**13. Checkpoint inhibitors in combination with chemotherapy**

In the process of immunotherapy, a combination with chemotherapy may be synergistic. Chemotherapy has been demonstrated to promote tumor cell antigen release, prompt class I MHC molecules, neoantigens, and expression of PD-L1, and stimulate activation of dendritic cells, which could improve the immune response release after or in the course of Immune Checkpoint Inhibitor treatment [78–80]. Combination therapies of checkpoint inhibitors and chemotherapy have showed significant results in TNBC. Pembrolizumab's safety profile and clinical efficacy have been examined in most of the analysis on inhibition of PD1 in TNBC. In highly positive PD-L1, untreated mTNBC patients who obtained pembrolizumab in conjunction with chemotherapy (PAX, nab-paclitaxel, carboplatin/gemcitabine), interim evaluation of the phase 3 KEYNOTE-355 (NCT02819518) trial shows a substantial increase in PFS (5.6 vs. 9.7 months) [81]. Pembrolizumab in combination with the microtubule inhibitor eribulin mesylate in the KEYNOTE-150/ENHANCE 1 (NCT02513472) trial showed a 25.6 percent ORR with an average progression free survival of 4.1 months [82]. The TONIC trial (NCT02499367) phase 2 analyzed the effectiveness of PD1 with nivolumab in previously treated mTNBC patients. The ORR for nivolumab treatment followed by doxorubicin was 35%, compared to 23% for CIS and 17% for patients who did not receive prior chemotherapy, implying that chemotherapy would cause an inflamed tumor microenvironment [83]. For LA or mTNBC patients treated with atezolizumab in conjunction with nab-paclitaxel, the clinical study GP28328 (NCT01633970) phase 1b showed an ORR of 39.4% and an average PFS of 5.5 months (**Table 4**) [84].

The first randomized Phase 3 trial to show the effectiveness of atezolizumab in conjunction with nab-paclitaxel in metastatic TNBC patients which were not treated previously was IMpassion130 (NCT02425891) [80]. The FDA and the European Medicines Agency (EMA) approved atezolizumab in conjunction with nab-paclitaxel as a primary trearment for PD-L1-positive, uneradicably, locally advanced, or mTNBC in 2019. The IMpassion131 trial (NCT03125902) phase 3 will

#### *Drug Repurposing - Molecular Aspects and Therapeutic Applications*


#### **Table 4.**

*Trials evaluating the use of immune checkpoint inhibitor in combination with chemotherapy.*

assess the protection and effectiveness of atezolizumab in combination with PAX as a primary treatment in TNBC patients. The IMpassion 132 study (NCT03371017) examines the potential of previously treated, untreated, locally advanced and mTNBC patients who have not been eligible for the IMpassion130 trial may benefit from atezolizumab and chemotherapy (capecitabine, gemcitabine/carboplatin). Randomized study GeparNuevo (NCT02685059) phase 3 results demonstrated that durvalumab in conjunction with neoadjuvant chemotherapy based on taxaneanthracycline provides clinical benefits in early TNBC from 44% to 53% of pCR (pathological complete response) [85]. A neo-adjuvant chemotherapy (paclitaxel plus carboplatin) NSABP B-59 (NCT03281954) phase 3 is currently being recruited with atezolizumab, followed by atezolizumab adjuvant and chemotherapy. The Impassion031 (NCT03197935) trial, which combines atezolizumab neoadjuvent with concurrent nab-paclitaxel and chemotherapy based on anthracyclines in patients with an early stage TNBC, recently published interim results. Patients who were given atezolizumab in combination with chemotherapy had a pCR rate of 57.6%, compared to 41.1% in patients who obtained chemotherapy in combination with placebo [86].
