【原】欧洲肿瘤内科大会乳腺癌研究精选

　　2023年10月20日至24日，欧洲肿瘤内科学会第47届大会在西班牙马德里隆重召开，大约3.3万位来自世界各地的肿瘤学家出席此次盛会，发表研究报告多达2563篇，数量如此之多，难免让人眼花缭乱。

　　2023年10月27日，英国《柳叶刀》肿瘤学分册发表资深编辑杰西卡·德威尔精选本届大会12篇研究报告进行的报道，其中仅1篇乳腺癌研究报告：TROPION-Breast01，由美国哈佛大学医学院麻省总医院癌症中心肿瘤内科医师阿迪亚·巴尔迪亚博士亲临全体大会现场口头报告，介绍了全球第二个靶向滋养层细胞表面抗原TROP2的抗体缀合药物德达托泊他单抗（4个小分子拓扑异构酶抑制剂德鲁替康通过可被癌细胞溶酶体蛋白酶裂解的四肽连接分子缀合于1个大分子达托泊他单抗）二或三线治疗激素受体阳性HER2阴性乳腺癌无法手术或远处转移患者的有效性和安全性。中国工程院院士中国医学科学院肿瘤医院徐兵河、中山大学肿瘤防治中心王树森、台湾大学医学院附属医院卢彦伸、哈尔滨医科大学附属肿瘤医院张清媛等中国学者也参与了该研究。

　　此前一期临床研究TROPION-PanTumor01初步发现德达托泊他单抗对激素受体阳性HER2阴性乳腺癌无法手术或已转移患者有效。TROPION-Breast01为全球多中心非盲随机对照三期临床研究，将732例激素受体阳性HER2阴性乳腺癌无法手术或远处转移并且已接受一或二线化疗患者按1∶1的比例随机分为两组：德达托泊他单抗组365例，每3周给予德达托泊他单抗6mg/kg进行单药治疗；研究者选择化疗组367例，从四种化疗药物（艾立布林、长春瑞滨、卡培他滨、吉西他滨）选择其中之一进行单药治疗。治疗直至进展或出现无法耐受的毒性。双重主要终点为根据盲法独立集中评审得出的无进展生存和总生存。

　　结果，根据盲法独立集中评审，德达托泊他单抗组与研究者选择化疗组相比：

• 中位无进展生存：6.9个月比4.9个月（95%置信区间：5.7～7.4、4.2～5.5）
• 进展或死亡风险：减少37%（风险比：0.63，95%置信区间：0.52～0.76，P<0.0001）
• 中位总生存：尚未达到中位（总死亡率23%）
• 总死亡风险：减少16%（风险比：0.84，95%置信区间：0.62～1.14）
• ≥3级不良事件发生率：20.9%比44.7%

　　因此，该研究结果表明，对于激素受体阳性HER2阴性乳腺癌无法手术或远处转移并且已接受一或二线化疗患者，德达托泊他单抗与研究者选择化疗相比，无进展生存获得统计学显著且有临床意义的改善，总生存似乎也有改善趋势，≥3级不良事件发生率显著较低且易于管理，支持德达托泊他单抗作为治疗此类患者的新选择。

　　不知德达托泊他单抗的TROPION-Breast系列研究，能否像德曲妥珠单抗的DESTINY-Breast系列研究一样，在乳腺癌治疗领域获得势如破竹、所向披靡的成功？不知德达托泊他单抗将来是否会与全球第一个TROP2抗体缀合药物戈沙妥珠单抗正面展开头对头的随机对照研究？不过，德达托泊他单抗这次没有选择三阴性乳腺癌，也可能说明德达托泊他单抗与德曲妥珠单抗一样，对激素受体阴性乳腺癌信心不足，两代TROP2抗体缀合药物对于三阴性乳腺癌可能没有机会实现关公战秦琼，具体有待下回分解。

Lancet Oncol. 2023 Oct 27. IF: 51.1

ESMO Congress 2023.

Jessica E Dwyer.

The ESMO Congress 2023 was held in Madrid, Spain, on Oct 20-24, 2023

EV-302 in bladder cancer

EV-302, an international, randomised, phase 3 trial investigated the efficacy of enfortumab vedotin plus pembrolizumab versus chemotherapy in patients with untreated, locally advanced, metastatic urothelial carcinoma. Thomas B Powles (Barts Cancer Institute, London, UK) reported the final analysis of dual primary endpoints of progression-free survival by BICR and overall survival. After a median follow-up of 17.2 months, among the 442 patients randomly assigned to the experimental group and 444 to the chemotherapy group, progression free survival was significantly improved (12.5 months vs 6.3 months; HR 0.45 [95% CI 0.38-0.54]; p<0.0001) and median overall survival was almost doubled in the experimental group (31.5 months vs 16.1 months; HR 0.47 [0.38-0.58]; p<0.0001]). These results support enfortumab vedotin plus pembrolizumab as the new first-line standard of care.

Adjuvant pembrolizumab in NSCLC

Jonathan D Spicer (McGill University Health Centre, Montreal, QC, Canda) presented the second interim analysis results of KEYNOTE-671, a phase 3 trial, in which patients with resectable stage II, IIIA, or IIIB2 non-small-cell lung cancer (NSCLC) were randomly assigned (1:1) to receive neoadjuvant pembrolizumab (200 mg) plus cisplatin-based chemotherapy followed by resection and adjuvant pembrolizumab (n=397), or placebo plus chemotherapy plus adjuvant placebo following resection (n=400). At 36 months, the primary endpoint of overall survival was improved in the pembrolizumab group (71.3%) versus the placebo group (64.0%; hazard ratio [HR] 0.72 [95% CI 0.56-0.93]; p=0.0052). Treatment-related adverse events of grade 3 or worse occurred in 45.2% of patients with pembrolizumab versus 37.8% with placebo.

Tarlatamab for SCLC

The bispecific T-cell engager tarlatamab has shown a favourable benefit-to-risk profile in patients with previously treated small-cell lung cancer (SCLC), according to the phase 2 DeLLphi-301 study presented by Luis Paz-Ares (Hospital Universitario 12 de Octubre, Madrid, Spain). Patients received either 10 mg (n=100) or 100 mg (n=88) of tarlatamab once every 2 weeks, and after a median follow up of 10.6 months, the primary endpoint of objective response rate (ORR) in the 10 mg group was 40.0% (97.5% CI 29.1-51.7) and in the 100 mg group was 31.8% (21.1-41.1). The most common treatment-emergent adverse event was cytokine release syndrome (51.1% in the 10 mg group, 60.9% in the 100 mg group).

Senaparib maintenance therapy for ovarian cancer

In the double-blind, phase 3 FLAMES study, Xiaohua Wu (Fudan University, Shanghai, China) and colleagues randomly assigned (2:1) patients with ovarian cancer to either 100 mg per day of senaparib (n=271), a novel PARP inhibitor, or placebo (n=133), stratified by their response to chemotherapy and BRCA mutation status. After a median follow-up of 22.3 months, the primary endpoint of progression-free survival by blinded independent central review (BICR) was significantly improved in the senaparib versus the placebo group (median not reached vs 13.6 months; HR 0.43 [95% CI 0.32-0.58]; p<0.0001), irrespective of BRCA mutation status. Incidence of grade 3 or worse adverse events was 66.3% versus 20.3%, respectively.

Targeted therapy for grade 2 glioma

Vorasidenib is an oral brain-penetrating dual inhibitor of mutant IDH1 and IDH2 enzymes which occur in nearly all patients with grade 2 gliomas. Deborah Blumenthal (Tel-Aviv Medical Center, Tel Aviv, Israel) presented results of the double-blind, phase 3 INDIGO trial where patients with grade 2 gliomas with mutant IDH1/2 were randomly assigned (1:1) to receive vorasidenib 40 mg daily (n=168) or placebo (n=163). After a median follow-up of 14.2 months, the median radiographic progression-free survival (primary endpoint) was 27.7 months with vorasidenib and 11.1 months with placebo (HR 0.39 [95% CI 0.27-0.56; p<0.0001). Grade 3 or worse elevation of alanine aminotransferase levels were seen in 9.6% of patients with vorasidenib.

Double ADC for urothelial cancer

In the DAD phase 1 trial, presented by Bradley A McGregor (Dana-Farber Cancer Institute, Boston, MA, USA), patients with refractory, metastatic urothelial carcinoma were given the antibody drug conjugates (ADCs), sacituzumab govitecan plus enfortumab vedotin on days 1 and 8 of a 21-day cycle, with dose adjustments based on dose-limiting toxicities and the number of patients treated at each prespecified dose level (DL). 24 patients were enrolled (nine to DL1, nine to DL2, and six to DL3); 23 were evaluable for dose-limiting toxicity assessment. 70% of patients had grade 3 or worse adverse events. At DL3, among five evaluable patients, three dose-limiting toxicities were seen. Among 21 patients evaluable for response, 15 had an overall response (71% [90% CI 51-87]). DL2 was selected as the phase 2 dose.

Bispecific antibody sabestomig for NSCLC

Sabestomig (AZD7789) is a monovalent, bispecific humanised antibody targeting PD-1 and TIM-3. TIM-3 is highly expressed in NSCLC and has a potential role in resistance mechanisms against PD-1 blockade. Benjamin Besse (Institut Gustave Roussy, Villejuif, France) presented the dose escalation results of the multicentre, open-label, first-in-human phase 1/2a trial of sabestomig in patients with stage IIIB-IV NSCLC who had received at least one previous systemic therapy including an anti-PD-(L)1 agent. 39 patients received doses of 2-2000 mg. Treatment-related adverse events occurred in 41% of patients, and were all grade 1-2, the most common of which was asthenia (8%), and there were no dose-limiting toxicities. Among 19 patients with treatment scans, 7 had stable disease (including two with unconfirmed partial responses), 11 had progression, and one was not evaluable. Recruitment is ongoing for phase 1, and two expansion cohorts are planned.

Intravesical erdafitinib for bladder cancer

Oral administration of erdafitinib can result in substantial systemic toxicity. Antoni Vilaseca (Hospital Clinic de Barcelona, Barcelona, Spain) described results from a multicentre phase 1 trial of TAR-210—a novel intravesical drug delivery system that provides local, continuous release of erdafitinib directly into the bladder—in patients with non-muscle-invasive bladder cancer with select FGFR alterations. Among 11 patients with recurrent high-risk cancer who were ineligible for cystectomy, nine (81.8%) were recurrence free at 1 year. Among 15 patients with recurrent intermediate risk disease with a history of low-grade papillary disease, complete response was seen in 13 (86.7%) patients. There were no dose-limiting toxicities and treatment was well tolerated.

Dual mAbs for cervical cancer

Jung-Yun Lee (Severance Hospital Yonsei University Health System, Seoul, South Korea) presented primary analysis results of AdvanTIG-202, a randomised, open-label, phase 2 trial that investigated use of tislelizumab plus ociperlimab versus tislelizumab monotherapy in patients with previously treated recurrent or metastatic cervical cancer who were not amenable to curative treatment. After a median follow-up of 7.4 months, among 138 patients randomly assigned (1:1) to combination therapy, the primary endpoint of ORR was 22.5% (95% CI 15.8-30.3), and in those with PD-L1 positive tumours (n=84) it was 26.2% (17.2-36.9). 93 (67.4%) of 138 patients had at least one treatment-related adverse event, with 18 (13.0%) having a grade 3 or worse event.

Neoadjuvant IO for dMMR colon cancer

High pathological response has been seen in MMR deficient (dMMR) colon cancer with neoadjuvant nivolumab plus ipilimumab. The phase 1 NICHE-3 study investigated use of neoadjuvant nivolumab plus relatlimab in resectable, locally advanced, dMMR colon cancer. As presented by Yara L Verschoor (Netherlands Cancer Institute, Amsterdam, Netherlands), patients were given two doses of nivolumab 480 mg plus relatlimab 480 mg at a 4-week interval, followed by surgery. Among 19 patients who underwent treatment and surgery without delays, the primary endpoint of pathological response rate was 100%, with 79% showing complete response. Grade 1-2 immune-related adverse events were observed in 14 (74%) of 19 patients, one (5%) patient had a grade 3 event. Accrual for stage 2 of the trial is ongoing.

Dato-DXd in breast cancer

Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate that targets TROP2 and has previously shown activity in hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer. Aditya Bardia (Harvard Medical School, Boston, MA, USA) presented results of the global phase 3 TROPION-Breast01 trial, in which patients with inoperable or metastatic HR+/HER2- breast cancer were randomly assigned (1:1) to Dato-DxD or investigator's choice of chemotherapy. Among 732 patients (365 assigned to Dato-Dxd and 367 to chemotherapy), progression-free survival by BICR (dual primary endpoint) was significantly improved (median 6.9 months [95% CI 5.7-7.4] with Dato-Dxd vs 4.9 [4.2-5.5] with chemotherapy; HR 0.63 [0.52-0.76]; p<0.0001); data for overall survival (dual primary endpoint) were not mature. A lower proportion of patients had grade 3 or worse adverse events on Dato-Dxd than on chemotherapy (20.9% vs 44.7%).

MARIPOSA-2

The combination of the EGFR-MET bispecific antibody amivantamab and the EGFR tyrosine-kinase inhibitor lazertinib showed improved survival outcomes in patients with EGFR-mutated NSCLC, as presented by Antonio Passaro (European Institute of Oncology, IRCCS, Milan, Italy). In the phase 3 MARIPOSA-2 trial, patients who had disease progression after osimertinib were randomly assigned (2:1:2) to amivantamab plus chemotherapy with lazertinib or without lazertinib, or to chemotherapy alone. After a median follow-up of 8.7 months, progression-free survival by BICR was significantly improved in both experimental groups (without lazertinib [n=131] HR 0.48 [95% CI 0.36-0.64]; p<0.0001; with lazertinib [n=263] 0.44 [0.35-0.56]; p<0.0001) versus chemotherapy alone (n=263). Overall survival data were immature. Predominant adverse events in the experimental groups were haematological, and EGFR and MET related.

DOI: 10.1016/S1470-2045(23)00563-6