At the meeting this year I gave an update on advances in the treatment of metastatic gastric cancer and I reviewed recent studies indicating what’s the optimal chemotherapy regimen, what is the role of genomic profiling, what are emerging new targets and what’s the role of immunotherapy drugs. In metastatic gastric cancer fluorinated pyrimidine and a platinum drug is really considered the standard of care. Whether or not adding a third drug, a taxane, enhances benefit, significantly increases toxicity and earlier studies did suggest potential modest benefits for up front taxane combination therapy versus just 5FU platinum. So I reviewed the older trial from Germany, Germany is the country that developed the FLOT regimen which is now 5FU, oxaliplatin, docetaxel as pre-operative treatment in gastric cancer, but it’s not clear whether that regimen should be routinely applied in metastatic disease. They conducted a randomised trial in patients 65 or over comparing 5FU oxaliplatin with or without the addition of Taxotere, docetaxel, and they showed no progression free or overall survival benefits for three drugs over two drugs and nearly a doubling of the rate of grade 3 and 4 adverse events.
Additional data came from a recent randomised trial from Japan that was presented at the ASCO meeting last year in 2018 by Yamada and colleagues from Tokyo which compared standard S1 cisplatinum with or without the addition of docetaxel. This was a trial in over 700 patients with metastatic gastric cancer and pretty convincingly showed no survival benefit for adding a taxane to two drug S1 cisplatinum. They also looked at intestinal versus diffuse histologies and saw no difference. So very compelling data that for the vast majority of patients two drug chemotherapy should be the standard in metastatic gastric cancer. In the US we typically use either infusional 5FU oxaliplatin or capecitabine oxaliplatin.
In terms of targeted agents we do have emerging data from genomic profiling that about 50% of gastric cancers are associated with overexpression of receptor associated tyrosine kinase pathways like HER2 and EGFR and MET, FGF. We now have an approved drug, trastuzumab, which improves outcome in first line chemotherapy in HER2 positive gastric cancer patients, so giving patients trastuzumab with first line chemotherapy is now standard. However, other HER2 targeted agents have virtually all failed in gastric cancer. Combining lapatinib with chemotherapy first line did not improve outcome. Dual targeted therapy, pertuzumab and trastuzumab combined with chemotherapy, was no better than chemotherapy plus trastuzumab alone. In the second line setting TDM1, which is trastuzumab emtansine, the conjugate of trastuzumab and an anti-microtubule agent, was no better than chemotherapy alone. So really trastuzumab is the only approved agent that improves outcome only in first line treatment.
Also an interesting other issue is whether or not, like in breast cancer we always continue trastuzumab into second and third line treatment, randomised trial data from Japan in a phase II trial showed no benefit in patients progressing on first line trastuzumab-based treatment. When patients got second line paclitaxel there was no benefit for continuing the trastuzumab. So that’s obviously an area of active research and there are a number of drugs in development including there’s a Daiichi drug which is a conjugate of a topoisomerase 1 inhibitor and trastuzumab which looks very promising in second line in trastuzumab resistant patients.
Also what we’ve learned from the genomic profiling is there is a subset of patients with gastric cancer that are MSI high. We know across the board in solid tumours that MSI high cancers respond quite vigorously to immune checkpoint inhibitors. So a good 5-7% of gastric cancers are MSI high and in the metastatic disease setting, at least in the United States, the drug pembrolizumab, which is a PD-1 inhibitor, is now approved to treat patients in the second line that are resistant to up front chemotherapy if they’re MSI high.
In terms of the emerging role of immunotherapy drugs there does appear to be a clear signal of activity for checkpoint inhibitors clearly in MSI high gastric cancers where response rates can exceed 50-60% even in chemotherapy refractory disease. For pembrolizumab the data support use of pembrolizumab in chemotherapy refractory patients that are PD-L1 positive. 1% or higher PD-L1 positive patients are candidates for pembrolizumab salvage therapy with responses in about 10-15% of patients.
Data from Japan show that nivolumab in chemotherapy refractory disease, another checkpoint inhibitor that targets PD-1, was better than best supportive care in chemotherapy refractory gastric cancer. The pembrolizumab data support the use of pembrolizumab in PD-L1 positive patients; nivolumab, the trial was done agnostic of PD-L1 and showed benefit in both PD-L1 positive and negative patients. So actually nivolumab is approved in Japan for chemotherapy refractory gastric cancer as a late line treatment with modest responses, about 10% of patients, but an improvement in one year survival over best supportive care from about 11% to 27%. The data look very similar to the pembrolizumab data in the PD-L1 positive patients.
So we hope to be able to refine the use of these drugs. We’re awaiting studies looking at earlier line use of checkpoint inhibitors. There are two ongoing trials of chemotherapy with nivolumab or chemotherapy plus pembrolizumab versus chemotherapy alone to see whether or not there is any kind of additive benefit in patients. Those trials are also looking at PD-L1 as a biomarker for identifying patients that might have a greater benefit.
I think it’s a very exciting time; we’ve got pathways that we’re studying actively. How can we optimally use checkpoint inhibitors? Should they be used only in PD-L1 positive MSI high patients? Will they benefit in earlier line use of treatment? But the take home message is two drug chemotherapy for most patients, trastuzumab in HER2 positive patients. We now should routinely test all patients with metastatic disease for HER2, PD-L1 and MSI high status because it’s going to have impact on treatment selection.