mCRC (e.g., IMBLAZE270, MODUL and KEYNOTE-028 trials), which is considered a cold tumor, intrinsically resistant to immune-checkpoint inhibitors. At this ASCO GI meeting, the results of a phase II non-randomized trial with durvalumab (anti-PD-L1) plus tremelimumab (anti-CTLA4) in 180 refractory metastatic CRC patients was presented: the patients progressed on all the standard treatments available. The combination of durvalumab and tremelimumab showed an improved overall survival (OS) compared to best supportive care (6.6 vs. 4.1 months, HR 0.72, 95 percent confidence interval 0.54 – 0.97, P = 0.07). It is crucial to note that the vast majority of enrolled patients were MSS (there were only 2 MSI-H patients). The authors concluded that this is the first study to demonstrate the effectiveness of immune-checkpoint blockade in CRC patients unselected for MMR deficiency, although a phase III trial to confirm these findings is warranted.
Another research team presented results from the KEYNOTE-181 trial; an important phase III randomized trial of pembrolizumab compared to chemotherapy (investigator choice) as second-line treatment in 628 patients with advanced esophageal cancer. As already shown in previous trials, patients with overexpression of PD-L1 (CPS > 10) significantly benefitted from pembrolizumab, with a median overall survival (OS) of 9.3 months vs. 6.7 in the control group, leading to a potential novel treatment for this subset of patients.
Immune-checkpoints inhibitors demonstrated promising results not only in metastatic disease but also in the adjuvant setting. The results from a phase II study was conducted in 24 patients with esophageal and gastroesophageal junction (GEJ) adenocarcinoma, who had residual disease after neoadjuvant chemoradiation and R0 resection. After esophagectomy, patients received durvalumab at a dose of 1,500 mg intravenously once a month for up to 1 year. After 11.7 months of median follow-up, 67 percent of patients remained disease-free. These findings translate to 1-year and projected 26-month relapse-free survival rates of 78.6 percent and 62.9 percent, respectively.
Although immunotherapy has revolutionized the treatment landscape for patients with several solid tumors, only a small subset benefits from this approach; therefore, many different strategies are currently under development to improve immune-checkpoint inhibitor efficacy. Among these strategies, the association of immunotherapy with targeted therapy or radiotherapy was reported to show promising results. On January 17th, Dr. Janjigian presented the data of the KEYNOTE-811 trial, investigating the activity of pembrolizumab plus trastuzumab and chemotherapy (capecitabine + oxaliplatin) in metastatic HER2-positive esophago-gastric adenocarcinoma. The investigators showed that 52 percent of patients had an objective response (OR) after 1 cycle of pembrolizumab plus trastuzumab (without chemotherapy, which was introduced in the second cycle). Overall, this combination proved to be very promising, with an OR rate of 87%, a complete response rate of 9%, a median progression-free survival (PFS) of 11.4 months, and 1-year OS rate of 76%. As the activity of single agent immune-checkpoint inhibitors is minimal in advanced pancreatic adenocarcinoma, Dr. Brar presented the results of a Phase I study combining durvalumab plus tremelimumab with stereotactic body radiation therapy (SBRT). The median PFS was 2.2 months, and the median OS was 4.9 months, with durable responses observed in 2 patients lasting over 12 months, suggesting that immunotherapy with SBRT is a potential new treatment for pancreatic cancer, warranting further investigations.
In the era of the personalized medicine, the widespread applicability of next-generation sequencing (NGS) in the clinical setting enables us to discover specific genomic alterations, which may be targeted using available therapies. Dr. Wainberg presented results from the dabrafenib (anti-BRAF) plus trametinib (anti-MEK) arm of the ROAR basket trial in pretreated patients with BRAF V600E mutated biliary tract cancer. Results were rather encouraging (ORR, 42 percent; mPFS, 9.2 months; and mOS, 11.7 months), underlining the importance of a tailored therapy in patients with limited effective options.
Another aspect of paramount importance is the use of integrative molecular profiling to identify signatures associated with response to standard chemotherapy. Dr. Knox showed results from the COMPASS trial, in which 180 patients with pancreatic cancer underwent comprehensive molecular profiling (whole genome sequencing (WGS), RNA sequencing, and GATA6 expression) at baseline. The authors found that patients with a classical genotype have more benefit from mFOLFIRINOX than those with a basal-like genotype (mPFS 7.1 vs. 2.6 months).
In conclusion, the ASCO GI 2019 meeting provided exciting new data as well as novel perspectives for the treatment of gastrointestinal cancer patients. We expect that future meetings will focus on immunotherapy combinations and how to increase the efficacy of our treatment by further developing combination therapies for specific genetic alterations.
Dr. Mohamed Salem is a GI medical oncologist at the Levine Cancer Institute.
Dr. Alberto Puccini is a medical oncology fellow at the University of Genoa, Italy.
Illustration by April Brust