T-DM1 Is Most Effective in Breast Cancer Patients With High HER2 Expression
In February 2013, the US Food and Drug Administration (FDA) approved a new type of therapy that combines the widely used HER2-targeted monoclonal antibody trastuzumab with the cytotoxic agent emtansine. The new drug, ado-trastuzumab emtansine (Kadcyla), known as T-DM1 during clinical research, is part of a new class of drugs called antibody-drug conjugates. T-DM1 directly binds tumor cells expressing HER2, delivering the attached cytotoxin specifically to tumor tissue and avoiding much of the toxicity to healthy tissue.
In the phase III EMILIA trial, among HER2-positive metastatic breast cancer patients who had been previously treated and progressed on trastuzumab combined with chemotherapy, T-DM1 extended overall survival by 5.8 months, from a median of 25.1 months in the lapatinib (Tykerb) plus capecitabine (Xeloda) control arm to a median of 30.9 months in the T-DM1 experimental arm. Patients treated with T-DM1 also experienced less toxicity than those in the control arm.
Now, researchers participating in the trial have identified tumor biomarkers that can identify those women eligible for the treatment who are most likely to benefit from T-DM1. Women with higher HER2 tumor levels were more likely to benefit from the therapy.
The results were presented by Jos Baselga, MD, PhD, physician-in-chief at the Memorial Sloan-Kettering Cancer Center in New York, at the American Association for Cancer Research (AACR) annual conference, held April 6–10 in Washington, DC.
The study authors used patient tissue samples collected during the EMILIA trial to analyze HER2 protein levels, HER2 mRNA levels, and PIK3CA mutation status.
The sub-analysis showed that patients whose tumor samples expressed greater than the overall median level of HER2 mRNA, considered to be high HER2 levels, derived greater benefit from T-DM1 compared with those who had low HER2 mRNA levels (median HER2 levels). Women who had high HER2 levels had an overall survival of 34.1 months compared to 26.5 months for women with low HER2 levels. Compared with women expressing high HER2 levels but treated with lapatinib and capecitabine in the control arm, those treated with T-DM1 had a 47% decreased risk for death.
“It had been suggested that since T-DM1 is an antibody-drug conjugate, perhaps tumors with less HER2 expression might still be vulnerable to the cytotoxic effects of DM1, [the cytotoxin portion of T-DM1],” said Mark Pegram, MD, professor of oncology at the Stanford School of Medicine, director of the Breast Cancer Program at the Stanford Women’s Cancer Center, and one of the study authors. “However, our data from the EMILIA trial do not support this hypothesis.” The current findings are consistent with a retrospective analysis of a phase II T-DM1 clinical trial in which patients with lower levels of HER2 had shorter progression-free survival compared to patients with higher HER2 levels, Pegram added. “Future trials will continue to stipulate that evidence for high HER2 expression and/or HER2 gene amplification be used as selection criteria for T-DM1 treatment,” said Pegram.
The analysis also showed that the PIK3CA mutation status of the tumor did not significantly affect the progression-free survival of patients treated with T-DM1. HER2-positive breast cancer that also harbors a PIK3CA mutation does not respond as well to standard HER2-positive therapies such as trastuzumab when compared with HER2-positive PIK3CA wild-type breast cancer, said Baselga.
T-DM1 treatment outcomes were found to be neutral with respect to PIK3CA status, said Baselga in a press conference at the AACR meeting. Unlike a monoclonal antibody against HER2, T-DM1 also delivers the cytotoxin emtansine, which is likely to facilitate inhibition of the PIK3CA tumor growth signals.
“Our data on PIK3CA mutation are very interesting since they suggest that DM1 may overcome relative resistance to HER2-targeted therapy associated with PIK3CA mutation,” said Pegram. “It will be important to evaluate this observation in patients with earlier-stage disease in future adjuvant and neoadjuvant studies, as it may help to prioritize which patients are best treated with T-DM1 to circumvent such resistance mechanisms.”
This analysis supports the notion that HER2-positive breast cancers are not the same biologically and can respond differently to therapy, depending on other underlying mutations and HER2 expression levels.
“The results are not practice-changing at this point,” said Baselga in a press conference at the AACR meeting. Baselga noted that he recommends testing for the presence of a PIK3CA mutation in patients with HER2-positive breast cancer in order to better identify the right course of treatment. “If these EMILIA biomarker results are confirmed, an antibody-drug conjugate appears to be a good way to treat patients with HER2-positive disease and a PIK3CA mutation,” he said.
Androgen Deprivation Therapy Resistance in Prostate Cancer—A Hypothesis
A role for the cancer progenitor cell population
Targeting prostate cancer stem cells may be a method of treating prostate cancer while avoiding the development of resistance to androgen deprivation therapy (ADT), according to preclinical results presented at the AACR annual meeting.
Prostate cancer is one of the most commonly diagnosed forms of cancer. In advanced disease, ADT is an effective treatment that results in remission in most cases. Unfortunately, within 6 to 20 months, most patients who saw benefit from ADT relapse into resistant disease. In this presentation, Dean Tang, MD, PhD, from the University of Texas MD Anderson Cancer Center, showed data that may help explain why ADT resistance occurs and how it can best be combated.
Androgen receptor expression is thought to be a primary driver of prostate cancer, and an elevated level of prostate-specific antigen (PSA) is thought to be a clear-cut marker for disease. But Dr. Tang noted that this expression is highly heterogeneous, even within the same patient. “You will see a significant population of cells lacking expression of either [androgen receptor or prostate-specific antigen],” he remarked. In many patient samples, low expression of PSA indicated a high tumor grade, and in lab results Dr. Tang showed that the progenitor cells in prostate cancers had low PSA levels. As the cells differentiated into mature epithelial cells, they gained PSA and became highly proliferative.
Dr. Tang next showed the results of a lineage-tracing experiment in cultured prostate cancer cells, in which cells expressed green fluorescent protein driven by the levels of PSA. Cells that did not express PSA expressed red fluorescent protein instead. In a pair of movies, Dr. Tang demonstrated that sorted cells with expression of green fluorescent protein, which indicated high PSA levels, were only able to divide symmetrically into two clones. However, cells starting as red, which indicated low PSA expression, were able to undergo division that generated a differentiated, green fluorescent protein–expressing cell while maintaining the original parent. This suggested that the PSA-low cell population possessed an important characteristic of progenitor cells, the ability to asymmetrically divide and maintain their populations.
This dichotomy between PSA-positive and PSA-negative cells was confirmed in vivo using mouse xenografts in serial transplantation experiments. These entailed growing a tumor xenograft in mice and then transplanting the tumor cells into a new mouse. The ability to form a new tumor is indicative of the level of self-renewal of the tumor and suggests a higher level of cancer progenitor cells. The results showed that, for several generations of passaging, the PSA-positive cells grew tumors more quickly, but as they were transplanted into new mice, their capacity diminished. In contrast, PSA-negative cells showed slow growth in the first few generations, but by the fourth passage, tumors were growing more quickly than PSA-positive cells. In addition, the PSA-negative cells maintained their tumorigenicity over more than 2 years’ worth of passages, suggesting that these cells had the ability to self-renew indefinitely, another hallmark of progenitor cells.
The results of these studies present an interesting paradigm for prostate cancer management. Cells expressing high levels of PSA tend to express androgen receptor and are, therefore, more likely to be effectively killed by ADT, resulting in the clinical endpoint of pathologic complete response. This therapy, however, would leave the more slowly proliferating progenitor cells untouched, so they can be promoted to reconstitute a tumor, possibly at a distant site, resulting in metastasis. Dr. Tang’s final thoughts on the matter summed up his hypothesis that “preferential targeting of these cells can be utilized in the adjuvant setting to prevent the recurrence of [prostate cancer] and, more importantly, metastasis.”
Pan-AKT Inhibitor ARQ092 Shows Promise in Solid Tumors in First-in-Human Trial
The pan-AKT inhibitor ARQ092 was shown to be well tolerated, avoiding dose-limiting toxicities that often haunt inhibitors of AKT signaling, according to results presented at the 2013 American Association for Cancer Research (AACR) meeting.
ARQ092 is a novel pan-AKT inhibitor that targets the pleckstrin homology domain of all AKT isoforms to stabilize the closed conformation and arrest enzyme function. It had been previously shown to be effective in both cell and mouse xenograft models of cancer. The data were presented by Mansoor Saleh, MD, director of research at Georgia Cancer Specialists and professor at the University of Alabama Comprehensive Cancer Center, Birmingham, Alabama.
Twenty-eight patients with advanced metastatic disease who had failed standard chemotherapy were enrolled in the trial, which evaluated toxicity and tolerance as primary endpoints. Pharmacokinetics, pharmacodynamics, and determination of optimal and maximum-tolerated dose were secondary endpoints in this study. Doses started with 10 mg once every 2 days and escalated to 10, 20, 40, and then 80 mg daily. If toxicity was experienced at the 80-mg-per-day dose, the patients were stepped down to a 60-mg daily dose.
Adverse events for the trial included mild and reversible fatigue, loss of appetite, diarrhea, and nausea. The most significant toxicity noted was hyperglycemia, which was seen in four patients taking the 80-mg daily dose and was attenuated when patients were stepped down to the 60-mg dose. Maculopapular rash was not seen until the 80-mg dose as well. Three of the patients developed a rash at this dosage, and this side effect was reversed by moving to the 60-mg dose. “Rash, which has been the Achilles’ heel of a variety of AKT inhibitors, was not predominant in [patients treated with] this particular agent,” noted Dr. Saleh. He also noted that the hyperglycemia tended to precede rash, suggesting doctors could use hyperglycemia as a predictor of future toxicity with ARQ092. The investigators were not able to determine maximum tolerated dose, since toxicity experienced at 80 mg was completely ameliorated by moving to the 60-mg dosing schedule.
The pharmacokinetic profile suggested that the drug had a 20- to 58-hour half-life, and the drug was still available in the body at 24 hours, suggesting ARQ092 could be useful in intermittent dosing schedules in the future. Nine patients total were also able to have their platelet-rich plasma tested for phosphorylation status of AKT. ARQ092 was shown to significantly reduce these levels, giving preliminary indication that the drug is working as expected in the body. Eleven of 20 patients who could be evaluated in the study also showed stable disease, but no partial or complete clinical response could be observed. “Disease stabilization clearly underscores the fact that patients were able to stay on the study for much longer in the presence of this particular agent,” said Dr. Saleh. Other clinical trials with ARQ092 are being planned in solid tumors and advanced lymphoma using intermittent dosing schedules. ARQ092 was developed by Arqule, Inc.
Antibody-Drug Conjugate Shows Promise in Platinum-Resistant Ovarian Cancer
A novel therapy has shown activity in patients with difficult-to-treat, advanced, platinum-resistant ovarian cancer. The drug, DMUC5754A (Genentech), is part of a new class of drugs called antibody-drug conjugates. At the 2013 meeting of the AACR, phase I trial results were presented by Joyce F. Liu, MD, MPH, of the Dana-Farber Cancer Institute and Harvard Medical School in Boston.
“Overall the drug was well tolerated, with a toxicity profile that is comparable to other therapeutics currently used in clinical practice,” Liu told ONCOLOGY. “We think the results are very encouraging in a patient population where response to other therapies is limited.”
DMUC5754A consists of a monoclonal antibody against the protein MUC16, found on ovarian cancer cells at high levels, and a toxin linked by a cleavable linker. Approximately 80% of ovarian cancer patients have tumors that have high expression of MUC16 (also known as CA-125), according to Liu. The toxin is the microtubule-disrupting agent monomethyl auristatin E (MMAE). The antibody directs the toxin specifically to ovarian cancer cells to kill them. Because the antibody delivers the toxin specifically to the ovarian tumor, an especially potent toxin can be used, one that would be too toxic as a general cytotoxic agent that would also affect healthy tissue.
The results from the phase I trial also showed that patients with the highest expression of MUC16, the target of the antibody portion of the drug, derived the most benefit from the treatment. In future trials, this is likely to facilitate the selection of only those patients who are most likely to benefit from treatment.
Platinum-resistant, advanced ovarian cancer represents an unmet need and is difficult to treat. Patients currently have few treatment options. Platinum-based chemotherapy remains the standard way to treat ovarian cancer, and platinum resistance is a major treatment challenge.
The phase I trial evaluated various doses of DMUC5754A in patients with advanced ovarian and pancreatic cancer. DMUC5754A was administered at doses ranging from 0.3 mg/kg to 3.2 mg/kg every 3 weeks. Forty-four patients with advanced, recurrent, platinum-resistant ovarian cancer enrolled and were treated; among those, one complete response and four partial responses were reported. All patients who responded were treated with a 2.4-mg/kg dose of the drug and had high MUC16 expression in their tumor cells. Six additional patients had minor responses.
Fatigue was the most common adverse event at all dose levels, occurring in more than half of the patients. Other common adverse events were vomiting, decreased appetite, nausea, diarrhea, and peripheral neuropathy. Peripheral neuropathy was manageable and reversible in most patients through dose delay and dose reductions, the researchers said.
Grade 3 adverse events included fatigue and neutropenia, both occurring in 9% of patients. Neutropenia and uric acid release were the only dose-limiting toxicities during the study. Both occurred at the maximum 3.2-mg/kg dose. Other serious drug-related adverse events were small intestine obstruction in two patients, hypocalcemia in one patient, and neutropenia in one patient.
The role of MUC16 in cancer development and progression is not yet clear. MUC16 is a large transmembrane protein that is found in abundance on ovarian cancer cells but not healthy tissue. Researchers speculate that it may help ovarian tumor cells to bind to mesothelial cells that line the peritoneal cavity.
The encouraging activity and safety profile of the antibody-drug conjugate warrants further trials in ovarian cancer patients, the investigators concluded. “I think the major remaining question is how this therapy compares against the standard treatments that we use in platinum-resistant ovarian cancer,” said Liu.
Discussions regarding further development of DMUC5754A, including a phase II ovarian cancer trial, are ongoing.