An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival ...interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine.
This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0–1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110.
Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab deruxtecan (n=261) or trastuzumab emtansine (n=263). Median duration of study follow-up was 28·4 months (IQR 22·1–32·9) with trastuzumab deruxtecan and 26·5 months (14·5–31·3) with trastuzumab emtansine. Median progression-free survival by blinded independent central review was 28·8 months (95% CI 22·4–37·9) with trastuzumab deruxtecan and 6·8 months (5·6–8·2) with trastuzumab emtansine (hazard ratio HR 0·33 95% CI 0·26–0·43; nominal p<0·0001). Median overall survival was not reached (95% CI 40·5 months–not estimable), with 72 (28%) overall survival events, in the trastuzumab deruxtecan group and was not reached (34·0 months–not estimable), with 97 (37%) overall survival events, in the trastuzumab emtansine group (HR 0·64 95% CI 0·47–0·87; p=0·0037). The number of grade 3 or worse treatment-emergent adverse events was similar in patients who received trastuzumab deruxtecan versus trastuzumab emtansine (145 56% patients versus 135 52% patients). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 39 (15%) patients treated with trastuzumab deruxtecan and eight (3%) patients treated with trastuzumab emtansine, with no grade 4 or 5 events in either group.
Trastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration.
Daiichi Sankyo and AstraZeneca.
Advanced, unresectable hepatocellular carcinoma has a dismal outcome. Multiple immune checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) have been approved for the ...treatment of advanced HCC. However, outcomes remain undesirable and unpredictable on a patient-to-patient basis. The combination of anti-PD-1/L1 with alternative agents, chiefly cytotoxic T-lymphocyte antigen-4 (CTLA-4) ICIs or agents targeting other oncogenic pathways such as the vascular endothelial growth factor (VEGF) pathway and the c-MET pathway, has, in addition to the benefit of directly targeting alterative oncogenic pathways, in vitro evidence of synergism through altering the genomic and function signatures of T cells and expression of immune checkpoints. Several trials have been completed or are underway evaluating such combinations. Finally, studies utilizing transcriptomics and organoids are underway to establish biomarkers to predict ICI response. This review aims to discuss the biological rationale and clinical advances in ICI-based combinations in HCCs, as well as the progress and prospects of the search for the aforementioned biomarkers in ICI treatment of HCC.
Breast cancer is the most frequent cancer amongst women worldwide including in Asia where the incidence rate is rapidly increasing. Even with treatment, around 30% of patients with early breast ...cancer progress to metastatic disease, with hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer the most common phenotype. First-line endocrine therapy targeting the estrogen receptor signaling pathway provides a median progression-free survival or time to progression of 6-15 months in HR + HER2- metastatic breast cancer. Recently, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, combined with endocrine therapy, have achieved more than two years median progression-free survival in HR + HER2- metastatic breast cancer. However, the characteristics of the Asian breast cancer population differ from those of Western populations and need to be considered when selecting a suitable treatment. Breast cancer is diagnosed at a younger age in Asian populations and late stage at presentation is generally more common in low-/middle-income countries than high-income countries. Consequently, the proportion of premenopausal women with metastatic breast cancer is higher in Asian compared with Western populations. While CDK4/6 inhibitors have been approved in the USA (FDA) since 2015, experience with them in Asia is more limited. We review the experience with the CDK4/6 inhibitor palbociclib in Asian patients with HR + HER2- metastatic breast cancer and provide guidance on the use of palbociclib in these patients.
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Background: Hepatic derangement commonly accompanies advanced HCC (aHCC) and limits the use of systemic therapies. We aimed to evaluate the use of single agent anti-PD-1 ...nivolumab or pembrolizumab in Child-Pugh (CP) grade B or C patients with aHCC. Methods: Consecutive aHCC patients with CP grade B (CPB) or C (CPC) liver function who received single agent nivolumab or pembrolizumab were analysed. Objective response rate (ORR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed. Results: Between May 2015 and June 2020, 61 patients were included. The median age was 60 (range 28-82). 81% and 4.8% had hepatitis-B and hepatitis-C related HCCs respectively. 72.1% (n = 44) were of CPB and 27.9% (n = 17) were of CPC. Amongst CPB patients, 19 (31.1% of all patients) had CP score 7 (CP7) and 25 (41.0% of all patients) had CP score 8 or 9. The median follow-up was 2.3 months. The ORR of CPB and CPC patients were 6.8% and 0% respectively (p = 0.553). The TTP of CPB and CPC patients were 2.1 months (95% C.I. 1.4-2.8) and 1.4 months (95% C.I. 0.6-2.1) respectively (p = 0.204). CPB patients had significantly better OS than CPC patients (3.1 months (95% C.I. 1.4-4.7), vs. 1.7 months (95% C.I. 1.0-2.4), p = 0.041). Compared to CP score ≥8 (CP≥8) patients, CP7 patients had significantly better OS (median OS CP7 6.7 months (95% C.I. 4.0-9.3), vs. CP≥8 1.8 months (1.2-2.4), p = 0.002). Patients with diuretic-refractory ascites had significantly worse OS compared to those without (1.7 months (95% C.I. 1.0-2.5) vs. 3.7 months (95% C.I. 0.1-7.3), p = 0.004). Portal vein (PV) thrombosis was also significantly associated with inferior survival, with median OS of patients with any PV thrombosis being 1.8 months (95% C.I. 1.0-2.5), compared to 5.3 months (95% C.I. 2.4-8.1) of those without (p = 0.004). The median number of doses given was 3 (range 1-34). Median treatment duration was 5.0 weeks (range 0-77). Overall, 25.4% of patients experienced TRAEs and 4.8% experienced grade ≥3 TRAEs. The most common TRAEs were skin-related (13.1%) and constitutional symptoms (6.6%). Conclusions: Nivolumab/pembrolizumab had acceptable safety in CPB/C patients with aHCC. CP7, absence of diuretic-refractory ascites and lack of PV thrombosis were associated with better survival.
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Background: Programmed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICI) is a standard therapy in advanced hepatocellular carcinoma (HCC) ...nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in advanced HCC patients with progression on prior ICIs. Methods: Advanced HCC patients with documented tumour progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analysed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed. Results: Twenty-five patients were included. The median age was 62 (range 51-83). 68% were of Child-Pugh (CP) grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range 2.76-30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% C.I. 1.61-4.31). Median OS was 10.9 months (95% C.I. 3.99-17.8) and the 1-year, 2-year and 3-year survival rates were 42.4%, 32.3% and 21.6% respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) grade 1 or 2. CP and ALBI grades were significantly associated with OS (p=0.006 and p<0.001 respectively). Overall, 52% of patients experienced TRAEs and 12% experienced grade 3 or above TRAEs. Conclusions: Ipilimumab and nivolumab/pembrolizumab can achieve durable antitumour activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.
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Background: In the phase III CELESTIAL trial, cabozantinib showed significant improvement in overall survival with good tolerability in advanced HCC population. We aimed to evaluate ...the efficacy, survival and tolerability of cabozatinib in advanced hepatocellular carcinoma (HCC) patients in a real life setting. Methods: Between February 2018 and October 2019, consecutive advanced HCC patients who received cabozatinib alone or in combination at University of Hong Kong Health System hospitals were analysed. Cabozantinib was administered at 60 mg continuously daily. Objective response rate (ORR), time-to-progression (TTP), overall survival (OS), and tolerability were evaluated. Results: Overall, 22 patients were included. The median age was 57.1 years (range 48.5-58.6). All patients except one were hepatitis B carriers. More than 80% of the patients had underlying Child-Pugh A cirrhosis. Most patients had metastatic disease (95.5%). More than 70% of patients received cabozantinib beyond second-line, and most of the patients had prior exposure to tyrosine kinase inhibitor (TKI) and/or immunotherapy. The median time from the start of first-line systemic treatment to the start of cabozantinib was 11.2 months. Cabozantinib was administered to 11 patients (50%) as single agent, while the other half received cabozantinib in combination with mostly immune checkpoint inhibitors. The median follow-up was 7.6 months. The table below shows the ORR. The overall median TTP and OS were 4.2 and 8.90 months, respectively. Interestingly, among those who received single agent cabozantinib, the median OS was 5.36 months in contrast to 12.32 months in the patients received combination. Overall, 90.9% of patients experienced treatment related adverse events (TRAEs) with transient liver function occurred in nearly 50% patients. Nevertheless, Grade 3/4 TRAEs was only 12%. Conclusions: Our present study showed that the use of cabozatinib in advanced HCC patients had good anti-tumour activity and survival benefits with acceptable toxicity profile. Table: see text
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Background: Immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) are widely adopted in contemporary advanced HCC (aHCC) treatment algorithms. Nevertheless, ...the optimal strategy for treatment after ICI exposure is unknown. We evaluated the pattern of use, response, survival and safety of TKIs in aHCC patients who previously received ICIs. Methods: We performed an international, multi-centre study of aHCC patients who received TKIs after prior treatment with ICIs. Objective response rate (ORR), disease control rate (DCR), time-to-progression (TTP), overall survival (OS) and adverse events (AE) were assessed. Results: Between January 2015 and December 2020, one-hundred and forty-eight patients were included. The median age was 63 (range 29-84) and 78.4% were of Child-Pugh Grade A. 75.7% had hepatitis-B related HCC. 64.9% received TKI as single agent and 35.1% received TKI in combination with other agents. 75% who received TKI combinations had concomitant ICIs. 48.6% had prior TKIs. The median follow-up was 23.3 months. For single agent TKI patients, the ORR was 14.6%, DCR was 38.5%, median TTP was 3.9 months (95% C.I. 3.3-4.5) and median OS was 8.6 months (95% C.I. 5.8-11.4). For patients receiving TKI combinations, the ORR was 25%, DCR was 38.5%, median TTP was 3.5 months (95% C.I. 1.7-5.2) and median OS was 15.1 months (95% C.I. 5.7-24.5). There were no significant differences in ORR, DCR and median OS between patients who had primary resistance to prior ICI compared to those with acquired ICI resistance and between those who were TKI-naive compared to those who were TKI-exposed. Notably, patients who received TKI-ICI combinations had significantly superior survival compared to single agent TKI patients (median OS 15.1 months (95% C.I. 6.7-23.5) vs. 8.6 months (95% C.I. 5.6-11.7), p = 0.011) but not significantly superior ORR, DCR or TTP. Amongst patients who received single agent TKI and were naive to both sorafenib and lenvatinib, those who received lenvatinib had significantly superior DCR, TTP and OS compared to those who received sorafenib (DCR 51.5% vs 25.8%, p = 0.035; median TTP 6.3 months (95% C.I. 3.0-9.7) vs. 1.8 months (95% C.I. 0-3.6), p = 0.003; median OS 12.0 months (95% C.I. 7.0-17.0) vs. 5.9 months (95% C.I. 1.9-10.0), p = 0.008). 70.3% and 15.5% of all patients, and 77.1% and 15.6% of patients who received single agent TKI experienced all grade and grade ≥3 AEs respectively. The most common AEs were hand foot syndrome, skin rash and diarrhea. Conclusions: TKIs can achieve encouraging anti-tumour response and survival outcomes with acceptable safety in prior ICI-treated aHCC patients. Moreover, TKI-ICI combinations were associated with better survival than single agent TKIs. Notably, among patients who received single agent TKIs, lenvatinib had significantly better responses and survival results than sorafenib.
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Background: Cabozantinib is licensed for use as second- or third-line treatment for sorafenib-exposed advanced hepatocellular carcinoma (aHCC) based on the phase III CELESTIAL ...trial. However, its use in the post-immune checkpoint inhibitors (ICI) setting has yet to be described. We evaluated the pattern of use, efficacy, survival and tolerability of cabozantinib in aHCC patients with previous treatment by ICIs. Methods: We did a multi-centre, territory-wide study analysing aHCC patients who received cabozantinib after prior ICIs. Objective response rate (ORR), disease control rate (DCR), time-to-progression (TTP), overall survival (OS) and treatment related adverse events (TRAEs) were assessed. Results: Thirty-one patients were included. The median age was 58.0 (range 41-85) and 77.4% had Child-Pugh A cirrhosis. 51.6% of patients received single agent cabozantinib and 48.4% received cabozantinib in combination with ICIs. ≥80% of patients received cabozantinib beyond the second-line and 93.5% of patients had prior TKIs. All patients received prior anti-PD-1 and 61.3% had prior anti-CTLA-4. The median follow-up was 15.2 months. For single agent cabozantinib patients, the ORR was 6.3%, DCR was 31.3% and median TTP was 3.5 months (95% C.I. 1.2-5.8). For cabozantinib-ICI combination patients, the ORR was 6.7%, DCR was 26.7% and median TTP was 2.3 months (95% C.I. 1.4-3.1). The overall median OS was 8.9 months (95% C.I. 5.7-11.9). Single agent cabozantinib patients had a significantly shorter OS compared to cabozantinib-ICI combination patients (8.3 months (95% C.I. 1.3-15.2) vs. 15.1 months (95% C.I. 11.1-19.2), p = 0.047). There was no significant difference in OS among patients with primary resistance to prior ICI regimes compared to those with acquired resistance (primary resistance 8.28 months (95% C.I. 5.04-11.5) vs. acquired resistance 8.90 months (95% C.I. 3.49-14.3), p = 0.472). Overall, 67.7% and 6.5% of patients experienced TRAEs of all grade and grade ≥3 respectively. The most common TRAE was hand-foot syndrome. 62.5% of single agent cabozantinib patients had any grade TRAE and no such patients had grade ≥3 TRAE. Conclusions: Cabozantinib had good anti-tumour activity and survival outcomes with acceptable toxicity in aHCC patients with previous treatment by ICIs.
This study evaluated the single- and multiple-dose pharmacokinetic (PK) variables of elbasvir and grazoprevir in healthy Chinese individuals.
This study was a 2-part, parallel-arm, open-label trial. ...In part 1, single-dose PK variables of elbasvir 10/50/100 mg and grazoprevir 50/100/200 mg were evaluated in 10 participants per drug. In part 2, 10-day multiple-dose PK variables of elbasvir 50 mg and grazoprevir 100 mg administered once daily alone and in combination were evaluated in 12 participants. Summary and inferential statistics of the PK parameters are reported. Elbasvir and grazoprevir PK parameters were also compared between Chinese participants and historical data from white participants.
Single-dose elbasvir and grazoprevir median Tmax were 2.9 to 4.0 and 1.9 to 3.0 hours after administration, respectively. Elbasvir AUC0–∞ and Cmax increased in a dose-proportional manner (slope estimate 90% CI, 0.92 0.84–1.01 and 0.98 0.86–1.09, respectively), whereas grazoprevir AUC0–∞ and Cmax increased in a greater-than-dose-proportional manner (slope estimate 90% CI, 1.42 1.27–1.57 and 1.96 1.64–2.29). After repeated administration, the accumulation ratios for AUC0–24, 24-hour concentration, and Cmax were 1.55, 1.57, and 1.38 for elbasvir and 2.03, 1.23, and 2.51 for grazoprevir. Co-administration of elbasvir 50 mg and grazoprevir 100 mg once daily did not have a clinically relevant effect on the PK variables of either drug. Median Tmax after co-administration versus alone was 3.0 hours versus 3.0 hours for elbasvir and 3.1 hours versus 3.0 hours for grazoprevir. Geometric mean ratios (90% CI) for elbasvir and grazoprevir AUC0–24 (Chinese/white participants) were 1.58 (1.03–2.42) and 1.21 (0.76–1.92). Elbasvir and grazoprevir, administered alone or concomitantly, were well tolerated.
In healthy Chinese individuals, administration of elbasvir and grazoprevir, alone or concomitantly, was generally well tolerated, with a thoroughly characterized PK profile. Elbasvir and grazoprevir exposures may trend higher in Chinese healthy participants relative to white healthy participants. Protocol number MK-5172 PN022.
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Background: In monarchE, abemaciclib (oral CDK4&6 inhibitor) plus endocrine therapy (ET) as adjuvant treatment for HR+, HER2- high risk early breast cancer (EBC), demonstrated a ...statistically significant improvement in invasive disease-free survival (IDFS) compared to ET alone. Here we present the efficacy and safety analysis of Chinese patients from monarchE. Methods: The overall study design was reported previously. Eligible patients were randomized to receive abemaciclib (150 mg BID for 2 years) combined with standard adjuvant ET or ET alone. The primary endpoint was IDFS per STEEP criteria. Secondary endpoints included distant relapse-free survival (DRFS), overall survival, and safety. Exploratory subgroup analyses were conducted among Chinese patients enrolled from Mainland China, Hong Kong, and Taiwan in the intent-to-treat (ITT) population. Results: A total of 501 Chinese patients were randomized to receive abemaciclib plus ET (259 patients) or ET alone (242 patients). At the time of data cutoff (July 8, 2020), 356 (71.1%) patients were still in the 2-year treatment period. A total of 26 IDFS events were observed (11 and 15 events in abemaciclib plus ET and ET arm, respectively). Comparing to ET alone, abemaciclib combined with ET reduced the risk of developing invasive disease or death by 34.3% (HR: 0.657, 95% CI: 0.301, 1.435) for Chinese patients, together with a clinically meaningful improvement in the 2-year IDFS rate (95.6% vs 92.1%). The addition of abemaciclib to ET also resulted in an improvement in DRFS (HR: 0.601, 95% CI: 0.245, 1.477) for Chinese patients, with the 2-year DRFS rate at 96.7% (ET alone: 93.4%). In the abemaciclib arm, the most frequent treatment-emergent adverse events (TEAEs) and grade ≥3 TEAEs: diarrhea (90.3% and 5.0%), leukopenia (76.8% and 21.2%), and neutropenia (76.4% and 23.9%), respectively. Conclusions: Abemaciclib combined with adjuvant ET demonstrated clinically meaningful IDFS and DRFS benefits among Chinese patients with HR+, HER2-, high risk EBC, which was consistent with the ITT population as reported previously. The safety profile of abemaciclib in Chinese EBC patients was consistent with global population and also with that observed in Chinese metastatic breast cancer patients. Clinical trial information: NCT03155997.
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