Florian Lordick, MD, PhD; Linda Brookes, MSc

Disclosures

November 24, 2014

Editor's Note: Targeted therapies show promise for improving the currently grim prognosis of advanced gastric cancer. At the European Society for Medical Oncology 2014 Congress (ESMO 2014), Florian Lordick, MD, PhD, professor of oncology, University of Leipzig, and director of the University Cancer Center at the University Hospital Leipzig, Germany, highlighted current and emerging targeted therapies in this disease.[1] Afterward, Prof Lordick, who has served as chair of the EORTC Gastric and Oesophageal Task Force and is now the secretary-elect of the EORTC Gastrointestinal Tract Tumor Working Group, spoke with Linda Brookes, for Medscape, about the targets he views as most promising for the development of new drugs.

"We are starting from a point of enormous unmet medical need," Prof Lordick stressed to Medscape, with patients with advanced gastric cancer currently having a dismal prognosis. "There is a lot of variety and heterogeneity in the chemotherapy regimens being used, but there is poor outcome with any chemotherapy in stage IV," he noted. "At bottom line, median survival is poor, reaching 8-11 months median in Europe and North America, and between 11 and 18 months in East Asia. Long-term survival rates are only 10%-25%."

Research into new targets for treatment has focused on the signal transduction pathways that underlie initial development and progression of gastric cancer. Molecular heterogeneity, a defining feature of gastric tumors, is driven by mutations and other genetic alterations. "As in other diseases, we have an increasing understanding of the genetic characteristics, but gastric cancer has high mutational frequencies and many copy number alterations, so it is not an easy task to find the ones that are relevant for this disease. The task will be to understand this genetic complexity and to figure out the drivers of tumor progression and signatures that we can tackle," commented Prof Lordick.

New Anti-HER2-Based Therapies

"HER2 is currently the only target we have that works for subgroups of gastric cancer," Prof Lordick noted. Amplification of the HER2 gene and overexpression of HER2 (human epidermal growth factor receptor 2) in gastric cancer has been confirmed in many studies.[2] In HER2-positive patients, survival is prolonged by treatment with the anti-HER2 monoclonal antibody trastuzumab, the first targeted agent to be approved in advanced gastric cancer. Trastuzumab has been available in the United States and Europe since 2010, following the demonstration of extended survival of 16.0 months with trastuzumab plus chemotherapy compared with 11.8 months with chemotherapy alone in the ToGA study.[3] A combination of trastuzumab and chemotherapy is now standard therapy for patients with a high HER2 score (3+) on immunohistochemistry (IHC) and for patients with an intermediate IHC score who are also positive on fluorescence in situ hybridization (FISH).[4]

However, Prof Lordick cautioned, "it is important to know that although the methods for testing for HER2 positivity are the same as in breast cancer, diagnosis of HER2 positivity in gastric cancer is not so straightforward. Gastric cancer is a complicated disease, even under the microscope—very heterogeneous—and we need well-trained pathologists and quality assurance to do this."

Another problem is development of resistance. "Unfortunately, even if the target is there and you have an active drug, sooner or later resistance develops," he explained. "We do not yet understand the resistance mechanisms of anti-HER2-directed treatment, and we cannot really predict when a patient will become resistant or not," he acknowledged. "This is the subject of research and also whether combination therapy could make a difference."

Although some HER2-directed approaches have not been successful—notably lapatinib, which failed to significantly improve survival in two phase 3 trials, TyTAN[5] and LOGiC,[6] —another HER2 antibody, pertuzumab, is under evaluation, according to Prof Lordick.

Pertuzumab targets the dimerization domain of HER2, preventing HER2 from dimerizing with other ligand-activated HER receptors such as HER3. Combining pertuzumab with trastuzumab may provide better HER2 signaling blockade and antitumor activity than either agent alone.

Pertuzumab plus trastuzumab combined with chemotherapy is currently undergoing evaluation as first-line treatment in patients with stage IV gastric cancer in the global phase 3 JACOB study.[7,8] The same HER2 antibody combination with standard chemotherapy is being studied in the neoadjuvant setting in the EORTC-sponsored INNOVATION trial.[9] The first stage of the trial will "pick the winner" in a comparison of two treatment options: chemotherapy with trastuzumab, and chemotherapy with trastuzumab plus pertuzumab; both options will be given before and after surgery. The second stage of the trial will be a randomized phase 3 comparison of the best experimental arm in the first stage vs chemotherapy alone.

Prof Lordick added that a new HER2 antibody-drug conjugate that comprises trastuzumab linked to the antimitotic agent mertansine (DM1), called ado-trastuzumab emtansine (TDM-1; known as trastuzumab emtansine outside the United States), is already in use in HER2-positive breast cancer and is now under evaluation as second-line treatment in stage IV disease in the phase 3 GATSBY study.[10]

Some Targeted Therapies Not Hitting Dead Center

Epidermal growth factor receptor (EGFR)-targeted therapy has not been successful in gastric cancer to date. Prof Lordick said. "Big multinational studies with EGFR-targeted treatment showed that it works in other diseases, the best example being colorectal cancer, where we have the active anti-EGFR-directed antibodies cetuximab and panitumumab. Unfortunately, the EXPAND and REAL3 studies in gastric cancer did not show any survival improvement when either cetuximab or panitumumab was added to chemotherapy."[11,12]

However, neither the EXPAND nor the REAL3 study was carried out in a biologically selected patient population, he stressed. "We did not stratify patients according to EGFR positivity on IHC or FISH; therefore, we do not know yet how to select patients for EGFR-directed treatment in gastric cancer." Retrospective analysis of each trial suggested that in a very small subgroup of patients with a very high immunoreactivity to EGFR, there may be a positive effect of the addition of cetuximab, Prof Lordick noted, "but this subgroup was rather small, and therefore I do not believe that there will be a consecutive study."

A more promising target, commented Prof Lordick, appears to be another tyrosine kinase inhibitor, mesenchymal epithelial transition factor (MET), with its natural ligand hepatocyte growth factor (HGF).[13] Rilotumumab, a monoclonal antibody directed against HGF, has recently produced some "very interesting" phase 2 data, he noted.[14] The combination of rilotumumab, epirubicin, cisplatin, and capecitabine yielded a progression-free survival (PFS) hazard ratio of 0.6 vs placebo (P = .016), which Prof Lordick viewed as evidence of a potential "strong efficacy in these tumors," 56% of which were defined as MET positive. The combination was generally well tolerated, with some hematologic toxicities, edema, and thrombosis.

A phase 3 study is ongoing with rilotumumab alone or with chemotherapy vs chemotherapy alone in MET-positive gastric cancer (RILOMET-1).[15,16] "We can say that anti-HGF therapy is potentially effective in gastric cancer," Prof Lordick commented, "but we have to wait for phase 3 results. The phase 3 study is being done in a selected patient population identified by a newly developed IHC score. If the score is positive, that will be a good signal for rilotumumab."

Another potential way to target this pathway is with AMG 337, a small molecule that targets the receptor tyrosine kinase MET receptor itself. Clear and durable responses in 10 patients with MET-amplified tumors were reported earlier this year.[17] "These preliminary results are promising, but we have to see if they will be validated in the larger phase 2 study, which is currently ongoing," Prof Lordick cautioned.[18]

Antiangiogenic Therapy: A Brighter Option?

"The really good news in gastric cancer is antiangiogenic treatment," commented Prof Lordick. "After the AVAGAST trial reported in 2011 that bevacizumab did not show a significant improvement in survival in combination with chemotherapy in gastric cancer,[19] our expectations that antiangiogenic treatment would be effective in gastric cancer went down towards zero," he admitted. Subgroup analysis on a regional basis showed "a signal that bevacizumab was not effective in Asian patients, but there was a hint for activity in the European and American patients." Nonetheless, "at the bottom line we were talking about a negative first-line study."

Antiangiogenic treatment in gastric cancer is now focused on ramucirumab, a monoclonal antibody directed against vascular endothelial growth factor receptor 2 (VEGFR-2). Ramucirumab was recently approved by the US Food and Drug Administration (FDA)[20] and given a positive opinion by the European Medicines Agency (EMA)'s Committee for Medicinal Products for Human Use (CHMP)[21] for the treatment of advanced gastric cancer or gastroesophageal junction adenocarcinoma with disease progression after prior platinum and fluoropyrimidine chemotherapy.

Supporting data for ramucirumab approval came from two phase 3 studies. In one, the REGARD trial,[22] ramucirumab was given as monotherapy and compared with best supportive care alone in patients with stage IV disease, showing an increase in median survival of 1.4 months (5.2 vs 3.8 months) over placebo. "For me it is interesting to see that this result was achieved without a lot of responses; there was only one complete response in the patients treated with ramucirumab and only seven (3%) partial responses," Prof Lordick commented. "But more patients on the ramucirumab arm reported stabilization or improvement of their quality of life, which is important in this situation. Clearly this is a drug that leads to stabilization and control of the tumor, but not so much to response."

It was a logical step to combine ramucirumab with active second-line chemotherapy in the RAINBOW study,[23] the results of which were published recently. In this trial of 665 patients with stage IV gastroesophageal cancers, standard treatment was paclitaxel given until progression, and the experimental arm was the combination of ramucirumab every second week and paclitaxel on a weekly basis, which improved median survival by 1.3 months, with an increase in responses. "What I find important is that a combination of ramucirumab and paclitaxel led to a 28% response rate. Having not seen this response rate in previous studies in second-line gastric cancer, and now for the first time we are also in the area of 10 months median survival, which we have not yet seen in previous studies in second-line, I think these results are really interesting for daily practice," said Prof Lordick. "This appears to be an active drug in second-line gastric cancer, where it can be given as monotherapy in patients who do not tolerate chemotherapy toxicity. Patient preference is an important issue, and for those who are still motivated to receive more chemotherapy and who have not experienced massive side effects in previous treatments, certainly the combination of paclitaxel and ramucirumab is the better recommendation because this is a very active treatment."

Prof Lordick has proposed an algorithm for integrating ramucirumab, which he expects will soon be incorporated into European clinical practice. Describing it, he explained: "We will probably evaluate patients for their ECOG performance status, tolerability, and side effects experienced during first-line chemotherapy. Of course, as always, patient preferences will play a role. I assume that for patients with better performance status and those with a need for remission, we will want to treat with a combination of paclitaxel and ramucirumab. For patients with a worse performance status we may choose ramucirumab as a monotherapy, but irinotecan or taxanes are also valid options as monotherapy. In a third group of patients, we will choose not to give any further active antitumor treatment."

Targeting Immune Checkpoints and 'Stemcellness'

Another potentially interesting target, Prof Lordick noted, is the modulation of immune checkpoints, PD-1 and PD-L1.[24] The first data with this class of agents in gastric cancer were presented during the congress. Pembrolizumab is an anti-PD-1 antibody that to date has shown antitumor activity in multiple tumor types, including melanoma and non-small cell lung cancer. In 39 gastric cancer patients with immunohistochemically PD-L1-positive tumors who had received two or more prior lines of therapy, the overall response rate (ORR) was 30%. Evidence was seen of an association between PD-L1 expression and PFS (P = .032) and ORR (P = .071).[25] The most common treatment-related adverse effects were hypothyroidism and fatigue. On the basis of the antitumor activity observed in this trial, a phase 2 study in advanced gastric cancer (KEYNOTE-059) is expected to begin enrollment in early 2015.

The development of drugs against stem cell characteristics will probably become an important new approach. Cancer stem cells are important for invasiveness of the tumor and for metastatic properties of cancer, and they play a role in chemotherapy and radiation therapy resistance, Prof Lordick explained. A first-in-class, orally administered small molecule, BBI608, is directed against the Stat3 and beta-catenin pathways, believed to be relevant for cancer stem cells. A randomized phase 3 study (BRIGHTER) has now been started in which BBI608, is being investigated as second-line therapy in gastric/gastroesophageal junction cancer.[26] "The BRIGHTER study has just been initiated in the United States, Europe, and Asia," commented Prof Lordick, "and we will be eagerly awaiting to see whether inhibition of cancer stemcellness may contribute to better anti-tumor effectiveness in gastric cancer."

Gastric cancer remains a challenging diagnosis, but targeted therapies are beginning to change the course of this disease. Prof Lordick underscores the importance of the work being done by the Cancer Genome Atlas Research Network to identify viable therapeutic targets.[27] "Their comprehensive analysis of human materials can link to prognosis and identification of new druggable pathways," concluded Prof Lordick, "and from this work I have hope that we can develop effective therapies."

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