Metastatic Triple Negative Breast Cancer: The TNT Trial Comparing Two Older Drugs Head to Head

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1 Metastatic Triple Negative Breast Cancer: The TNT Trial Comparing Two Older Drugs Head to Head The TNT clinical trial was conducted in the United Kingdom with enrollment beginning August 2008, and recruitment ending March It was conducted by the Principal Investigator Andrew Tutt from King s College in London. The purpose of this trial was to see which might be better treatment of patients with newly diagnosed recurrent or locally advanced breast cancer needing chemotherapy: Docetaxel (Taxotere) or Carboplatin? Taxanes such as Docetaxel or Paclitaxel have been widely used over the last 20 years. Carboplatin is an old drug as well and has not been thought to be a good breast cancer drug, but recent drug studies have caused a renewed interest, particularly for patients with triple negative breast cancer. Eligible patients were those with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer. Patients were not eligible if they had received adjuvant taxane within 12 months, they had received previous platinum treatment, or if they had received nonanthracyclines for metastatic breast cancer.!

2 This randomized Phase III trial enrolled 376 patients, 188 patients in each of the two arms. One arm was to receive Carboplatin for 6 cycles, the other arm to receive Docetaxel at full licensed dosage for 6 cycles. If a patient s disease progressed during the trial, they were eligible to crossover to the other arm if appropriate. Thirty five patients had locally advanced disease and 341 patients were metastatic. 85% had received prior adjuvant chemotherapy, and 35% had received prior taxane based adjuvant chemotherapy. Thirty one patients had the BRCA1 mutation, and 12 had the BRCA2 mutation. Platinum s have been used since the 1980 s and taxanes since the 1990 s. The side effects were as expected. Overall there were more Grade 3 or Grade 4 side effects seen for patients receiving Docetaxel as compared to Carboplatin (for neuropathy about 5% vs 1% and for low white blood counts and fever 25% vs 2%). It was determined that there was no significant difference in the response rate in either arm. Approximately 50% of the participants crossed over to the other arm at disease progression and the performance of both drugs was similar. Progression free survival on Carboplatin was 4.8 months and on Docetaxel was 5.2 months. Overall survival on Carboplatin was 10.7 months and 10.8 months on Docetaxel. These differences were not statistically significant. When the BRCA1/2 mutation was known, the patients with a germline BRCA1/2 mutation experienced a much better progression free survival on Carboplatin, 68% compared to 33% for patients on Docetaxel. This difference was statistically significant. Of the 376 patients, 211 in the locally defined triple negative population had RNA that was suitable for Prosigna PAM50 analysis. Of these, 174 were called Basal like, 38 non-basal like, 22 HER2 enriched, and 14 Luminal like. In the 174 Basal like patients, the performance of both Carboplatin and Docetaxel was similar. However, in the non-basal like group, the performance rate of Docetaxel was 74% and with Carboplatin it was 17%. This difference is statistically significant, with an exact p value < 0.01.

3 ! Dr. Tutt stressed that we should not jump to conclusions with these findings. Further work needs to be done and analyzed, as this study only included a very small population in the subsets. He also stressed that more needs to be learned about the biology behind this small subset of patients. In conclusion, the TNT trial has shown that there is no difference in response to Carboplatin or Docetaxel in unselected triple negative breast cancer. Patients with a BRCA1/2 mutation show a slightly better response to Carboplatin than Docetaxel. The trial supports BRCA1/2 genotyping in metastatic triple negative breast cancer to make better treatment choices. Further investigation is required of Homologous Recombination repair mechanisms (HRD), as well as basal and nonbasal like subgroups of triple negative breast cancer drug sensitivities. Dr. George Sledge, MD, (Professor of Medicine and Chief of the Division of Oncology of Stanford University, and Chief of Oncology at the Stanford Women's Cancer Center) said that "the clear demonstration that platinating agents are superior in a patient who has a BRCA mutation is quite important and certainly will direct therapy for many of us. Indeed, mainly it will get us doing a whole lot more BRCA testing that we have done previously, I suspect." "This study has a lot of qualifiers - small numbers, wide confidence intervals - but if it's reproducible, there is probably some fascinating biology going on there that we don't understand." (Medscape Oncology Insights Dec. 22, 2014)

4 There was also a poster presented that compared two treatment protocols in patients with metastatic triple negative breast cancer, and another on molecular changes during treatment of metastatic triple negative breast cancer. The first was Gemcitabine with Cisplatin or Paclitaxel in Metastatic Triple Negative Breast Cancer. This was a Chinese Breast Cancer Study Group (CBCSG) 006 trial where 236 metastatic patients were randomized to receive either a gemcitabine and cisplatin combination or a gemcitabine and paclitaxel combination. Both were administered on a 21 day cycle. The gemcitabine plus cisplatin patients experienced more nausea, vomiting, anorexia, and constipation. The gemcitabine plus paclitaxel patients experienced more anemia, alopecia, and peripheral neuropathy. The conclusion was that the gemcitabine plus cisplatin combination has more toxic side effects, but performs better in terms of progression free survival, and is cheaper to administer. Overall survival data still needs to be acquired to determine the long term impact of the drug combination. The second poster was A Phase II Trial of Doxil, Carboplatin, and Bevacizumab in Metastatic Triple Negative Breast Cancer and Molecular Correlates of Response. 31 patients that were previously untreated were enrolled in the trial from They were to receive treatment on a 28 day cycle. Bevacizumab was discontinued during the study, and was found to not have any clinical benefit. Median progression free survival was 5.6 months and median overall survival was 11.9 months. 13 patients were alive at 10 months or longer. 1 patient had complete tumor response, 14 had partial response, and 9 had stable disease. Conclusions were that alterations were seen in the P53 pathway followed by the PI3K pathway, transcription regulators, RTK s, and DNA repair pathways. Evolution of tumor genomic profiles results in a higher number of alterations following treatment with doxil and carboplatin. Additional genomic profiling is needed to yield insights into markers of sensitivity and mechanism of resistance to anthracycline and/or platinum. Lecture: General Session 3, S3-01. The TNT Trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally

5 advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012) PI: Dr. Andrew Tutt, MD, King s College London. Poster: P Gemcitabine with cisplatin or paclitaxel in metastatic triple-negative breast cancer. PI: Dr. Xichun Hu, MD, PhD, Fudan University Shanghai Cancer Center. Poster: P A Phase II trial of doxil, carboplatin and bevacizumab in metastatic triple negative breast cancer and molecular correlates of response. PI: Dr. Kim M. Hirschfield, MD, PhD, Rutgers Robert Wood Johnson Medical Group, The Cancer Institute of New Jersey, New Brunswick, NJ. Submitted By: Karen S. Durham Susan G. Komen Lindale, Texas USA