SAN FRANCISCO — Treatment with cabozantinib (Cometriq, Exelixis) has shown promising objective tumor responses and progression-free survival in patients with advanced carcinoid and pancreatic neuroendocrine tumors (pNETs), according to findings presented here at the Gastrointestinal Cancers Symposium (GICS) 2017.
Among the 20 patients with pNETs, a clinical benefit was observed in 90%, which was a combination of partial response and stable disease.
Similar findings were also observed for the 41 patients with carcinoid tumors, with cabozantinib conferring a clinical benefit of 78%, also partial responses and stable disease.
"The median progression-free survival for both cohorts in this phase 2 study are encouraging in the context of historical results," said lead author Jennifer A. Chan, MD, MPH, from the Dana-Farber Cancer Institute, Boston, Massachusetts.
"Adverse events were consistent with what has already been reported, and most were low grade," she added.
Cabozantinib has already been approved for the treatment of renal cell carcinoma and medullary thyroid carcinoma. The drug is a tyrosine kinase inhibitor that acts on many targets, including MET, vascular endothelial growth factor (VEGF) receptors, AXL and RET.
Dr Chan explained that previous studies have shown that these targets are important in NETs. For instance, VEGF pathway inhibitors have shown activity in advanced disease, and increased expression of MET correlates with decreased overall survival in pancreatic NET. She noted that "in preclinical models of NET, cabozantinib has been shown to decrease metastases and invasion."
Responses in Pretreated Patients
In this phase 2 prospective study, patients with progressive, well-differentiated, grade 1-2 carcinoid tumors (n = 41) or pNETs (n = 20) were enrolled in parallel cohorts and treated with cabozantinib, 60 mg daily.
There was no limit on previous therapies, and the pNET group tended to be heavily pretreated. The median number of prior therapies was 3; 60% of patients had received sunitinib (Sutent, Pfizer). The carcinoid group was less heavily pretreated, with a median of 1 prior therapy; 29% of patients had received everolimus (Afinitor, Novartis).
Patients were restaged every 2 months for the first 6 months and then every 3 months. The primary endpoint was objective response rate, as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and secondary endpoints included progression-free survival, overall survival, safety, and tolerability.
When the data were analyzed in July 2016, 5 (25%) patients in the NET group and 9 (22%) in the carcinoid group remained on treatment.
When looking at the outcomes, the researchers found that 15% (n = 3) of patients with pancreatic NET achieved a partial response, 75% (n = 15) had stable disease, and 2 patients were not evaluated.
"Several of the patients categorized with stable disease had a significant reduction in disease but didn't quite reach RECIST criteria for partial response," Dr Chan pointed out. "Also of note, one of the patients who achieved a partial response had already been treated with sunitinib and everolimus."
Among the patients with carcinoid tumors, 6 achieved a partial response (15%) and 26 (63%) had stable disease. Additionally, 2 patients (5%) experienced progressive disease and 7 (17%) stopped treatment before restaging. Two responses were observed in patients who had received prior everolimus.
At a median follow-up duration of 23.3 months, progression-free survival reached 21.8 months in the pNET cohort and 31.4 months in the carcinoid group.
Dr Chan noted that "recognizing the limitation of interpreting progression-free survival data, and in an uncontrolled phase 2 trial, as well as comparing data to other clinical trials, the results we observed do appear encouraging."
In addition, these results compare favorably to those of other phase 2 and phase 3 trials that looked at tyrosine kinase inhibitors and everolimus for the treatment of NETs. The progression-free survival for these trials ranged from about 8 to 16 months.
Toxicities were largely consistent with previous observations and were typically mild or moderate in severity. The most common treatment-related grade 3/4 adverse events included hypertension (13%), hypophosphatemia (11%), diarrhea (10%), lymphopenia (7%), thrombocytopenia (5%), fatigue (5%), and increased lipase or amylase (8%).
Dr Chan concluded that "it will be important to confirm the activity of cabozantinib in a randomized phase 3 setting."
In his discussion of the abstract, Vincent Picozzi, MD, director of the Pancreas Cancer Center of Excellence at Virginia Mason Cancer and Digestive Diseases Institute in Seattle, Washington, pointed out that progression-free survival is the preferred primary endpoint for phase 2/3 studies in advanced NET.
"Overall survival is not often used as a primary endpoint due to length of survival, crossover, and use of subsequent agents," he said. "But should we be holding ourselves to a higher standard?"
Overall, he agreed with Dr Chan that further exploration is needed and eagerly awaited.
"Cabozantinib is an interesting drug in this setting. There's a clear biologic rationale and it was very tolerated," Dr Picozzi summarized. "The results are intriguing, but I'm uncertain how cabozantinib will broadly impact progression-free and overall survival in NET. The activity is worth exploration, but perhaps in the context of controlled randomized phase 2 setting."
Dr Chan reports relationships with Bayer, Ipsen, Merck, Novartis, Pfizer, POZEN, and Sanofi; several coauthors also report relationships with industry. Dr Picozzi reports relationships with AbbVie, Aduro Biotech, Amgen, Celgene, Clovis Oncology, FibroGen, Halozyme, Immunomedics, Incyte Halozyme, Johnson & Johnson, OncoMed, Taiho Pharmaceutical, and Theranostics Health.
Gastrointestinal Cancers Symposium (GICS) 2017. Abstract 228. Presented January 20, 2017.