Early-Stage Cancer Trials Support Promise of Precision Medicine, Immunotherapy

June 17, 2016, by NCI Staff

Findings from several early-stage clinical trials featured at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago last week reflect the dominant trends in cancer treatment: targeted therapies and immune-based treatments.

Although the results of these trials won’t change patient care immediately, in each case the trial investigators and other researchers agreed that the findings point in that direction. 

Precision Medicine Trial in Action

Results from one of the trials presented at the ASCO meeting demonstrate how researchers are using new clinical trial approaches to speed the development of more precisely tailored cancer therapies. These trials, sometimes called umbrella or basket trials, enroll patients based not on the type or location of their cancer but on whether their tumors have molecular alterations that can be targeted by approved or investigational therapies.

The results of the ongoing MyPathway trial, presented by John D. Hainsworth, M.D., of Sarah Cannon Research Institute, showed that targeted therapies that are already approved for some patients with breast and stomach cancer and melanoma may also be effective against other cancer types.

MyPathway enrolled patients with advanced cancer whose tumors had genetic alterations in any of four specific signaling pathways: HER2, BRAF, EGFR, and Hedgehog. Patients in the trial were treated with one of four drugs approved by the Food and Drug Administration that target these particular alternations. None of the patients in the trial had a cancer type for which the drugs are already approved.

The research team reported results for the first 129 patients treated, approximately 25% of whom had a partial tumor response. Patients with 12 different cancer types responded to treatment. However, patients with several specific cancer types whose tumors had alterations in either the HER2 or BRAF genes were more likely to respond, with nearly 30% experiencing reductions in the size of their tumors.

Patients with HER2 alterations were treated with a combination of trastuzumab (Herceptin®) and pertuzumab (Perjeta®), with responses seen most frequently in patients with colorectal, bladder, and biliary cancer. Patients with BRAF mutations were treated with vemurafenib (Zelboraf®), and responses were seen most commonly in patients with non-small cell lung cancer.

Based on these findings, the research team is enrolling additional patients with these cancers whose tumors have these alterations, Dr. Hainsworth said during a press briefing. 

More cancer clinical trials are starting to use “a tumor-agnostic approach,” said Sumanta Kumar Pal, M.D., of City of Hope Cancer Center, who moderated the briefing, and this new approach will eventually affect patient care.

Dr. Hainsworth agreed, but cautioned that treating patients based primarily on the molecular makeup of their tumors rather than the site of origin will be a step-wise progression “as more and more of this type of evidence becomes available and as more [targeted] drugs … become available.” 

Continued March of Immunotherapy in Bladder Cancer

Immunotherapies continue to be an area of intense focus in oncology, with different types of immune-based treatments being developed and tested against both solid tumors and blood cancers.

Researchers have been particularly encouraged by findings from studies showing that immunotherapy may provide new treatment options in cancers for which progress has been limited. One example is in bladder cancer, including findings from a phase II trial in patients with advanced bladder cancer presented at the ASCO meeting. The trial tested the immune checkpoint inhibitor atezolizumab (Tecentriq™) as initial treatment for patients with advanced disease.

The FDA recently approved atezolizumab for patients with bladder cancer whose cancer has progressed after prior treatments—the first new therapy to be approved for this disease in 20 years. Although several checkpoint inhibitors have been approved by the FDA, atezolizumab is the first checkpoint inhibitor that targets a protein on tumor cells (as well as other cells in the tumor microenvironment) called PD-L1. Two other approved checkpoint inhibitors target PD-L1’s binding partner, PD-1, which is found on immune cells.

The 119-patient trial presented at ASCO was intended to determine whether the drug may be effective earlier in the disease, when patients are first diagnosed with metastatic bladder cancer.

Because of certain clinical factors (primarily poor health), patients in the trial could not receive treatment with the chemotherapy drug cisplatin (Platinol®), a standard initial treatment for advanced bladder cancer. All patients in the trial received atezolizumab.

After a median follow-up of approximately 14 months, 24% of patients in the trial had responded to the PD-L1 inhibitor. Seven percent of patients had a complete disappearance of their disease (complete response) and 17% had a partial response, reported the trial’s lead investigator, Arjun Balar, M.D., of the Perlmutter Cancer Center in New York.

The median overall survival for patients in the trial, which was a secondary endpoint, was 14.8 months, which is better than what is historically seen in this patient population, Dr. Balar explained during a press briefing.

“The survival data that we’re seeing are very provocative,” he said.

Patients also handled the treatment well. Only 6% of patients in the trial stopped treatment due to side effects. By comparison, about 20% of patients with advanced bladder cancer who receive chemotherapy typically stop treatment because of side effects.

Responses were seen in patients regardless of whether their tumor cells expressed PD-L1, Dr. Balar reported. But, he noted, there is still significant controversy about the best method of testing for PD-L1 expression.

In bladder cancer, he said, some evidence suggests that PD-1 or PD-L1 expression may not be the best marker for determining who might respond to checkpoint inhibitor therapy. Other factors, such as the number of genetic mutations in a patient’s tumor and the location of the tumor in the bladder, may be more important.

Based on the evidence thus far, he said, these other factors “seem to have a significant impact on who is responding and who isn’t.” 

New Class of Drug Shows Promise in Stomach Cancer

The results from another phase II trial of a different drug that spurs the immune system into action point to a potential new treatment for patients with stomach cancer. The drug, a monoclonal antibody called IMAB362 or claudiximab, targets claudin18.2, a protein that helps to form a component of cell membranes called tight junctions.

Claudin18.2 is overexpressed by tumor cells in several cancers, including gastric and pancreatic cancer, explained the trial’s lead investigator, Salah-Eddin Al-Batran, M.D., of the Institute of Clinical Cancer Research in Frankfurt, Germany. IMAB362 appears to work primarily by binding to tumor cells and then recruiting components of the immune system to attack them. The drug is the first agent that targets claudin18.2 to be tested in human clinical trials.

The trial enrolled 252 patients receiving initial treatment for metastatic gastric cancer whose tumors overexpressed claudin18.2. The patients were randomly assigned to receive standard chemotherapy or chemotherapy plus IMAB362.

In patients treated with IMAB362 plus chemotherapy, the median time to disease progression was 7.9 months, compared with 4.8 months in patients treated with chemotherapy alone. Median overall survival was 13.2 months with IMAB362 plus chemotherapy and 8.4 months with chemotherapy alone. Among those patients whose tumors expressed the highest levels of claudin18.2, median overall survival was 16.7 months with IMAB362 plus chemotherapy and 9.0 months with chemotherapy alone.

Nearly 40% of patients treated with IMAB362 plus chemotherapy experienced some tumor shrinkage, compared with 25% of patients treated with chemotherapy alone. Approximately 10% of patients who received both treatments had complete responses, compared with 3% of those treated with chemotherapy alone. 

The combination therapy was also well tolerated, with few patients experiencing serious side effects. The most common serious side effects were neutropenia and vomiting, which Dr. Al-Batran said may be caused specifically by IMAB362.

The trial results, he said, “provide a strong rationale for a confirmatory phase III trial” of IMAB362 in patients with stomach cancer.