From among 4,500 abstracts to be presented at this year’s ASCO, an official pre-ASCO press cast featured results of 5 chief clinical trials. Regarding the press cast, Michael Link, MD, President of ASCO, said, “Today’s studies demonstrate improvements in precision medicine that identify and exploit cancer’s genetic weak spots to halt tumor growth and in some cases eradicate disease. Other studies give us valuable new tools and information to lessen the short- and long-term side effects of cancer treatment for our patients.”
The 5 highlighted studies were:
• Pre-adjuvant therapy of high-risk prostate cancer with abiraterone.
• Combining a BRAF inhibitor and a MEK1 inhibitor—two molecularly targeted agents—to treat advanced melanoma.
• Use of an antipsychotic medication to treat breakthrough chemotherapy-induced nausea/vomiting.
• Crizotinib in pediatric tumors driven by ALK genetic abnormalities.
• The sorry state of primary care physicians’ knowledge about late effects of chemotherapy in cancer survivors.
Pre-adjuvant Abiraterone Treatment
In a randomized Phase 2 trial, 6 months of treatment with abiraterone [Zytiga; Jansenn Biotech] along with hormonal therapy given prior to prostatectomy to men with high-risk early prostate cancer eradicated cancer cells in about one-third of patients. Abiraterone is currently FDA approved for metastatic prostate cancer. This trial was conducted in the pre-adjuvant setting.
The study included 58 men with 1 or more of these high-risk features:
• Gleason score 8-10 (71% of men)
• PSA level >20 ng/ml (19%)
• T3,T4 bulky disease (24%)
• High PSA velocity (16%)
• Extra nodal disease could be included
Patients were randomized to receive 3 months of treatment with leuprolide alone or 3 months of leuprolide plus abiraterone plus low-dose prednisone. After 3 months of treatment, all patients in the trial were treated for another 3 months of neoadjuvant therapy with abiraterone, leuprolide, and prednisone. After of 6 months of neoadjuvant therapy, radical prostatectomy was performed and pathological response evaluated.
pCR was 10% for those treated with abiraterone for 6 months vs 4% for those who received leuprolide for 3 months and then abiraterone for 3 months, and near pCR was observed in 24% and 11%, respectively. Total response rate was 34% vs 15%, respectively; the difference between groups was not statistically significant.
“These results are particularly amazing in this incredibly high-risk group of patients, and suggest that this combination therapy could improve outcomes for a substantial number of men, said lead author Mary-Ellen Taplin, MD, Harvard Medical School and the Dana-Farber Cancer Institute, Boston, MA. Larger, longer trials are needed to confirm this approach (i.e., neoadjuvant use of abiraterone plus hormones plus prednisone).
Combining a BRAF inhibitor and a MEK1 inhibitor in Advanced Melanoma
Results of an early Phase 1B trial found that combining two investigational oral targeted therapies—the BRAF inhibitor dabarafenib and the MEK inhibitor trametinib—appeared to halt disease progression in patients with metastatic melanoma. The lead author of the study, Jeffrey Weber, MD, of H. Lee Moffitt Cancer Center, Tampa, FL., went on to say that while not a comparative study there were different side effects than those reported with a single-agent BRAF inhibitor.
About 50% of all melanomas harbor a mutation in the BRAF gene, and the related MEK pathway is highly active in those patients, providing a rationale for the dual targeted approach. The Phase 1B study included a subset of 77 patients with advanced melanoma who were enrolled in a larger 4-part study. The trial identified the following dose as recommended for further study: dabarafenib 150 mg/trametinib 2 mg.
Again noting that this was not a comparative study, Dr. Weber said that use of the combination significantly decreased skin toxicity if one compared these results with those reported with BRAF inhibitors. For example, only 3% of patients developed squamous cell carcinomas compared with about 15% to 25% of patients treated with other BRAF inhibitors; another 5% developed actinic keratosis which is much lower than with a BRAF inhibitor alone, Dr. Weber commented. Pyrexia was the only side effect that was slightly higher with the combination and this tended to occur along with chills, fatigue, and nausea; grade 3 pyrexia was reported in 8% of patients.
Using a waterfall plot to assess tumor shrinkage on the combination therapy, Dr. Weber said: “This is among the best results I’ve seen. About 95% of patients had stable disease, partial response, or complete response.” Median PFS was 10.8 months, which he called “extremely encouraging.”
Olanzapine for Chemotherapy-Induced Nausea/Vomiting (CINV)
Olanzapine [Zyprexa; Eli Lilly], an approved antipsychotic agent, was more effective than metoclopramide (standard anti-emetic treatment) in controlling breakthrough CINV in patients treated with highly emetogenic chemotherapy who received guideline-recommended anti-emetic therapy.
“This is the first Phase 3 study to show that a treatment is effective for breakthrough CINV, which afflicts about 50% to 60% of patients taking highly emetogenic chemotherapy,” said lead author Rudolph Navari, MD, Indiana University School of Medicine, South Bend, IN.
The study enrolled 205 chemotherapy-naïve patients treated with cisplatin, doxorubicin, and cyclophosphamide. All patients received guideline-recommended drugs to prevent nausea and vomiting, but 80 patients experienced breakthrough CINV and were randomized to olanzapine (n=42) or metoclopramide (n=38) for 72 hours of treatment.
Control of emesis was achieved in 71% of those treated with olanzapine vs 32% of the metoclopramide group; nausea was controlled in 67% and 24%, respectively. Both of these results were statistically significant (P<.01); no grade 3 or 4 toxicity was observed in either group.
Crizotinib in ALK-driven Pediatric Tumors
An early Phase 1 study suggests that Pfizer’s crizotinib (Xalkori, approved to treat lung cancer) may be an effective approach to anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumors (IMT), and neuroblastoma in select children with aggressive forms of these cancers, which commonly have ALK gene abnormalities, said lead author Yael Mosse, MD, Children’s Hospital of Philadelphia, PA.
ALK gene abnormalities are present in 80% to 95% of ALCL cases, 50% of IMT cases, and 10% to 15% of aggressive neuroblastomas. The study included 70 children with these cancers who had progressed on standard therapies. Patients received one of 6 different doses of oral crizotinib twice daily and stayed on the drug until it was no longer well tolerated.
In ALCL, 88% (7/8) patients experienced complete response, with no detectable disease for as long as 18 months. The majority of 7 patients with IMT experienced effects ranging from tumor shrinkage to complete tumor regression. Of the 27 patients with neuroblastoma, 8 had known ALK mutations; of these, 2 of 8 had complete response, 2 had minor responses, and 1 had stable disease. Responses were also seen among 19 neuroblastoma patients with unknown ALK status; 1 complete response and 6 with prolonged stable disease.
The high degree of activity seen with crizotinib in these childhood tumors will lead to larger trials in ALCL and other childhood tumors, said Dr. Mosse.
Knowledge Gap About Late Effects of Chemotherapy Among Primary Care Providers
A large survey of 1,072 primary care providers (PCPs) and 1,030 medical oncologists who treat breast and colorectal cancer revealed a troubling knowledge gap among the PCPs regarding late effects of chemotherapy in cancer survivors. The survey asked questions about four commonly used chemotherapy agents: doxorubicin, cyclophosphamide, paclitaxel, and oxaliplatin.
Among PCPs, 55% correctly identified cardiac dysfunction as a late effect of doxorubicin compared with 95% of oncologists; 26% of PCPs correctly identified peripheral neuropathy as a late effect of paclitaxel compared with 97% of oncologists; 22% of PCPs correctly identified peripheral neuropathy as a late effect of oxaliplatin compared with 96% of oncologists. For cyclophosphamide, premature menopause was correctly identified as a late effect by 15% of PCPs and 71% of oncologists, and secondary malignancy was correctly identified as a late effect by 17% of PCPs and 62% of oncologists.
Lead author, Larissa Nekhlyudov, MD, Harvard Medical School, Boston, MA, noted that with more than 12 million cancer survivors, late effects of chemotherapy are becoming increasingly important. She said that survivorship plans should address this knowledge gap and relay information to patients and to PCPs so that they can provide optimal management to cancer survivors.
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