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2016 Gastrointestinal Cancer Symposium - January 21-23, San Francisco, California, USA
Congress Highlights by Dr Elizabeth Smyth
Dr Dung T Le presented the initial results of the Phase I/II Checkmate 032 study which assessed the efficacy of the anti-PD-1 antibody nivolumab in advanced gastric and gastroesophageal junction cancers. Patients in this study, who were not selected using PD-L1 status, were treated with nivolumab 3 mg/kg intravenously every 2 weeks until disease progression or withdrawal due to toxicity. Fifty nine patients were treated in the phase I part of the study, the majority (83%) of whom had already received at least 2 previous lines of treatment. The overall response rate (ORR) was 14%, and 19% of patients had stable disease. Thirty eight percent of 40 patients who had PD-L1 testing on their tumours were PD-L1 positive, and patients who were PD-L1 positive (at a ≥1% level) had a higher ORR of 27%. However the ORR in PD-L1 negative patients was 12%, implying that PD-L1 positivity was not required for response. Median duration of response for responding tumours was 7.1 months, and time to response was 1.6 months for responding patients (n=8). The proportion of patients alive at one year was 36%. No new toxicities for nivolumab were demonstrated in the gastric cancer patient population and only 17% of patients had a ≥ grade 3 AE, and there were no treatment related deaths. Grade 3-4 increased AST, ALT and pneumonitis each occurred in one patient.
Updated results were also presented for the phase Ib KEYNOTE-028 (NCT02054806) study of the anti-PD-1 antibody pembrolizumab for patients with previously treated oesophageal cancer. Patients in this study were required to demonstrate PD-L1 positivity for study entry. Twenty three patients have been treated to date, of whom 74% were squamous cell carcinoma. 17% of patients had a ≥ Grade 3 treatment related AE, and there were no treatment related deaths. There were one case (of any grade) each of adrenal insufficiency and rash, and two of hypothyroidism. The ORR was 30%, all of which were partial responses, by histology this was 40% for adenocarcinoma (2/5 patients) and 29% for squamous cell carcinoma (5/17 patients). Median time to response was 3.7 months, and median duration of response was not reached (range 5.5-11.8+ months). An interferon-γ related 6 gene expression signature which had been developed in melanoma patients demonstrated that delays in progression and radiological responses were more likely to occur in patients with high levels of the immune gene signature scores. A similar pattern had also previously been demonstrated in patients with gastric and head and neck cancers treated with pembrolizumab.
Taken together, these results demonstrate encouraging efficacy for anti-PD1 therapy in gastroesophageal cancer, with response rates in line with those seen in other non-melanoma solid tumours. Although the numbers of patients treated are small, it appears that durable remissions may be achieved for subset of patients. Numerous larger trials are currently recruiting patients to anti-PD1 therapy in the first line and treatment refractory settings, and detailed analysis of these larger datasets will be required in order to better determine the relationship between PD-L1 status and of other molecular drivers such as microsatellite instability to response to anti-PD1 therapies.
In contrast, disappointing results were reported for a large trial of targeted therapy for patients with advanced HER2 positive gastroesophageal cancer. Dr Kang and colleagues reported the results of the GATSBY study, which was a phase 2/3 global study of T-DM1 vs a taxane in patients with previously treated HER2 positive (IHC 3+ or IHC 2+/FISH positive). One hundred and seventeen patients were treated with a taxane, and 228 with T-DM1 on a 2.4mg/kg weekly schedule. Seventy seven percent of patients had previously received trastuzumab therapy. There was no significant difference in overall survival between the two arms of the study; this was 8.6 months for paclitaxel treated patients and 7.9 months for patients treated with T-DM1. Overall response rates and progression free survival results were also similar, with no evidence of benefit in any subgroup analysis. Although thrombocytopenia and anemia were less common in patients treated with taxanes, neutropenia and febrile neutropenia were substantially less common in patients treated with T-DM1 (4.5% vs 38.7% and 0.9 vs 9.9% respectively). However overall rates of AEs, SAEs and treatment continuations due to AEs were similar between arms. These results are disappointing as trastuzumab had demonstrated significant benefits for patients with HER2 positive gastroesophageal cancer in the first line setting, and use of T-DMI is associated with improved survival in HER2 positive breast cancer patients who are refractory to trastuzumab. However, as the magnitude of benefit due to anti-HER2 therapy is less for patients with gastroesophageal cancer than for breast cancer due to a worse overall prognosis and heterogeneity of HER2 expression it is not completely unexpected. Whether adding a second HER2 blocking antibody such as pertuzumab will further improve outcomes for HER2 positive gastroesophageal cancer is unknown; the results of the JACOB combination study of pertuzumab, trastuzumab and cisplatin based first line chemotherapy are eagerly awaited in order to answer this question.
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