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Knowns and unknowns in management of advanced/metastatic gastric and GEJ cancer

Naureen Starling

Please note: This video and presentation is currently unavailable but will be published shortly.

Dr Starling begins her session with a case study involving a 68-year old female who presented with hiccups and progressive dysphagia. An endoscopy revealed a moderately differentiated adenocarcinoma at the GEJ, which was HER2. Peritoneal metastases were found during the CT scan indicating Stage IV disease, and her performance score was 1.

The attendees were asked to vote on a list of possible treatment options, and the most popular choice was cisplatin + capecitabine/5-FU regimen, and the second choice was an oxaliplatin + capecitabine/5-FU regimen. A panel discussion followed, comparing doublet versus triplet therapy (i.e., adding a taxane or anthracycline). Although there is similar efficacy, there is lessened toxicity using a doublet regimen; however, the panel cautioned on the lack of clinical trial data comparing doublet to triplet therapy.

There are a variety of 1st-line treatment regimens in advanced oesophago-gastric cancer that are based on Level 1 (Phase III trial) evidence. The efficacy data on overall survival are fairly comparable among all of the 1st-line doublet and triplet regimens; thus selecting which one to use is patient-specific based on the response rate you are trying to achieve coupled with disease burden, performance status, and the patient’s perspective.

With 2 decades of clinical trial data using chemotherapy, overall survival in this patient population has increased from 3 months to only 9-11 months, which, in Dr Starling’s opinion, is very slow progress that must be addressed.

Clinical trial data using S1 showed positive results for mean overall survival (of > 1 year) in Japanese patients, but failed to meet the primary endpoint in a trial in a Western population. Further, toxicity profiles were substantially different for Asian populations versus Western populations, which is a common finding among this cancer cohort.

There are two targeted therapies used in the 1st line setting; HER2 and VEGFR-2. In the TOGA study there was a survival benefit when trastuzumab was added to chemotherapy verus chemotherapy alone. Hence, all patients with advanced oesophago-gastric cancer must be tested for HER2 status and targeted therapy started in the HER2+ subgroup (which is estimated at 1 in 5 patients).

Can we improve targeting in HER2+ gastric cancers? The CLEOPATRA trial in patients with HER2+ breast cancer showed a 6.1 month median increase in progression-free survival with cisplatin/capecitabine + trastuzumab + pertuzumab versus cisplatin/capecitabine + trastuzumab. These data led to the JACOB study in gastric cancer, for which results are not yet available.

For 2nd-line therapy, HER2-directed therapy in advanced gastric cancer showed no overall survival benefit for trastuzumab versus taxane (paclitaxel or docetaxel), and thus is not recommended. It is thought that the heterogeneous nature of HER2+ gastric cancer plays a role in this lack of benefit. The new ESMO clinical practice guidelines recommend trastuzumab plus platinum or fluoropyrimidine-based chemotherapy for HER2+ gastric cancer.

The case-study patient was started on EOX (epirubicin, oxaliplatin and capecitabine), and showed progression after 4 cycles of chemotherapy with new subcutaneous metastases. She had persistent Grade 1 neuropathy and her performance status was 1. The audience was asked to vote on her next treatment. Paclitaxel + ramucirumab was most popular, second was enrolment in a clinical trial. The panel also suggested that ramucirumab or irinotecan would also be viable options.

A point was raised on maximising quality of life verus overall survival when using epirubicin. In Dr Starling’s clinic, they do not see the excessive toxicities discussed by others; further, they manage the haematological toxicities well and maintain quality of life as a priority.

Overall survival with 2nd-line chemotherapy offers only moderate survival benefits relative to best supportive care, so it is questionable to offer palliative chemotherapy unless the patient has reasonable fitness.

Clinical trial data (REGARD) on agents that target VEGFR-2 show that ramucirumab gives similar survival benefits as chemotherapy, so in the case where chemotherapy would not be tolerated, then ramucirumab may be a good choice. Level 1 evidence was shown in the RAINBOW study which tested paclitaxel + ramucirumab as 2nd line showed a significant improvement in all parameters, including the primary endpoint of overall survival. Of note was the difference between Asian and Western populations, with Asian population faring better on both arms of the study.

Dr Starling reviews Phase II data on ramucirumab as a 1st-line agent and a Phase III study on bevacizumab. Neither study showed statistical benefits on survival. Further clinical trial data (RAINFALL) is forthcoming to help determine if ramucirumab has a role in a 1st-line setting.

A 3rd-line clinical study using apatinib showed a positive effect on survival in an Asian population; this study may need to be repeated in a Western population.

Many clinical trials have shown negative results, including Phase III trials of: EGFR inhibitors in advanced gastric/GEJ cancers, EGFR/HER2 apatinib in advanced gastric/GEJ cancers, and the MET signalling pathway. For 2nd line targeting both the FGFR (SHINE study) and the PARP inhibition (GOLD study) were negative.

An interesting Phase II study targeting CLDN18.2+ gastric cancers with IMAB362 (FAST study) showed significant improvement in progression-free survival in the EOX + IMAB362 arm versus EOX.

There are 5 ongoing Phase III studies that are due to report results over the next year or two. An emerging area of research is targeting of the PD-L1/PD-1 pathway using checkpoint inhibitors. Pembrolizumab, nivolumab and PDR001 target PD-1, and Durvalumab, atezolizumab and avelumab target PD-L1. In the last few minutes, Dr Starling reviews the clinical trial data for pembrolizumab and nivolumab, noting that these agents, if positive in clinical trials will offer up an alternative to chemotherapy.  

Dr Starling’s final thoughts are that an interesting number of immunotherapy combination trials are emerging, and as we discover more about the complexity of this disease using biomarkers, we need to do smarter, quicker trials to assess combinations of chemotherapy agents and checkpoint inhibitors.

In conclusion, Dr Starling refers to the ESMO treatment algorithm for advanced gastric/GEJ adenocarcinoma, which neatly summarises the data given in this presentation.