Gastric cancer is one of the most common forms of cancer and the third-leading cause of cancer-related death worldwide. Clinical data shows that patients with advanced gastric cancer have a dismal prognosis. There is much heterogeneity in the choice of chemotherapy doublet and triplet regimens used to treat patients and survival is also extremely variable from country to country. Companies are now striving towards developing targeted therapies for advanced gastric cancer. Exploiting biomarkers is a dominant strategy and clinical data presented at the recent ESMO conference highlighted significant advances in the treatment of gastric cancer.

Approximately 17 percent of patients with advanced gastric cancer are HER2-positive and this biomarker is used to select patients eligible for, and those likely to respond to, treatment with the anti-HER2 drug trastuzumab (Roche/Genentech/Chugai's Herceptin,) (Bang Y, 2010). Trastuzumab was approved for the treatment of HER2-positive gastric cancer patients in the United States in (October 2010) and in Europe in (January 2010). However, not all anti-HER2 drugs have been clinically successful ? lapatinib (GlaxoSmithKline's Tykerb/Tyverb), an anti-EGFR/HER2 drug, famously failed to meet its endpoint of significantly improving overall survival in the TYTAN and LOGIC Phase III trials in gastric cancer  despite success in breast cancer. Nevertheless, the anti-HER2 therapies, pertuzumab (Roche/Genentech/Chugai's Perjeta) and ado-trastuzumab emtansine (Roche/Genentech/Chugai's T-DM1; Kadcyla), both in late stage development (in the Phase III JACOB and GATSBY trials, respectively) for gastric cancer hold much promise and Decision Resources believes that the future of the drug armamentarium for HER2-overexpressing gastric cancer patients is bright. Of note, at ESMO 2014 Sandra Swain reported that pertuzumab demonstrated ?unprecedented? success in metastatic breast cancer with an overall survival improvement of 15.7 months in the Phase III CLEOPATRA study.

Attempts to identify other biomarkers in gastric cancer have been less fruitful. The anti-EGFR Phase III trials, EXPAND and REAL-3, for cetuximab (Bristol-Myers Squibb/Eli Lilly/Merck KGaA's Erbitux) and panitumumab (Amgen's Vectibix) failed to meet their primary endpoints, casting a large shadow over the future prospects of other anti-EGFR drugs. However, in both trials EGFR overexpressing patients were not preselected as an inclusion criterion in the trial, and later subgroup analysis of the EXPAND study showed that cetuximab may be effective in the subgroup of patients that highly express EGFR (Lordick et al 2013).  The ongoing Phase III ENRICH trial of the anti-EGFR inhibitor nimotuzumab (Daiichi Sankyo) is however preselecting patients by EGFR status (i.e., only patients with an immunohistochemistry [IHC] status of 2+ or 3+ are included). Data from this trial may seal the fate of EGFR inhibitors for this indication.

A number of trials in gastric cancer are investigating c-Met as a potential biomarker. The c-Met inhibitor onartuzumab (Roche/Genentech/Chugai's MetMab) was being developed for multiple cancer indications including gastric cancer where it reached Phase III development; however, this trial was discontinued earlier in 2014. The Phase III trial of the anti-c-Met drug, rilotumumab (Amgen) is evaluating efficacy in advanced gastric cancer patients preselected for c-Met overexpression by IHC. AMG 337 is a c-Met inhibitor in early phase development for gastric cancer and other solid tumors. Early phase data for rilotumumab and AMG 337 in c-Met overexpressing patients looks promising and points towards a potentially effective new treatment option for a new subgroup of patients.

A number of companies have taken the anti-angiogenic approach to drug development for gastric cancer. The Phase III AVAGAST trial of bevacizumab (Roche/Genentech/Chugai's Avastin) in gastric cancer demonstrated no significant overall survival benefit, although a trend towards a benefit was observed in the European population (compared with East Asian data).  Despite this negative trial developers are still pursuing other anti-angiogenic inhibitors, and are likely encouraged by the FDA approval of Eli Lilly's ramucirumab (Cyramza) for gastric cancer in April 2014. Ramucirumab has also received CHMP recommendation in Europe based on positive clinical efficacy data from the REGARD trial as the first targeted agent for the second-line treatment setting in gastric cancer. Furthermore, the RAINBOW study demonstrated that ramucirumab is even more effective when used in combination with paclitaxel compared with use as a single agent (Wilke et al 2014).

The immune checkpoint inhibitors, particularly anti-PD-1 and PD-L1 therapies, have generated much interest in oncology indications and the first data for this class of agents in gastric cancer were presented at ESMO 2014. Pembrolizumab (Merck & Co?s. Keytruda) is an anti-PD-1 antibody that to date has shown good antitumor activity, and good safety and tolerability in multiple tumor types including melanoma and non-small cell lung cancer (NSCLC) (Ribas A, 2014; Rizvi NA, 2014). Data from the gastric cohort of the Phase Ib (KEYNOTE-012) trial evaluating pembrolizumab in PD-L1-positive advanced solid tumors were presented at ESMO 2014.  In this study 40 percent of patients were defined as PD-L1-positive by IHC staining. Efficacy data presented showed that overall response rate (ORR) was 30.8 percent and disease control rate (DCR) 43.6 percent (Muro K et al, 2014). By comparison, in the REGARD trial, ramucirumab demonstrated an ORR of 3 percent and DCR of 49percent (Fuchs et al., 2014). Subgroup analyses of the pembrolizumab data shows that the median time to response was typically longer in non-Asian patients compared with Asian patients, however Asian patients were more heavily pretreated with at least two prior therapies compared with non-Asian patients.  Overall, 41 percent had a decrease in tumor burden following pembrolizumab. Adverse events were similar to those reported previously for melanoma and NSCLC patients receiving pembrolizumab and very few were grade 3 or higher. These findings presented at ESMO support the development of PD-L1 inhibitors in gastric cancer and a Phase II study for is set to begin enrolling early in 2015.

The Cancer Genome Atlas Research Network recently published a comprehensive characterization of gastric adenocarcinoma into four subtypes based on multiplatform analysis of molecular, genomic and epigenomic profiles of 295 primary tumors (TCGA, 2014). This seminal work could potentially help to identify new drug targets and patient populations most likely to benefit. Interestingly, the ?Epstein-Bar virus-positive? subgroup contained gastric tumors that overexpress PD-L1/2. Advances in immunotherapy and biomarker research will likely drive the future of gastric cancer as this indication begins to move away from chemotherapy and towards targeted therapy thanks to an improved molecular understanding of this complex disease.

Sehrish Rafique is a business insights analysts on the Oncology team at Decision Resources Group.

Bibliography

Bang Y, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesphageal junction cancer (ToGA): a Phase 3, open-label, randomized controlled trial [electronic]. Lancet. August 20, 2010.

The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014  ep 11;513(7517):202-9. doi: 10.1038/nature13480. Epub 2014 Jul 23.

Fuchs CS, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastroesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9.

Hong DS, et al. First-in-human study of AMG 337, a highly selective oral inhibitor of MET, in adult patients (pts) with advanced solid tumors. J Clin Oncol 32:5s, 2014 (suppl; abstr 2508)

Lordick F, et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncology 2013;14:490?9.

Muro K et al.  A phase 1b study of pembrolizumab (Pembro; MK-3475) in patients (Pts) with advanced gastric cancer. ESMO 2014 (abstr LBA15)

Ribas A., et al. Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL). J Clin Oncol 32:5s, 2014 (suppl; abstr LBA9000)

Rizvi  NA, et al. Safety and clinical activity of MK-3475 as initial therapy in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 32:5s, 2014 (suppl; abstr 8007)

Swain S, et al. Final overall survival (OS) analysis from the CLEOPATRA study of first-line (1L) pertuzumab (Ptz), trastuzumab (T), and docetaxel (D) in patients (pts) with HER2-positive metastatic breast cancer (MBC). ESMO 2014 (Presidential Symposium 350O_PR)

Wilke et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Sep 17. pii: S1470-2045(14)70420-6. doi: 10.1016/S1470-2045(14)70420-6.

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