These are the highlights at this year's ASCO Annual Meeting for gastrointestinal malignancies—specifically colorectal cancer, gastro-esophageal cancer, pancreatic neuroendocrine tumors, carcinoid tumors, pancreatic cancer, and hepatocellular carcinoma.
The indisputable highlight in colorectal cancer was the demonstration that anti-PD-1 immune checkpoint inhibitors have significant activity in patients with hypermutated cancers.
A high frequency of DNA mutations can be either induced by exogenous carcinogens like UV light (melanoma) and cigarette smoke (lung cancer) or linked to deficient DNA mismatch repair enzymes, the key genetic alteration in Lynch syndrome and in sporadic cancers due to methylation of the MLH1 mismatch repair gene promoter region. About 15 to 20 percent of stage II, eight to 10 percent of stage III, and four to five percent of stage IV colorectal cancers exhibit the deficient mismatch repair phenotype (synonymous with MSI-H) and thus accumulate hundreds to thousands of mutations which can lead to the expression of immunogenic neo-antigens.
In a Phase II study presented at ASCO 2015 (and simultaneously published in the New England Journal of Medicine), pembrolizumab, a PD-1 antibody, showed remarkable activity as salvage therapy in heavily pretreated patients with the deficient mismatch repair phenotype (MSI-H) with a response rate of more than 60 percent and a disease-control rate of more than 90 percent. Some of the responses showed a remarkable long duration. The same level of activity was found in non-colorectal cancer MSI-H tumors, whereas not a single patient with mismatch repair proficient (MSS) colorectal cancer showed a response.
These findings open the door for further studies investigating the MSI-H phenotype as a strong predictive biomarker for anti-PD-1/PD-L1 antibodies, which have already become standard of care in other malignancies. Given the remarkable activity observed in the presented trial it is conceivable that off-label use of the approved immune checkpoint inhibitors will be considered by oncologists and patients.
With MSI-H colorectal cancer now being identified as a subgroup for a specific therapeutic intervention, ASCO 2015 demonstrated that two additional subgroups, BRAF mutated and HER-2 overexpressing, could benefit from specific targeted approaches.
It has long been recognized that activating BRAF mutations, which are found in about eight to 10 percent of colorectal cancers, are associated with poor prognosis with standard treatment options. In contrast to BRAF-mutated melanoma, where the use of a BRAF inhibitor as a single agent exhibits a high response rate, albeit commonly of short duration, the same approach has only minimal activity in BRAF-mutated colorectal cancer. ASCO 2015 now showed several clinical trials with rationally designed combinations of a BRAF inhibitor, EGFR antibody, and a third agent that could either be a MEK inhibitor, a PI3K inhibitor, or conventional chemotherapy.
The most intriguing results were reported with a combination of vemurafenib (BRAFi), cetuximab (EGFR antibody), and irinotecan in pretreated patients with colorectal cancer. The combination appeared to be well tolerated and showed remarkable activity in a Phase I/Ib study with a response rate of 35 percent and a progression-free survival of 7.7 months—both results not previously seen in BRAF-mutated colorectal cancer. This combination is currently being tested in a randomized Intergroup trial, S1406, and could establish itself as a new standard of care in this patient population.
The other molecular subgroup of colorectal cancer that is emerging as a target for specific intervention is characterized by HER-2 overexpression. A pivotal trial presented at the meeting demonstrated a 35 percent response rate in patients with heavily pretreated, HER-2 positive colorectal cancer with a combination of lapatinib and trastuzumab. HER-2 overexpression can be found in about four to five percent of RAS wild-type colorectal cancer and has been correlated with a lack of response to EGFR antibodies. Some of the responses observed with the HER-2 targeted combination were found to be quite durable.
Taken together, the results of significant activity of specific targeted intervention in molecular subgroups of colorectal cancer could open the door for innovative therapies in the 15 to 20 percent of cancers characterized by MSI-H, BRAF mutation, or HER-2 overexpression. It is conceivable that routine clinical workup of a patient with stage IV colorectal cancer will soon include testing for these molecular alterations in addition to standard RAS mutational analysis (KRAS/ NRAS exons 2,3,4).
In recent years, radioembolization of liver metastases has become one of the treatment options for colorectal cancer patients with liver-limited or liver-dominant metastases. The role of radioembolization (or SIRT: selective internal radiation therapy) as part of standard first-line therapy was investigated in the SIFLOX study, which compared mFOLFOX6 with mFOLFOX6 plus SIRT in 530 patients. The use of bevacizumab was optional in this trial.
The primary endpoint, improvement in overall PFS, was not reached (10.2 vs 10.7 months for FOLFOX vs FOLFOX plus SIRT, p=0.43), but it is of note that 40 percent of patients had extrahepatic disease, which was naturally not influenced by the liver-directed approach.
The secondary endpoint of PFS of liver metastases was reached with a hazard ratio of 0.69 (12.9 vs 20.5 months, p=0.002). In spite of an increased rate of responses in liver metastases (78.7% vs 68.8%) no increased rate of liver resection was seen, with SIRT. Overall survival data were not mature yet at presentation.
The data indicate that SIRT could potentially be considered as a component of standard therapy in patients with liver-limited disease. Its definitive role in the management of patients with metastatic colorectal cancer will be further elucidated by two other randomized trials that will be presented within the next one to two years.
One potentially practice-changing trial in gastro-esophageal cancers was presented by David Cunningham: The OE05 trail randomized 886 patients with non-metastatic adenocarcinomas of the distal esophagus and gastro-esophageal junction to a neoadjuvant chemotherapy approach with either four cycles of ECX (epirubicin, cisplatin, capecitabine) or two cycles of cisplatin/fluorouracil (CF). As expected, ECX was significantly more toxic than CF—in particular with regard to hematologic side effects and diarrhea.
In this large study no difference in resection rates and progression-free and overall survival was found, which questioned the importance of anthracyclines and a prolonged duration of neoadjuvant therapy in this setting. In fact, based on these data a neoadjuvant treatment approach along the lines of the MAGIC trial with a platinum/fluoropyrimidine combination now appears to be an appropriate standard of care. In contrast, the role of anthracyclines in the management of esophago-gastric adenocarcinomas appears to be decreasing.
With regard to targeted therapy in gastro-esophageal cancers, ASCO 2015 showed interesting data for pembrolizumab and regorafenib.
The Cancer Genome Atlas project had identified four different subgroups of gastric cancer based on their gene-expression profiles two of which—the Epstein-Barr related and the MSI-H cancers—are thought to be candidates for immunotherapy. The proof of principle for the activity of PD-1 antibodies was brought about by data from a Phase II study with pembrolizumab in 39 patients with PD-L1 positive tumors based on immunohistochemistry.
Cancers were identified as positive for PD-L1 when stromal staining or staining in at least one percent of tumor cells was noted. Single-agent pembrolizumab induced sometimes durable responses in about 33 percent of patients based on investigator assessment. Intriguingly, median overall survival in this pretreated cohort of patients was remarkably long, at 11.4 months. Additional studies are underway to define the role of PD-1 inhibitors in gastric cancers.
The efficacy of anti-VEGF therapy in advanced gastro-esophageal cancers has been demonstrated by two Phase III trials in which ramucirumab, a monoclonal antibody against VEGF-R2, showed benefit in overall survival, either as single agent or in combination with paclitaxel.
Regorafenib is an oral multi-kinase inhibitor with significant anti-angiogenic properties, which is approved as single-agent salvage therapy in patients with metastatic colorectal cancer. In a randomized Phase II trial with a 2:1 randomization of regorafenib versus placebo in 150 patients in second- or third-line metastatic gastro-esophageal cancer, regorafenib demonstrated a significant improvement in PFS with a hazard ration of 0.40 (median PFS 2.6 vs 0.9 months, p<0.0001). Overall survival showed a trend in favor of regorafenib.
The results confirm the activity of anti-angiogenic therapy in gastro-esophageal cancers. The role of regorafenib in this setting will need to be further defined in subsequent studies.
In Further Noteworthy GI Cancer News at the Meeting:
- A randomized Phase II study of everolimus with or without bevacizumab in patients with advanced pancreatic neuroendocrine tumors (PNET), an increased overall response rate was noted in the bevacizumab arm (31% vs. 12%, p=0.005), but no significant improvement in PFS or OS was seen;
- A single-arm Phase II study of bevacizumab as a single agent in PNET showed a 14 percent response rate;
- A Phase III trial in 402 patients with metastatic carcinoid tumors compared octreotide with either interferon alpha or bevacizumab. Although the bevacizumab arm showed higher response rats (12% vs. 4%, p=0.008), no difference in PFS was seen. The toxicity profile favored the bevacizumab arm;
A randomized Phase II study in pancreas cancer demonstrated the activity of PEGPH20, a hyaluronase that is able to degrade a hyaluronan (HA) layer around tumor cells, when added to a gemcitabine/nab-paclitaxel combination. The activity appeared to be limited to patients whose tumors were classified as “HA-high” by immunohistochemistry; and
- In a single arm Phase II study in 47 pretreated patients with advanced hepatocellular carcinoma, the PD-1 antibody nivolumab revealed a remarkable response rate of 19 percent, some of which were very durable. Immune-checkpoint inhibitors will be further investigated in future trials in this malignancy, which clearly constitutes an unmet need.