A Novel, Targeted Drug Yields Promising Results In Stomach And Esophageal Cancer

Of all the experimental anti-cancer drugs considered at the recent ASCO meeting, one caught my attention. It’s a monoclonal antibody that binds Claudin-18.2, a protein abundantly present in a subset of gastric, esophageal, pancreatic, bile duct and other tumor types. The claudin molecule also appears in some lung and mucinous ovarian cancers, and represents a target for novel treatment.

The first-in-class antibody, called IMAB362 or Claudiximab, is manufactured by Ganymed Pharmaceuticals (Mainz, Germany). An abstract on this drug’s effectiveness in advanced gastric and esophageal cancers, based on a phase 2 study involving 161 patients, was presented by Dr. Salah-Eddin Al-Batran, a medical oncologist and director of the Institute of Clinical Cancer Research at Nordwest Hospital in Frankfurt am Main, Germany.

As reported, the antibody extended overall survival, from 8.4 to 13.2 months, in patients with advanced gastric or esophageal cancer. All 161 participants in the randomized study had tumors that tested positive for Claudin-18.2. They were randomized to receive either chemotherapy plus the antibody, or chemotherapy alone. The hazard ratio for death—the chances of dying—for those who received IMAB362 on the study was approximately half (0.51) that for those who got chemo alone.

It’s an impressive, albeit preliminary, result. The main caveat is that the results apply only to Claudin-18.2 positive tumors. The biomarker’s presence in tumor specimens was determined by CLAUDETECT18.2, a pathology test developed by Ganymed, the drug-maker and sponsor of the trial.

As detailed by Dr. Al-Batran in his presentation, in-house pathologists deemed tumors positive when at least 40% of the cancerous cells appeared to have Claudin-18.2 at a level of 2-3+, which is a fairly crude but standard way of assessing protein in biopsy samples by immunohistochemistry. Of 686 patients enrolled in the larger FAST trial for whom the protein could be checked in a biopsy specimen, just over half (352) were deemed Claudin-negative or “low,” and on that basis were deemed ineligible for randomization.

So yes, I’m writing, and excited, about an industry-sponsored, biomarker-dependent study of an experimental cancer drug of unknown cost (likely to be in the range of other monoclonal antibodies, in the range of $10,000 per month, very-very approximately). The findings of the late-breaking abstract have not been formally published. Caution is due.

That said, the data look very good. And discussion-worthy. Because there will be plenty more drugs like this in oncology: antibodies and other off-the-shelf drugs, of all types, which can be given with predictable benefit to cancer patients with “matching” tumors, as targeted therapies.

I read with interest of a discussion among oncologists at the meeting in Chicago after the findings were presented by Dr. Al-Batran. As reported in the ASCO Daily News, one concern raised was that the chemotherapy “backbone” used in this study, a combination abbreviated as EOX, for Epirubicin, Oxaliplatin and capecitabine (brand: Xeloda) may not have been optimally dosed, such that the control chemotherapy arm, in the randomized study of IMAB362, appeared weaker than expected, based on some prior reports on that drug combination.

I’d counter with two points. First, at whatever dose EOX was prescribed in this randomized trial, addition of the antibody clearly upped the response rate and survival. So, regardless of the EOX dosing level, these data support that the anti-Claudin-18.2 antibody helps patients with Claudin-18.2 tumors. Second, the combination of chemotherapies, EOX, is no walk in the park for patients who receive it. Perhaps this antibody, or other future targeted drugs, will permit future patients to receive lower doses of chemo, with less toxicity.

Besides that the antibody, IMAB362, extended overall survival in patients with Claudin-18.2 positive tumors, and delayed tumor progression, it appears to have been well-tolerated. There seems to have been no increase in major toxicity over chemo alone, with one exception: patients getting IMAB362 had significantly more nausea and vomiting. That could be, and I asked Dr. Al-Batran about this, from tumor in the stomach or lower esophagus responding to the drug and then sloughing off, irritating the upper gut and causing patients to vomit. While he did not suggest this is the explanation, by email he indicated that this side effect could be reduced by optimizing anti-nausea treatment.

Nausea and vomiting are side effects I don't dismiss or consider lightly. These symptoms need aggressive management. They diminish the quality of patients' lives during treatment. They can also lead to kidney and other problems, requiring hospitalization. Patients with severe vomiting can become dehydrated and, if they hardly eat over months, malnourished. During the ASCO discussion, the question of the chemotherapy’s contribution to this problematic side effect was raised, and that, indeed, could factor in.

Back to the up-side of IMAB362: If these data are confirmed and extended, this new antibody might be likened to Herceptin, a drug that binds Her2 in some breast and other tumors, or Rituxan, that binds CD20 on lymphoma cells. It may be the real deal, a precise treatment that works on malignant cells that have tested positive for the relevant molecule.

The results suggest that this antibody could help many people with Claudin-18.2-positive tumors. And that would be many people. Gastric cancer represents the fourth or fifth most common malignancy around the globe. Although the incidence has been dropping in the U.S. and Europe for most of a century, in Asia, South America and elsewhere it remains comparatively frequent, and a killer. Total new diagnoses approach 1 million per year, worldwide. Most patients with stomach cancer, even in regions with modern oncology care, die from the disease if it can’t be treated locally, which happens in the vast majority of cases.

This study also included esophageal cancers. For patients with those tumors, unless they’re removed early, the overall prognosis is even worse. According to the NCI, fewer than 20% of patients live 5 years after an esophageal cancer diagnosis. Most patients get treated with surgery, radiation and chemotherapy. Yet these tumors tend to grow back.

Note that patients with Her2-positive tumors were not eligible for this trial. The FDA has approved Herceptin, an antibody that binds the Her2 protein, for advanced cases of tumors of the stomach and gastro-esophageal junction (where the stomach meets the esophagus) that demonstrate increased levels of Her2.

The report highlights the potential value of companion diagnostics in directing drugs to patients who are most likely to benefit. Conversely, these kinds of tests, if they’re truly predictive (unlike PDL-1 assays, another story), might nudge oncologists to prescribe other cancer medications instead, or none, for patients whose tumors are unlikely to respond, and so spare them the costs, toxicity and time of trying ineffective drugs.

Finally, I wondered how the antibody works. The target molecule, Claudin-18.2, is encoded by this gene. The protein normally participates in tight junctions, links between epithelial cells that prevent leakage between separate body spaces containing fluid.

At the meeting, I asked Dr. Al-Batran if the new drug might simply cause cancers to break apart by binding Claudin-18.2 and disrupting the tumor cells' integrity. Evidently that’s not the case, he indicated. Rather, Claudin-18.2 protein is abnormally exposed in epithelial cells lining the stomach or esophagus when cancer is present. In malignancies when the molecule is exposed, the antibody works by two immune-dependent processes: antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC).