The annual meeting of the American Association for Cancer Research (AACR) focuses on preliminary studies with promising findings for the treatment of cancer. This year’s conference was held in Washington, DC, from April 6-10, 2013. Selected highlights of early studies presented at the annual meeting follow. It is hoped that these encouraging preliminary findings will be confirmed by larger studies and lead to advances in cancer care.
Antibody-Conjugate Encouraging in Platinum-Resistant Ovarian Cancer
T-DM1 was the first antibody-drug conjugate to gain US Food and Drug Administration approval for HER2 (human epidermal growth factor 2)-positive metastatic breast cancer. A preliminary study suggests that a second antibody-drug conjugate is active in platinum-resistant ovarian cancer, and if the encouraging early results are confirmed by clinical trials, this would fulfill an unmet need for a difficult-to-treat cancer with limited treatment options.
The antibody-drug conjugate DMUC5754A includes a monoclonal antibody that recognizes the MUC16 protein expressed by ovarian cancer cells, which is linked to a potent antimitotic toxin called MMAE (monomethyl auristatin E). The antibody targets MUC16 and the toxin is released selectively into tumor cells that express MUC16, limiting the effects of the toxin on healthy tissues and organs.
MMAE is so potent that it could not be delivered directly to patients, explained lead author Joyce Liu, MD, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
The phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of DMUC5754A in 44 women with advanced, recurrent, platinum-resistant ovarian cancer. Among these heavily pretreated patients, 1 complete response and 4 partial responses were reported. All 5 of the responses were observed in patients with high expression of MUC16 in their tumor cells.
The maximum tolerated dose was identified as 2.4 mg/kg, and the antibody-drug conjugate was given every 3 weeks. Dose-limiting toxicities included one grade 4 neutropenia and one grade 4 uric acid increase, occurring at a higher dose level. Grade 3 adverse events included fatigue in 9% of patients and neutropenia in 9%. Fatigue was the most common adverse event at all dose levels, occurring in 57% of patients. Nausea, vomiting, decreased appetite, diarrhea, and peripheral neuropathy were also reported.
“If the activity of this drug is confirmed in additional trials, this will represent a real step forward in finding new, effective treatments for advanced ovarian cancer,” Liu said.
Liu J, Moore K, Birrer M, et al. Targeting MUC16 with the antibody-drug conjugate (ADC) DMUC5754A in patients with platinum-resistant ovarian cancer: a phase I study of safety and pharmacokinetics. Presented at: American Association for Cancer Research 2013 Annual Meeting; April 9, 2013; Washington, DC. Abstract LB-290.
Genetically Engineered T Cells Show Promising Activity in Pediatric Leukemia
A small preliminary study suggests that a unique immunotherapy called “anti-CD19 chimeric antigen receptor (CAR) T-cell therapy” can achieve complete remission in children with acute lymphocytic leukemia (ALL) who relapse after bone marrow transplant (BMT).
“Childhood ALL is the most common malignancy in pediatric patients. The majority of children can achieve remission, but this comes with the price of long therapy, toxicity, and cost, with no guarantee of long-term cure. Children who relapse have limited therapeutic options, and new therapies are sorely needed,” stated lead author of the study Daniel W. Lee, MD, assistant clinical investigator in the Pediatric Oncology Branch of the National Cancer Institute in Bethesda, Maryland.
Anti-CD19 CAR T cell therapy is a new way to treat childhood cancer, he continued. This therapy uses the patient’s own immune cells that have been collected and then modified and expanded in the laboratory to attach to the CD19 protein expressed by leukemia cells.
Activation of the T cells for immunity requires 2 signals, Lee explained. Leukemia cells do not generate the second signal required, and therefore the leukemia is not controlled. “Genetically engineered T cells get around this by being designed specifically to recognize the CD19 antigen. When they are reinfused into the patient, the receptor fires 2 signals and activates the T cells to kill the target tumor tissue,” he added.
At AACR, Lee reported results in the first 4 patients treated with anti-CD19 CAR T-cell therapy. Three patients had ALL and had received BMT, and 1 patient had B-cell lymphoma. All patients received fludarabine and cyclophosphamide prior to receiving the CAR T cells. One ALL patient had a complete response (CR), and a second ALL patient had a transient CR, with minimal residual disease remaining. The B-cell lymphoma patient did not respond.
The adverse effects were temporary and not seen in every patient, Lee continued. They included fever and low blood counts and were easily managed in hospital.
“Graft-versus-host disease is a side effect of concern in patients treated with BMT. We saw no evidence of this in the first 3 ALL patients we treated who had undergone previous BMT,” he said.
“Anti-CD 19 CAR T cells represent a new way to attack childhood leukemia. Preliminary evidence suggests that we can induce complete remission in patients refractory to other therapies,” Lee stated.
Lee DW III, Shah N, Stetler-Stevenson M, et al. Autologous-collected anti-cd19 chimeric antigen receptor (CAR) T cells for acute lymphocytic leukemia (ALL) and Non-Hodgkin’s lymphoma (NHL) in children who have previously undergone allogeneic stem cell transplantation (HSCT). Presented at: American Association for Cancer Research 2013 Annual Meeting; April 8, 2013; Washington, DC. Abstract LB-138.
Intermittent Vemurafenib May Overcome Resistance
Vemurafenib is a relatively new effective option for the treatment of melanoma, but most patients who respond will develop resistance. Studies by researchers at Novartis suggest that an intermittent dosing strategy may be able to overcome the resistance that occurs with standard continuous dosing.
“We were excited about the translational science that led to approval of the BRAF inhibitor vemurafenib, which extends survival in these patients. But most patients relapse with lethal drug-resistant disease,” explained Darrin Stuart, PhD, Novartis Institutes for Biomedical Research in Emeryville, California, who presented results of early animal and human studies.
In a previous study, Stuart and colleagues implanted xenografts of BRAF-expressing tumors in mice and found that the tumors developed resistance to vemurafenib. But possibly more important was the observation that the tumors were dependent on the drug for their proliferation. When drug treatment was withdrawn, the tumors stopped growing and regressed.
The next step was to determine if the drug dependency of the tumors was exhibited in humans. The investigators collaborated with scientists at the Royal Marsden Hospital in London, United Kingdom, and evaluated 42 patients with vemurafenib-resistant tumors. Of these, 19 patients had computed tomography scans obtained after drug treatment was stopped. Fourteen of 19 scans showed regression in the rate of tumor growth.
Stuart and colleagues then performed another experiment on mice implanted with BRAF-expressing tumor xenografts and treated them with vemurafenib 4 weeks on and 4 weeks off (intermittent strategy) or continuous vemurafenib. None of the tumors in the animals treated intermittently developed resistance.
This suggests that a drug holiday and intermittent treatment could be beneficial in patients taking vemurafenib and might overcome resistance. Stuart was not at liberty to discuss Novartis’ plans for the future, but stated that intermittent dosing was a strategy that he hopes researchers will pursue.
Das Thakur M, Fisher R, Salangsang F, et al. Modeling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Presented at: American Association for Cancer Research 2013 Annual Meeting; April 8, 2013; Washington, DC. Abstract LB-144.
Genetic Analysis Identifies 4 Subsets of Squamous Cell Carcinoma of the Head and Neck
Comprehensive genetic analysis by The Cancer Genome Atlas (TCGA) identified 4 different subtypes of squamous cell carcinoma of the head and neck (SCCHN). The analysis included 279 patients with previously untreated SCCHN. This is the eighth tumor type analysis of TCGA to be presented.
“Our study will likely become a landmark research tool for HNSCC for many years as we gradually unlock the secrets of this massive data set,” said David N. Hayes, MD, MPH, a medical oncologist who is associate professor at the University of North Carolina at Chapel Hill.
SCCHN is the fifth most common cancer worldwide and the sixth most common type in the United States. Forty-five thousand new cases are diagnosed each year. Smoking is a risk factor, as is the epidemic of human papilloma virus (HPV). Among the 279 patients included in the study, 80% were tobacco related and 13% were HPV positive.
“There is incredible pressure for these tumors to acquire a specific set of losses and gains. If you look across different tumor types, they have assumed a similar set of gains and losses across chromosomes; this may provide patterns that can be leveraged across a set of tumors,” he said. “We need to understand the mutations or individual alterations in the 15 most significant mutated genes in SCCHN.”
In the study, significant mutations were found in the following genes: CDKN2A, TP53, PIK3CA, NOTCH1, HRAS, and NFE2L2.
Looking at all gene expression subtypes of SCCHN, tumors organize themselves into 4 groups that are reproducible. These subtypes tend to go along with differences in mutation patterns and chromosomal alterations, Hayes explained. The 4 subtypes are:
- Atypical subtype with no amplification of epidermal growth factor receptor (EGFR), HPV positive, and a high rate of phosphatidylinositide 3-kinase (PIK3CA) mutations
- Classical subtype, also seen in squamous cell lung cancer, associated with 2 key mutations: KEAP 1 and NFE2L2
- Mesenchymal subtype, mostly mutations of FGR 1 and FGR, and
- Basal subtype, highly associated with SOX2 amplifications and overexpression.
Some of these alterations overlap with squamous cell carcinoma of the lung, which is also a tobacco-related cancer. “We frequently see altered genomes in other tobacco-related cancers. One of the striking findings we observed was a high degree of similarity to other squamous tumors, including lung squamous cell carcinoma. Lessons learned from studying the similarities and differences between tumors, such as copy number alterations, will be an angle to pursue to better understand altered pathways in cancer. The idea that they share properties that go beyond the type of cancer means that this could be studied at a model systems level.”
Additional key observations of this study include:
- Other patients as well as those who are HPV positive have infrequent EGFR gene amplification
- HPV-positive tumors have a high rate of PIK3CA gene mutations
- Patients infected with HPV almost never have p53 alterations
- In patients who are HPV negative, druggable mutations include EGFR, FGR, and CNCCC21.
“We have made a lot of observations, but this also makes things more complicated. We are able to recognize patterns, and some of these patterns may turn out to be druggable, or actionable in the future,” Hayes stated.
“This is robust information that gives us data on mutational analysis and copy numbers, expression, promoter methylation, and other aspects of SCCHN. This data set confirms other publications indicating that there is a clear difference between HPV-positive patients who usually have a better prognosis and are easier to treat than HPV-negative patients. HPV-negative patients have many more mutations than HPV-positive patients,” stated Giuseppe Giaccone, MD, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC. Giaccone moderated a press conference at which these data were presented.
Hayes DN, Grandis J, El-Naggar AK. Comprehensive genomic characterization of squamous cell carcinoma of the head and neck in The Cancer Genome Atlas. Presented at: American Association for Cancer Research 2013 Annual Meeting; April 7, 2013; Washington, DC. Abstract 1117.
Drug Combination Potentially Effective in BRCA-Deficient Solid Tumors
Two orally available experimental drugs achieved response in patients with BRCA-deficient solid tumors in a phase 1 study of 38 patients. Responders were patients with BRCA mutations and incurable pancreatic, breast, and ovarian tumors.
“There is definitely a group of responders who appear to benefit from this drug combination. This should be studied in a new, much larger prospective trial,” said lead author Geoffrey Shapiro, MD, PhD, Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts.
Among the 38 patients, 16 had BRCA-deficient cancers. Patients received treatment with sapacitabine and seliciclib—2 drugs developed by Cyclacel Pharmaceuticals, Inc. Sapacitabine causes single-strand DNA breaks that are converted to double-strand DNA breaks during replication. The investigators in the phase 1 trial hypothesized that seliciclib would interfere with the repair of damaged DNA and enhance the cytotoxicity of sapacitabine, Shapiro explained.
Patients were treated with sequential administration of both drugs for 10 days, followed by an 11-day rest period. During the dose-escalation phase of the study, patients without BRCA mutations had stable disease. Two observations during the dose-escalation phase had researchers focusing on the patients with BRCA mutations: one, it was reported that the repair of DNA breaks caused by sapacitabine is dependent on the homologous repair pathway, which includes BRCA proteins and is downregulated in their absence; the second was a partial response (PR) observed in a patient with pancreatic cancer who was found to be a BRCA-mutation carrier.
The trial was then limited to patients with BRCA-deficient cancers. Three additional PRs were observed (2 with breast cancer and 1 with ovarian cancer). The PRs have been durable in 3 patients (from 9 to 21 months). These 3 patients are continuing on study.
In total, 6 of the 16 BRCA-mutation carriers benefited from the drug combination (4 with PRs and 2 with stable disease).
Shapiro said that nonresponders were heavily pretreated and too compromised to tolerate a cycle of the combination therapy, and were therefore not evaluable.
“Among the BRCA-proficient group, several patients had prolonged stable disease, but the response was not as dramatic as in the BRCA-deficient group,” he said. “Going forward, the combination therapy has the most chance of efficacy in BRCA-deficient patients.”
Sequential administration of the 2 experimental agents was used in the trial. Concurrent administration of sapacitabine and seliciclib will be studied, as will different dosing schedules.
PARP (poly ADP-ribose polymerase) inhibitors are effective in BRCA-deficient patients. Shapiro said the responders in the trial had not been pretreated with a PARP inhibitor. “We need to determine if the combination works in patients pretreated with PARP. Finally, we have some drug classes that address inherited cancers,” Shapiro stated.
Shapiro GI, Hilton J, Cleary JM, et al. Responses to sequential sapacitabine and seliciclib in patients with BRCA-deficient solid tumors. Presented at: American Association for Cancer Research 2013 Annual Meeting; April 9, 2013; Washington, DC. Abstract LB-202.