Anti-CTLA-4 in Breast Cancer
CTL-associated antigen 4 (CTLA-4) can interact with its target ligand, CD80 or CD86, thereby limiting T-cell activation.23,24 Therapeutic blockade of CTLA4 with monoclonal antibodies (mAbs) has been shown to enhance T-cell activation in vivo. Two humanized mAbs targeting CTLA-4, including tremelimumab and ipilimumab, are active in the clinic.25,26 Vonderheide et al provided the first evidence for the use of tremelimumab in breast cancer cases.27 In this Phase I study, tremelimumab in combination with exemestane was investigated in 26 advanced ER+ and/or PR+ BC cases. This combination was tolerable in these patients. At the maximum tolerated dose, there were no grade 3 or 4 treatment-related events. The best clinical response was stable disease ≥12 weeks in 11 patients (42%). In addition, the use of single-agent tremelimumab has not been evaluated in breast cancer patients.27 Ipilimumab is an FDA-approved antibody targeting CTLA-4 and has shown well tolerability and activity in metastatic melanoma. In a pilot study, preoperative treatment with ipilimumab alone or in combination with cryoablation was safe and feasible for patients with operable breast cancer without surgical delay.28 There have been no trials to establish the clinical feasibility and tolerability of monotherapy of humanized mAbs against CTLA-4 in metastatic breast cancer.
Clinical Progress of Combination Therapy with Immunotherapy in Metastatic Breast Cancer
Immune Checkpoint Therapy Plus Radiotherapy
Radiotherapy has a central role in the treatment of breast cancer. Although historically known to be immunosuppressive, emerging data have recognized that radiation can induce the immune response and inhibit the effect of existing immune checkpoints. The effects of radiotherapy on the immune system are through its contribution to immunogenic cell death, tumor neoantigen presentation, and cross-priming. Radiotherapy can significantly modulate tumor microenvironment and can also increase the percentage of antigen-experienced T cells and effector memory T cells.29,30 In preclinical TNBC models, Dovedi et al showed that low-dose fractionated radiotherapy could upregulate the expression of PD-L1 on tumor cells.31 The combination of radiation therapy and PD-1/PD-L1 signaling blockade generated effective antitumor immunity and long-term tumor control.31,32 Emerging clinical trials are currently ongoing to investigate the use of combined immunoradiotherapy in the treatment of breast cancer. A phase 1 pilot study (NCT02303366) aimed to describe the safety and biological effects of combining stereotactic ablative body radiosurgery (SABR) and pembrolizumab in patients with oligometastatic breast carcinoma. The study was completed normally, and we look forward to the final results. Another single-arm Phase II study (NCT02730130) evaluated the efficacy of pembrolizumab plus radiotherapy in patients with metastatic TNBC. 17 patients were enrolled. The median number of prior chemotherapy lines was 3. Pembrolizumab 200mg was administrated intravenously within 3 days of the first radiation fraction. The primary endpoint was overall survival at week 13. Finally, 9 patients were evaluated for efficacy at week 13. Three of them (33%) had a partial response. One patient (11%) had stable disease. 5 cases progressed after treatment. Both partial and stable responses were durable for at least 21 weeks. The combination was well-tolerated.33 Besides, a phase II trial (NCT02499367) from the Netherlands aims to investigate if short-term induction treatment with radiation could contribute to synergistic activity with nivolumab in TNBC patients. Its current status is recruiting.
In a poorly immunogenic metastatic mouse breast cancer model, treatment with local radiation and CTLA-4 blockade could induce significant anti-tumor immunity and prolong the survival of mice.34 Jiang et al evaluated the combination of local radiation and tremelimumab in patients with inoperable locally recurrent or metastatic breast cancer. The primary objective was to investigate the maximum tolerated dose (MTD) of combination therapy. The second objective was to evaluate clinical response. This trial has a great limitation that only 6 patients were recruited. One stable disease was achieved as the best response. Tremelimumab at 3mg/kg combined with radiation therapy appears to be well-tolerated. Due to the extremely small sample size, it is difficult to discern any definitive conclusion from this trial.35
Combination Therapy of Immunotherapy and Chemotherapy
The combination of chemotherapy may be synergistic in the process of immunotherapy. The rationale is that chemotherapy may induce the concomitant release of tumor antigens, a decrease of inhibitory immune cell populations, and an increase of cytokine mediators.36 Nab-paclitaxel is a rational partner and is thought to affect the activity of immunotherapy. A phase 1b clinical trial (NCT01633970) investigated the safety, tolerability and clinical activity of atezolizumab combined with nab-paclitaxel in metastatic TNBC. Thirty-three women with stage IV or locally recurrent TNBC were enrolled. The median follow-up time was 24.4 months. Patients were given concurrent intravenous atezolizumab and intravenous nab-paclitaxel. The primary endpoints were safety and tolerability. All patients (100%) had at least 1 treatment-related adverse event. About 24 patients (73%) had grade 3/4 adverse events. The toxicity of dual therapy was manageable. The ORR was 39.4% (95% CI, 22.9–57.9%), including 1 CR and 12 PRs. The DCR was 51.5% (95% CI, 33.5–69.2%). Conclusively, they detected a manageable toxicity profile and clinical efficacy of combination therapy in mTNBC. Large randomized clinical trials are needed to confirm its efficacy.37
IMpassion130 (NCT02425891) was the first randomized Phase III trial to demonstrate the efficacy of atezolizumab plus nab-paclitaxel in untreated metastatic TNBC. A total of 902 patients were enrolled from 41 countries, of which 38.6% from Europe, 25.5% from United States and Canada, 16.1% from Asia, 15.2% from Latin America and 4.7% from Australia. 902 patients were randomly assigned at a ratio of 1:1 to receive atezolizumab plus nab-paclitaxel or place plus nab-paclitaxel. Prior to treating patients with atezolizumab, tumor samples were evaluated for PD-L1 expression by immunohistochemical testing. PD-L1 expression was assessed in tumor-infiltrating immune cells as a percentage of tumor area (<1% [=PD-L1 negative] or ≥1% [=PD-L1 positive]). The primary endpoints was PFS and OS. The median PFS were 7.2 months in the combination group and 5.5 months in the monotherapy group (HR, 0.8; 95% CI, 0.69–0.92; p=0.002). Among patients displaying PD-L1-positivity, the median PFS was 7.5 months and 5.0 months, respectively (HR, 0.62; 95% CI, 0.49–0.78; p<0.001). In the interim OS analysis, the difference in OS did not reach significance in the intention-to-treat (ITT) population. Due to the hierarchical statistical analysis procedure, there was no formal testing of OS in the PD-L1-positive population. However, Kaplan-Meier analyses showed a meaningful improvement in the PD-L1-positive group: the OS hazard ratio was 0.62 (95% CI:0.45–0.86), and the median OS was 25.0 months in the atezolizumab-nab-paclitaxel group compared to 15.5 months in the placebo-nab-paclitaxel group. Recently, an updated OS analysis was reported at ASCO 2019.38 The updated interim OS analysis was consistent with the 1st analysis. The median OS data of ITT patients did not reach statistical significance, but a 7.0-month improvement in median OS was observed in PD-L1-positive patients with combination treatment compared with atezolizumab monotherapy. The combination regimen was tolerated and consistent with the known safety profiles of both drugs.39 These results led to accelerated FDA approval of atezolizumab in combination with nab-paclitaxel for patients with PD-L1-positive metastatic TNBC.
Eribulin mesylate in combination with pembrolizumab has been also investigated in patients with metastatic TNBC.40 The updated results of ENHANCE1 (NCT02513472) showed that the combination of eribulin and pembrolizumab resulted in an ORR of 26.4% (95% CI, 18.3–35.9). Treatment-emergent adverse events (TEAEs) for the combination group were similar to those observed in each therapy. Eribulin combined with pembrolizumab has shown efficacy in patients with mTNBC, regardless of PD-L1 expression or prior lines of chemotherapy. Of the 106 evaluable mTNBC patients, 49 were PD-L1-positive and the ORR was 30.6%. For patients with PD-L1-negative (n=49), the ORR was 22.4%. The results of ENHANCE 1 provide us with hope for studying the combination of eribulin and checkpoint inhibitors in the treatment of metastatic breast cancer. Doxorubicin and cyclophosphamide have been reported to induce immunogenic cell death and type 1 interferon immune responses in breast cancer. An ongoing trial (NCT03409198) is ongoing to evaluate Doxorubicin and cyclophosphamide combined with Ipilimumab and Nivolumab in patients with metastatic hormone receptor-positive breast cancer. Another ongoing phase II trial (NCT03095352) is underway to investigate pembrolizumab plus carboplatin compared to carboplatin alone in breast cancer with chest wall metastasis.
Combination Therapy of Immunotherapy and HER-2-Targeted Therapy
Preclinical studies have demonstrated that the combination of HER-2 and PD-L1 inhibitors has a synergistic effect in HER-2-positive breast cancer.41 Besides, Tregs were found to be increased in HER-2-positive breast cancer patients who failed to achieve pCR, which displays the development of an immunosuppressive phenotype.42 Trastuzumab has been reported to modulate immune activity, mediate antibody-dependent cellular cytotoxicity (ADCC) and promote T-cell response.43 Clinically, data from the PANACEA study (NCT02129556) demonstrated the durable clinical benefit of pembrolizumab plus trastuzumab in patients with PD-L1-positive, trastuzumab-resistant, advanced, HER-2-positive breast cancer. In this single-arm, multicenter trial, 6 patients were enrolled in phase 1b and 52 patients in Phase 2. For the phase 1b trial, no dose-limiting toxicities were tested. In the phase 2 trial, six of the forty PD-L1-positive patients achieved an objective response when treated with the flat dose of pembrolizumab plus standard trastuzumab. However, in PD-L1-negative tumors, there were no objective responders. Pembrolizumab combined with trastuzumab was well tolerated and had durable anti-tumor activity in patients with PD-L1-positive tumors.44 Besides, the use of pembrolizumab in combination with carboplatin and trastuzumab for advanced HER-2-positive breast cancer is being evaluated in a randomized phase II trial (NCT03095352).
The KATE2 trial was the first study to study atezolizumab combined with trastuzumab emtansine (T-DM1) in previously treated HER-2-positive metastatic breast cancer (NCT02924883). Of the 202 patients who progressed after treatment with trastuzumab and a taxane, they were randomly assigned in a 2:1 manner to receive atezolizumab or placebo plus TDM1. The primary endpoint was investigator-assessed PFS. The KATE2 trial revealed no statistically significant difference in PFS among ITT population who received atezolizumab plus TDM1 (PFS was 8.2 months; 95% CI 5.8–10.7) relative to placebo plus TDM1 (PFS: 6.8 months, 95% CI 4.0–11.1) (HR was 0.82; 95% CI 0.55–1.23; p=0.3332). The combination group did not demonstrate a clinically significant PFS benefit when compared with TDM1 monotherapy.45 At the 2019 ESMO Congress, the final analysis of KATE2 for efficacy and safety was updated. In the ITT population, 1-year OS was 89% in both groups. In the PD-L1 immune cell-positive subgroup, the 1-year OS data was numerically higher in the atezolizumab plus TDM1 arm than in the placebo plus TDM1 arm (1-year survival rate of 94% vs 88%; HR=0.74, 95% CI: 0.42–1.30).46 Grade 3–5 adverse events occurred in 52.6% of those who received atezolizumab versus 44.8% who received placebo. Further, atezolizumab in combination with T-DM1 or with trastuzumab and pertuzumab are also being evaluated in patients with HER-2-positive breast cancer by a phase 1b, open-label study (NCT02605915). A single-arm, phase 2a clinical trial investigated the safety and efficacy of combining atezolizumab with paclitaxel, trastuzumab, and pertuzumab in patients with locally advanced or metastatic HER-2-positive breast cancer (NCT03125928).
A phase 1 study assessed the safety and clinical activity of durvalumab and trastuzumab in heavily pretreated HER-2-positive MBC patients. Patients were enrolled on a standard 3+3 dose escalation schedule. 14 patients who had <1% PD-L1 expression were evaluable for the response. There was no dose-limiting toxicities at dose level 1 (n=6) or dose expansion (n=9) during cycle 1. No responses were observed, only with 29% patients showing stable disease at week 6. In this phase 1 trial, no significant efficacy was detected in heavily pre-treated HER-2 positive MBC patients.47
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