2013 Annual Meeting of the American Association for Cancer Research
At the 2013 AACR Annual Meeting, results from phase I clinical trials provided insight into new and emerging druggable targets and targeted therapies. The following summary highlights some of the key findings.
Antibody-Drug Conjugate for Difficult-to-Treat Ovarian Cancer
The novel antibody-drug conjugate (ADC) DMUC5754A, which combines a targeted antibody against the MUC16 protein and a toxin resulting in targeted cell-killing of MUC16-expressing ovarian tumor cells, has shown a promising level of activity and was well tolerated.1
This is the first ADC study focused on ovarian cancer and could represent a new drug type for this type of cancer if further validated.
MUC16 expression level may serve as a useful predictive biomarker: patients who had the highest MUC16 expression were more likely to respond to the treatment.
One complete response and four partial responses were documented among the 44 patients with advanced, recurrent, platinum-resistant ovarian cancer enrolled in the trial. Six other patients had a minor response.
ADCs are a relatively novel treatment modality that can target potent toxins directly to the tumor without affecting surrounding nontumor tissue. According to presenter Joyce F. Liu, MD, an instructor of medicine at Dana-Farber Cancer Institute and Harvard Medical School in Boston, there is potential to treat earlier-stage patients with DMUC5754A, as MUC16 expression is typically present at initial diagnosis.
Michael Birrer, MD, PhD
“[These are] encouraging responses, especially in MUC16 expressing tumors,” said Michael Birrer, MD, PhD, of Massachusetts General Hospital Cancer Center, one of the study researchers. “If this is validated in future trials, then it could be a new and novel therapeutic [for ovarian cancer].”
Targeting the PI3K and AKT Pathways
in Solid Tumors
The next-generation PI3 kinase (PI3K) inhibitor GDC- 0032 has shown signs of efficacy in patients with advanced cancers that were mutated for the PI3K alpha gene.2
According to Dejan Juric, MD, attending physician and investigator at the Termeer Center for Targeted Therapies at Massachusetts General Hospital in Boston and lead investigator of the first-in-human trial, the drug’s safety profile was favorable and the side effects manageable. Side effects that occurred in more than 10% of the patients included fatigue, diarrhea, nausea, loss of appetite, vomiting, and hyperglycemia. One grade 4 case of hyperglycemia at the highest dose level tested (16 mg daily) occurred during the trial.
Hyperglycemia is a side effect that signals the drug is hitting its targets, since the PI3K pathway is necessary in glucose metabolism, Juric said.
As of August 1, 2012, 34 patients with advanced solid tumors were enrolled in the trial in one of five dosing cohorts. A total of five patients had a clinical partial response while on treatment. Four of the six patients with PI3K alpha-mutated breast cancer, as well as one patient with lung cancer, also harboring a mutation in PI3K alpha, had partial responses. A patient with HER2-positive breast cancer had an unconfirmed partial response.
As many as 40% of hormone receptor–positive breast cancers, as well as many other cancer types, harbor a mutation in the PI3K alpha gene. The phase I GDC-0032 trial is ongoing and enrolling patients with advanced solid tumors as well as a separate cohort of patients with hormone-positive breast cancer for treatment in combination with endocrine therapy.
Another oral targeted agent, ARQ 092, which targets the AKT pathway, was shown to be active in a spectrum of different solid tumors including colorectal, endometrial, and neuroendocrine tumors, and the drug demonstrated a manageable side-effect profile.3