Efficacy of administration sequence: Sacituzumab Govitecan and Trastuzumab Deruxtecan in HER2-low metastatic breast cancer.

BACKGROUND: Current guidelines recommend that patients with HER2-low metastatic breast cancer (MBC) receive sequentially two antibody-drug conjugates (ADCs): Sacituzumab Govitecan (SG) and Trastuzumab Deruxtecan (T-DXd), despite a similar payload. However, the effectiveness of one after another is unknown. METHODS: ADC-Low is a multicentre, retrospective study evaluating the efficacy of SG and T-DXd, one after another, with or without intermediary lines of chemotherapy, in patients with HER2-low MBC. RESULTS: One hundred and seventy-nine patients were included: the majority with HR-negative tumours received SG first (ADC1) (n = 100/108) while most with HR-positive tumours received T-DXd first (n = 56/71). Median progression-free survival 2 was short: 2.7 months (95% CI: 2.4-3.3) in the whole population, respectively, 3.1 (95% CI: 2.6-3.6) and 2.2 months (95% CI: 1.9-2.7) for patients receiving T-DXd or SG second (ADC2). Intermediary lines of chemotherapy between ADC1 and ADC2 had no impact. Primary resistance to ADC2 occurred in 54.4% of patients. Certain patients showed initial response to ADC2. CONCLUSIONS: Clinical benefit of sequentially administered SG and T-DXd is limited for most patients. Nevertheless, a subset of patients might benefit-on the short term-from a second ADC. Additional studies are needed to identify patients who could benefit from two ADCs with similar payloads.

High-depth sequencing of paired primary and metastatic tumours: Implications for personalised medicine.

BACKGROUND: Next-generation sequencing of large panel of genes had been associated with clinical benefit in a significant proportion of patients with advanced cancer. However, the molecular profile of the primary tumour from the initial surgical specimen might significantly differ from the molecular profile in a tumour sample obtained from a biopsy of a metastatic site. PATIENTS AND METHODS: We compare the genetic profile of primary tumours and paired metastases by using a large panel of cancer genes. Training and validation set including a total of 152 primary and metastatic tumour pairs were sequenced (up to 429 genes) focussing on variants described in the Catalogue of Somatic Mutations in Cancer (COSMIC). RESULTS: Training and validation set including a total of 152 primary and metastatic tumour pairs were sequenced focussing on variants described in COSMIC. Agreement rate between the couples of primary and metastasis on COSMIC variants was 65% (24/37) and 43% (49/115) in the training and validation cohort, respectively. That rose to 74% (20/27) and 58% (42/73) when focussing on targetable mutations. In five cases, the discordance was related to appearance of secondary resistance mutation, giving a targetable refined agreement rate of 67% (67/100). CONCLUSION: Up to 40% of paired primary tumour/metastases have discordant molecular profile. Liquid biopsies may overcome, in the near future, the limits of tumour tissue genotyping.

A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1).

BACKGROUND: Several expression array studies identified molecular apocrine breast cancer (BC) as a subtype that expresses androgen receptor (AR) but not estrogen receptor α. We carried out a multicentre single-arm phase II trial in women with AR-positive, estrogen, progesterone receptor and HER2-negative (triple-negative) metastatic or inoperable locally advanced BC to assess the efficacy and safety of abiraterone acetate (AA) plus prednisone. PATIENTS AND METHODS: Patients with a metastatic or locally advanced, centrally reviewed, triple-negative and AR-positive (≥10% by immunohistochemistry, IHC) BC were eligible. Any number of previous lines of chemotherapy was allowed. AA (1000 mg) was administered once a day with prednisone (5 mg) twice a day until disease progression or intolerance. The primary end point was clinical benefit rate (CBR) at 6 months defined as the proportion of patients presenting a complete response (CR), partial response (PR) or stable disease (SD) ≥6 months. Secondary end points were objective response rate (ORR), progression-free survival (PFS) and safety. RESULTS: One hundred and forty-six patients from 27 centres consented for IHC central review. Of the 138 patients with sufficient tissue available, 53 (37.6%) were AR-positive and triple-negative, and 34 of them were included from July 2013 to December 2014. Thirty patients were eligible and evaluable for the primary end point. The 6-month CBR was 20.0% [95% confidence interval (CI) 7.7%-38.6%], including 1 CR and 5 SD ≥6 months, 5 of them still being under treatment at the time of analysis (6.4+, 9.2+, 14.5+, 17.6+, 23.4+ months). The ORR was 6.7% (95% CI 0.8%-22.1%). The median PFS was 2.8 months (95% CI 1.7%-5.4%). Fatigue, hypertension, hypokalaemia and nausea were the most common drug-related adverse events; the majority of them being grade 1 or 2. CONCLUSIONS: AA plus prednisone treatment is beneficial for some patients with molecular apocrine tumours and five patients are still on treatment. CLINICALTRIALSGOV: NCT01842321.

Quality of reporting of phase II trials: a focus on highly ranked oncology journals.

BACKGROUND: Phase II trials represent an essential step in the development of anticancer drugs. This study assesses the quality of their reporting in highly ranked oncology journals, investigates predictive factors of quality, and proposes reporting guidelines. PATIENTS AND METHODS: We reviewed the table of contents of all volumes of eight peer-reviewed oncology journals published in English between January and December 2011 with a 2011 impact factor (IF)>4. Two reviewers assessed the quality of each report by using a 44-point overall quality score (OQS). Primary end point definition, justification of sample size, and definition of the evaluable population, were assessed separately to establish a 3-point key methodological score (KMS). Exploratory analyses identified predictive factors associated with scores. RESULTS: One hundred fifty-six articles were included. The median OQS was 28 (range: 9-35). OQS subsection analysis showed that reporting of statistical methods was low with a median OQS of 3. Median KMS was 2 (range 0-3). Primary end point definition, justification of sample size and definition of the evaluable population were reported in only 107 (68.6%), 121 (77.6%), and 52 (33.3%) cases, respectively. At multivariate analysis, registration on clinicaltrials.gov and IF>10 were associated with improved OQS. No associations for KMS were observed. CONCLUSION: Phase II trial reporting is still poor even in journals with strict editorial policies. This may lead to biased interpretation of phase II trial results. Besides using a checklist during the preparation of their manuscript, authors should also provide reviewers and readers with the last version of the study's protocol.