Janjigian Highlights Lessons Learned from 2020 Gastrointestinal Cancers Symposium

Yelena Y. Janjigian, MD

Although data from a number of trials presented during the 2020 Gastrointestinal Cancers Symposium proved to be negative, according to Yelena Janjigian, MD, the information yielded from those research efforts offers greater insight on how to optimally treat patients across gastrointestinal malignancies.

For example, results from the phase III JAVELIN Gastric 100 study showed that avelumab (Bavencio) failed to improve overall survival (OS) when used as a frontline maintenance treatment following induction chemotherapy in patients with unresectable, locally advanced, or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) cancer.¹

Avelumab missed both of the trial’s OS-based primary endpoints. The median OS was 10.4 months (95% CI, 9.1-12.0) in the avelumab arm versus 10.9 months (95% CI, 9.6-12.4) in the chemotherapy arm (HR, 0.91; 95% CI, 0.74-1.11; P = .1779). Furthermore, the 24-month OS rates were 22.1% (95% CI, 16.8-28.0) with avelumab versus 15.5% (95% CI, 10.8-20.9) with chemotherapy. The HR for OS among patients with PD-L1—positive tumors was 1.13 (95% CI, 0.57-2.23; 1-sided P = .6352).

“This was a relatively small study considering the question that it was trying to answer had to do with maintenance therapy, which has been a very exciting research question that has been postulated in gastric cancer, among other diseases,” said Janjigian. “Unfortunately, [these results] put a brake on maintenance strategies in this disease.”

The colorectal cancer (CRC) space saw more positive data with the phase III BEACON CRC trial. Results showed that encorafenib (Braftovi) plus cetuximab (Erbitux) with or without binimetinib (Mektovi) led to longer maintenance of quality of life (QoL) and an improvement in survival over the current standard of care in patients with BRAF V600E—mutated metastatic CRC.²

Both the doublet, composed of encorafenib plus cetuximab, and triplet regimens reduced the risk of QoL deterioration by ≥40% per multiple QoL assessment instruments versus the standard-of-care regimen. Updated OS data showed a median OS of 9.3 months with either the doublet or triplet regimens versus 5.9 months in the control arm, at a median follow-up of almost 13 months.

Previously reported data published in the New England Journal of Medicine showed that after a median follow-up of 7.8 months, the median OS in the triplet arm was 9.0 months compared with 5.4 months in the control arm (HR, 0.52; 95% CI, 0.39-0.70; P <.001).³ In the doublet arm, the median OS was 8.4 months (HR versus control, 0.60; 95% CI, 0.45-0.79; P <.001).

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Gastrointestinal Malignancies, Janjigian, chief of Gastrointestinal Oncology Service and medical oncologist at Memorial Sloan Kettering Cancer Center, highlighted key updates from the 2020 Gastrointestinal Cancers Symposium and explained the impact that new data will have on clinical practice.

OncLive: What were some of the top abstracts that were presented at the 2020 Gastrointestinal Cancers Symposium?

Janjigian: Unfortunately, most of the trials [that read out at the symposium] were negative. We saw data from the JAVELIN [Gastric] 100 study in gastric cancer; this was an eagerly awaited study of first-line maintenance avelumab, which is an anti—PD-L1 drug, in patients with stage IV gastric cancer. Patients had been treated with induction chemotherapy [consisting of oxaliplatin plus 5-fluorouracil or capecitabine (Xeloda)]. After the induction regimen, patients were randomized to receive avelumab maintenance or standard of care, which in most cases, involves continuing [the same] chemotherapy [regimen]. The patients were not selected for PD-L1 expression and unfortunately, overall, this was a negative study.

If you remember, the [study of] maintenance ipilimumab (Yervoy) [in gastric cancer] was similarly negative, so we need to really rethink how we target this disease. What is the appropriate therapy? Also, most importantly, how do we select patients based on biomarker studies? We know that gastric cancer is quite heterogenous and, for microsatellite instability—high and mismatch repair-deficient tumors, immunotherapy is possibly very important in the first-line setting.

Pembrolizumab (Keytruda) is approved by the FDA for use in third-line setting—after progression on standard chemotherapy. Data presented at the 2019 ESMO Congress and updated [data presented] at [the 2020 Gastrointestinal Cancers Symposium] suggest that pembrolizumab is very important to consider in first-line therapy in metastatic gastric cancer. When compared with chemotherapy, pembrolizumab imparted an important survival benefit.

[At the symposium], we saw another negative study from Asia in surgical cases with gastric cancer. Once again, no clear benefit [was observed] for peritoneal lavage or peritoneal-directed washings in [patients with] gastric cancer and cytology-positive disease. The same question comes up over and over again: Should we do more localized therapy and try to cure these patients? The bottom line is, the data suggest that these patients have advanced disease; unless we select for specific biology in tumor subsets, the treatment is palliative in intent in the majority of [those with] gastric cancer [who have] peritoneal spread. There is no role for surgical resection or these peritoneal therapies [in these patients].

The data from the phase III BEACON CRC trial in CRC were positive. Could you speak to those findings?

In CRC, probably one of the more exciting updates was the BEACON CRC study [examining a] combination of [the BRAF inhibitor encorafenib plus cetuximab with or without the MEK inhibitor binimetinib] compared with chemotherapy. These data were initially presented and then subsequently published in the New England Journal of Medicine, and clearly there's benefit for a combination of inhibitors with BRAF/MEK as well as cetuximab in CRC. The question of whether or not a triplet regimen is necessary is yet to be determined.

This is an important update that Scott Kopetz, MD, PhD, FACP, of The University of Texas MD Anderson Cancer Center, presented [at the 2020 Gastrointestinal Cancer Symposium]: It's important to treat and target these patients with BRAF-mutant tumors as these cancers tend to be much more aggressive in nature. Perhaps earlier lines of therapy for those with BRAF-mutant tumors is to come. Regardless, this [trial] is proof of principle that these tumors are targetable, that doublet therapy is likely sufficient, and based on the survival benefit presented by Dr. Kopetz, [the triplet regimen also outperformed standard of care].

What other notable trials in CRC presented at the 2020 Gastrointestinal Cancers Symposium did you want to highlight?

A study from Japan mostly confirmed what [we already do in] practice in [terms of] metastatic CRC. [Results showed] no clear benefit in removing the primary tumor unless there's a role for curative surgery. In most patients with stage IV disease who were treated with chemotherapy, removing the colon primary in metastatic CRC actually resulted in worse outcomes and worse toxicity from chemotherapy. As such, that should be avoided. Again, this is more confirmation [of what we already knew], but it really is an important study to note.

References

1. Moehler MH, Dvorkin M, Ozguroglu M, et al. Results of the JAVELIN gastric 100 phase 3 trial: avelumab maintenance following first-line (1L) chemotherapy (CTx) vs continuation of CTx for HER2— advanced gastric or gastroesophageal junction cancer (GC/GEJC). J Clin Oncol. 2020;38(suppl 4; abstr 278). doi: 10.1200/JCO.2020.38.4_suppl.278.
2. Kopetz S, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab with or without binimetinib for BRAFV600E-mutant metastatic colorectal cancer: quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). J Clin Oncol. 2020;38(suppl 8; abstr 8). doi: 10.1200/JCO.2020.38.4_suppl.8.
3. Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381(17):1632-1643. doi: 10.1056/NEJMoa1908075.