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Trastuzumab deruxtecan (T-DXd) demonstrated significantly improved efficacy over trastuzumab emtansine (T-DM1) in DESTINY-Breast03 (median follow-up, 28 months). We report updated efficacy and safety analyses, including secondary and exploratory efficacy endpoints (median follow-up, 41 months) of DESTINY-Breast03. Patients with advanced HER2-positive metastatic breast cancer previously treated with taxane and trastuzumab were randomized to T-DXd (5.4 mg per kg (261 patients)) or T-DM1 (3.6 mg per kg (263 patients)). The primary endpoint was progression-free survival (PFS) by blinded independent central review and was previously reported. The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate, duration of response and PFS (all by investigator assessment) and safety. At data cutoff, 20 November 2023, median PFS by investigator assessment was 29.0 versus 7.2 months (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.24–0.38), the 36-month PFS rate was 45.7% versus 12.4% and median OS was 52.6 versus 42.7 months (HR, 0.73; 95% CI, 0.56–0.94) with T-DXd versus T-DM1, respectively. Treatment-emergent adverse events were consistent with the previous analyses. No new instances of grade ≥3 interstitial lung disease or pneumonitis occurred (all grade rate, 16.7% (T-DXd) versus 3.4% (T-DM1)). With longer follow-up, T-DXd continued to demonstrate superior efficacy over T-DM1 with a manageable safety profile. ClinicalTrials.gov registration: NCT03529110 . Secondary and selected exploratory endpoints of the DESTINY-Breast03 trial of trastuzumab deruxtecan or trastuzumab emtansine in patients with advanced HER2-positive breast cancer are reported, including updated efficacy and safety data after a median follow-up of 41 months.

Sacituzumab govitecan demonstrated significant progression-free survival benefit over chemotherapy in the phase 3 TROPiCS-02 trial in patients with pretreated, endocrine-resistant hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ and HER2–) metastatic breast cancer with limited treatment options. Here, we report the protocol-specified final analysis of overall survival and endpoints by trophoblast cell-surface antigen 2 (Trop-2) expression and other variables. In this randomised, open-label, multicentre, phase 3 trial, which took place in 91 centres across North America (the USA and Canada) and Europe (Belgium, France, Germany, Italy, the Netherlands, Spain, and the UK), patients were randomly assigned (1:1) to receive sacituzumab govitecan or chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). Patients had confirmed HR+ and HER2– locally recurrent inoperable or metastatic breast cancer and had received at least one previous endocrine therapy, a taxane, and a CDK4/6 inhibitor in any setting and two to four previous chemotherapy regimens for metastatic disease. The primary endpoint was progression-free survival (previously reported and not included in this analysis), and secondary endpoints included overall survival, objective response rate (ORR), and patient-reported outcomes. Overall survival was assessed using stratified log-rank tests and Cox regression. Trop-2 expression was assessed in tumour tissue by immunohistochemistry. In the statistical testing hierarchy, ORR and patient-reported outcomes were tested sequentially if overall survival was significant. This study is registered with ClinicalTrials.gov, NCT03901339. At the data cutoff date of July 1, 2022, 543 of 776 screened patients were randomly assigned between May 30, 2019, and April 5, 2021, with 272 patients in the sacituzumab govitecan group and 271 patients in the chemotherapy group. With a 12·5-month (IQR 6·4–18·8) median follow-up, 390 deaths occurred among 543 patients. Overall survival was significantly improved with sacituzumab govitecan versus chemotherapy (median 14·4 months [95% CI 13·0–15·7] vs 11·2 months [10·1–12·7]; hazard ratio [HR] 0·79, 95% CI 0·65–0·96; p=0·020); survival benefit was consistent across Trop-2 expression-level subgroups. ORR was significantly improved with sacituzumab govitecan compared with chemotherapy (57 [21%] patients vs 38 [14%]; odds ratio 1·63 [95% CI 1·03–2·56]; p=0·035), as was time to deterioration of global health status and quality of life (median 4·3 months vs 3·0 months; HR 0·75 [0·61–0·92]; p=0·0059) and fatigue (median 2·2 months vs 1·4 months; HR 0·73 [0·60–0·89]; p=0·0021). The safety profile of sacituzumab govitecan was consistent with previous studies (including the TROPiCS-02 primary analysis and the ASCENT trial). One fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment. Sacituzumab govitecan demonstrated statistically significant and clinically meaningful benefit over chemotherapy, with a 3·2-month median overall survival improvement and a manageable safety profile. These data support sacituzumab govitecan as a new treatment option for patients with pretreated, endocrine-resistant HR+ and HER2– metastatic breast cancer. Gilead Sciences.

T cells play a vital role in the anti-tumoural response, and the presence of tumour-infiltrating lymphocytes has shown to be directly correlated with a good prognosis in several cancer types. Nevertheless, some patients presenting tumour-infiltrating lymphocytes do not have favourable outcomes. The TCR determines the specificities of T cells, so the analysis of the TCR repertoire has been recently considered to be a potential biomarker for patients’ progression and response to therapies with immune checkpoint inhibitors. The TCR repertoire is one of the multiple elements comprising the immune system and is conditioned by several factors, including tissue type, tumour mutational burden, and patients’ immunogenetics. Its study is crucial to understanding the anti-tumoural response, how to beneficially modulate the immune response with current or new treatments, and how to better predict the prognosis. Here, we present a critical review including essential studies on TCR repertoire conducted in patients with cancer with the aim to draw the current conclusions and try to elucidate whether it is better to encounter higher clonality with few TCRs at higher frequencies, or higher diversity with many different TCRs at lower frequencies.

CLEOPATRA is a phase 3 study to compare the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive first-line metastatic breast cancer. The results of the primary analysis showed significantly longer median progression-free survival in the pertuzumab group than in the placebo group. Interim analysis of overall survival favoured the pertuzumab group but was not significant. Here, we report results for overall survival after an additional year of follow-up. The study was a double-blind randomised trial undertaken at 204 centres in 25 countries. Patients with HER2-positive metastatic breast cancer who had not received previous chemotherapy or biological treatment for their metastatic disease were randomly assigned to receive either pertuzumab, trastuzumab, and docetaxel (n=402) or the same regimen with a matching placebo replacing pertuzumab (n=406). Randomisation was in a 1:1 ratio, stratified by geographical region and previous treatment status. The primary endpoint was progression-free survival (assessed independently), which has been reported previously; no follow-up data were gathered for the primary endpoint. Secondary endpoints included overall survival, progression-free survival (assessed by investigator), objective response rate, and safety. Median follow-up was 30 months in both groups. Efficacy endpoints were analysed in the intention-to-treat population and safety was analysed by treatment received. The study is completed but safety and survival data continue to be followed up. This trial is registered with ClinicalTrials.gov, number NCT00567190. In the intention-to-treat population, 267 patients died by data cutoff (May 14, 2012), 154 (38%) of 406 in the placebo group and 113 (28%) of 402 in the pertuzumab group. Median overall survival was 37·6 months (95% CI 34·3–NE [not estimable]) in the placebo group but had not been reached (95% CI 42·4–NE) in the pertuzumab group (hazard ratio 0·66, 95% CI 0·52–0·84; p=0·0008). Investigator-assessed median progression-free survival was 12·4 months (95% CI 10·4–13·5) in the placebo group and 18·7 months (16·6–21·6) in the pertuzumab group (hazard ratio 0·69, 95% CI 0·58–0·81). Serious adverse events were reported in 115 (29%) of 396 patients who received placebo, trastuzumab, and docetaxel and 148 (36%) of 408 who received pertuzumab, trastuzumab, and docetaxel, and included febrile neutropenia, neutropenia, diarrhoea, pneumonia, and cellulitis. Overall, adverse events were similar to those reported at the primary analysis with respect to frequency, severity, and specificity. Our analysis shows a significant improvement in overall survival with pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer, compared with placebo, trastuzumab, and docetaxel. Since this effect was not achieved at the expense of adverse events, this regimen represents a substantial improvement on the standard of care for this population of patients. F Hoffmann-La Roche, Genentech.

HER2-positive breast cancer consists of four intrinsic molecular subtypes—luminal A, luminal B, HER2-enriched, and basal-like—and a normal-like subtype, with the HER2-enriched subtype having the highest activation of the EGFR–HER2 pathway. We aimed to test the hypothesis that patients with the HER2-enriched subtype benefit the most from dual HER2 blockade. PAMELA is an open-label, single-group, phase 2 trial done in 19 hospitals in Spain. We recruited female patients aged at least 18 years with previously untreated, centrally confirmed HER2-positive, stage I–IIIA invasive breast cancer regardless of hormone receptor status. Patients were given lapatinib (1000 mg per day orally) and trastuzumab (loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks intravenously) for 18 weeks; hormone receptor-positive patients were additionally given letrozole (2·5 mg per day orally; if menopausal) or tamoxifen (20 mg per day orally; if premenopausal). Surgery was done 1–3 weeks after the last dose of study treatment. Intrinsic molecular subtypes of tumour biopsy samples taken at baseline (day 0) and day 14 were determined with the PAM50 predictor. The primary outcome was the ability of the HER2-enriched subtype to predict pathological complete response at the time of surgery. The primary outcome was assessed in the evaluable population (ie, all patients who had initial tumour biopsy samples available and who underwent definitive surgery) and safety was assessed in all patients who received at least one part of study treatment. This study is registered with ClinicalTrials.gov, number NCT01973660, and is completed. Between Oct 28, 2013, and Nov 26, 2015, we recruited 151 patients, of whom 14 (9%) discontinued treatment and 137 (91%) completed treatment as planned. At baseline, most patients had the HER2-enriched subtype (101 [67%]), followed by luminal A (22 [15%]), luminal B (16 [11%]), basal-like (nine [6%]), and normal-like (three [2%]) subtypes. At the time of surgery, 46 (30%, 95% CI 23–39) of 151 patients had pathological complete response in the breast. 41 (41%, 31–51) of 101 patients with the HER2-enriched subtype and five (10%, 4–23) of 50 patients with non-HER2-enriched subtypes achieved pathological complete response at the time of surgery (odds ratio 6·2, 95% CI 2·3–16·8; p=0·0004). The HER2-enriched subtype can identify patients with HER2-positive breast cancer who are likely to benefit from dual HER2 blockade therapies. GlaxoSmithKline, Susan Komen Foundation, CERCA Programme—Generalitat de Catalunya, Banco Bilbao Vizcaya Argentaria Foundation, Pas a Pas, and the Breast Cancer Research Foundation.

In patients with metastatic HER2-positive breast cancer that had progressed after primary therapy, treatment with the antibody–drug conjugate trastuzumab deruxtecan resulted in a higher response rate and longer progression-free survival than trastuzumab emtansine. Since trastuzumab deruxtecan was associated with interstitial pulmonary fibrosis, close monitoring of pulmonary function is warranted.

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.

PHERGain was designed to assess the feasibility, safety, and efficacy of a chemotherapy-free treatment based on a dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab in patients with HER2-positive early breast cancer (EBC). It used an 18fluorine-fluorodeoxyglucose-PET-based, pathological complete response (pCR)-adapted strategy. PHERGain was a randomised, open-label, phase 2 trial that took place in 45 hospitals in seven European countries. It randomly allocated patients in a 1:4 ratio with centrally confirmed, HER2-positive, stage I–IIIA invasive, operable breast cancer with at least one PET-evaluable lesion to either group A, where patients received docetaxel (75 mg/m2, intravenous), carboplatin (area under the curve 6 mg/mL per min, intravenous), trastuzumab (600 mg fixed dose, subcutaneous), and pertuzumab (840 mg loading dose followed by 420 mg maintenance doses, intravenous; TCHP), or group B, where patients received trastuzumab and pertuzumab with or without endocrine therapy, every 3 weeks. Random allocation was stratified by hormone receptor status. Centrally reviewed PET was conducted at baseline and after two treatment cycles. Patients in group B were treated according to on-treatment PET results. Patients in group B who were PET-responders continued with trastuzumab and pertuzumab with or without endocrine therapy for six cycles, while PET-non-responders were switched to receive six cycles of TCHP. After surgery, patients in group B who were PET-responders who did not achieve a pCR received six cycles of TCHP, and all patients completed up to 18 cycles of trastuzumab and pertuzumab. The primary endpoints were pCR in patients who were group B PET-responders after two treatment cycles (the results for which have been reported previously) and 3-year invasive disease-free survival (iDFS) in patients in group B. The study is registered with ClinicalTrials.gov (NCT03161353) and is ongoing. Between June 26, 2017, and April 24, 2019, a total of 356 patients were randomly allocated (71 patients in group A and 285 patients in group B), and 63 (89%) and 267 (94%) patients proceeded to surgery in groups A and B, respectively. At this second analysis (data cutoff: Nov 4, 2022), the median duration of follow-up was 43·3 months (range 0·0–63·0). In group B, the 3-year iDFS rate was 94·8% (95% CI 91·4–97·1; p=0·001), meeting the primary endpoint. No new safety signals were identified. Treatment-related adverse events and serious adverse events (SAEs) were numerically higher in patients allocated to group A than to group B (grade ≥3 62% vs 33%; SAEs 28% vs 14%). Group B PET-responders with pCR presented the lowest incidence of treatment-related grade 3 or higher adverse events (1%) without any SAEs. Among HER2-positive EBC patients, a PET-based, pCR-adapted strategy was associated with an excellent 3-year iDFS. This strategy identified about a third of patients who had HER2-positive EBC who could safely omit chemotherapy. F Hoffmann-La Roche.

In a randomized trial comparing pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel, the pertuzumab combination resulted in a median overall survival of 56 months in women with metastatic HER2-positive breast cancer. The overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer results in more aggressive disease with a poor prognosis. 1 The humanized anti-HER2 monoclonal antibodies pertuzumab and trastuzumab are more active in combination than alone because of more comprehensive signaling blockade. 2 , 3 We investigated combination therapy with docetaxel for first-line treatment of HER2-positive metastatic breast cancer in the Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) trial. Analysis of the primary end point showed that patients who received pertuzumab, trastuzumab, and docetaxel (pertuzumab group) had a significantly longer median progression-free survival, as assessed by independent reviewers, than did those . . .

Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants. Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8–7·8) in the buparlisib group versus 5·0 months (4·0–5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67–0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0–7·0) in the buparlisib group vs 4·5 months (3·3–5·0) in the placebo group (HR 0·80 [95% CI 0·68–0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9–7·1) in the buparlisib group versus 4·0 months (3·1–5·2) in the placebo group (HR 0·76 [0·60–0·97], one-sided p=0·014). The most common grade 3–4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [<1%]), and rash (45 [8%] vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [<1%] of 570) and increased aspartate aminotransferase (14 [2%] vs one [<1%]). No treatment-related deaths occurred. The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination. Novartis Pharmaceuticals Corporation.