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Weekly Paclitaxel given concurrently with Durvalumab has a favorable safety profile in triple-negative metastatic breast cancer.

ABSTRACT: Therapeutic anti-PD-L1 antibodies are safe as a monotherapy, albeit with minimal efficacy in triple-negative breast cancer (TNBC). This trial aimed to test the safety and efficacy of Durvalumab and Paclitaxel in metastatic TNBC. In this open-label, one-arm trial, five cycles of weekly paclitaxel were delivered intravenously (IV) concurrent with Durvalumab that was given IV every 2 weeks. The combination was preceded by one cycle of paclitaxel alone, for immunological priming, followed by Durvalumab solo until disease progression or unacceptable toxicity. Between 2017 and 2019, 14 patients received at least one cycle of the combination therapy. The therapy was safe with no-dose limiting toxicity, except one case of skin lesions. Adverse events (AEs) were reported in 71% of patients, and there was no death due to the combination therapy. Regardless of grade, the most common AEs were headache and peripheral neuropathy, as each happened in four patients (29%), followed by fatigue and skin rash in three patients (21%) each. Grade 3/4 AEs were experienced by three patients (21%), with the most common being headache and anemia, which happened in two patients (14%). The confirmed objective response rate (ORR) was observed in five patients with a median duration of 10.0 months. Median Progression-free survival (PFS) and overall survival (OS) were 5 and 20.7 months, respectively. The combination of Durvalumab and Paclitaxel is safe, leaving room for additional agents. This is the first report on the combination of Durvalumab and Paclitaxel in the treatment of TNBC (NCT02628132).

SUBMITTER: Ghebeh H

PROVIDER: S-EPMC8476586 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Our study aimed to compare the efficacy and safety of nab-paclitaxel plus cisplatin (AP) with nab-paclitaxel plus gemcitabine (AG) in patients with metastatic breast cancer (MBC). We collected data from two single-arm, phase II MBC studies. In NCT01149798, seventy-three MBC patients received 125 mg/m2 nab-paclitaxel on days 1, 8 and 15 followed by 75 mg/m2 cisplatin on day 1 of a 28-day cycle. In NCT01550848, eighty-four MBC patients received 125 mg/m2 nab-paclitaxel and 800 mg/m2 gemcitabine on days 1, 8, and 15 of a 28-day cycle. The endpoints were the overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety profiles of these regimens. Among the 157 patients included, the ORR were 67.1% and 52.4% for the AP and AG arms, respectively (odds ratio [OR] = 0.246; hazard ratio [HR] = 1.485; 95% confidence interval [CI], 0.762-2.985). After median follow-up periods of 26.3 and 23.3 months in the AP and AG arms, the median PFS were 9.8 months (95%CI, 8.1-11.6) and 8.1 months (95%CI, 6.8-9.4), respectively, while the median OS were 26.9 months (95%CI, 22.4-31.4) and 25.5 months (95%CI, 19.3-31.4), respectively. Neither PFS nor OS adjusted for the number of metastases, occurrence of liver metastasis and chemotherapeutic lines differed significantly between the two arms (PFS:HR = 0.769; 95%CI, 0.541-1.092; p = 0.142; OS:HR = 0.686; 95%CI, 0.426-1.104; p = 0.120). However, PFS was significantly better with AP than with AG in metastatic triple-negative breast cancer (mTNBC) patients (HR = 0.308; 95%CI, 0.129-0.732; p = 0.008). Adverse events were more common with AP than with AG, except for edema and myalgia. Both regimens showed substantial efficacy and were tolerated well in MBC patients. mTNBC who received AP rather than AG showed longer PFS. However, adverse events were more common with AP. Thus, AP may be worth recommending to mTNBC, while AG may be a better alternative for MBC patients with other subtypes.

Project description:The absence of chemotherapeutic target hormone receptors in breast cancer is descriptive of the commonly known triple-negative breast cancer (TNBC) subtype. TNBC remains one of the most aggressive invasive breast cancers, with the highest mortality rates in African American women. Therefore, new drug therapies are continually being explored. Microtubule-targeting agents such as paclitaxel (Taxol) interfere with microtubules dynamics, induce mitotic arrest, and remain a first-in-class adjunct drug to treat TNBC. Recently, we synthesized a series of small molecules of substituted tetrahydroisoquinolines (THIQs). The lead compound of this series, with the most potent cytostatic effect, was identified as 4-Ethyl-N-(7-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl) benzamide (GM-4-53). In our previous work, GM-4-53 was similar to paclitaxel in its capacity to completely abrogate cell cycle in MDA-MB-231 TNBC cells, with the former not impairing tubulin depolymerization. Given that GM-4-53 is a cytostatic agent, and little is known about its mechanism of action, here, we elucidate differences and similarities to paclitaxel by evaluating whole-transcriptome microarray data in MDA-MB-231 cells. The data obtained show that both drugs were cytostatic at non-toxic concentrations and caused deformed morphological cytoskeletal enlargement in 2D cultures. In 3D cultures, the data show greater core penetration, observed by GM-4-53, than paclitaxel. In concentrations where the drugs entirely blocked the cell cycle, the transcriptome profile of the 48,226 genes analyzed (selection criteria: (p-value, FDR p-value < 0.05, fold change -2< and >2)), paclitaxel evoked 153 differentially expressed genes (DEGs), GM-4-53 evoked 243 DEGs, and, of these changes, 52/153 paclitaxel DEGs were also observed by GM-4-53, constituting a 34% overlap. The 52 DEGS analysis by String database indicates that these changes involve transcripts that influence microtubule spindle formation, chromosome segregation, mitosis/cell cycle, and transforming growth factor-β (TGF-β) signaling. Of interest, both drugs effectively downregulated "inhibitor of DNA binding, dominant negative helix-loop-helix" (ID) transcripts; ID1, ID3 and ID4, and amphiregulin (AREG) and epiregulin (EREG) transcripts, which play a formidable role in cell division. Given the efficient solubility of GM-4-53, its low molecular weight (MW; 296), and capacity to penetrate a small solid tumor mass and effectively block the cell cycle, this drug may have future therapeutic value in treating TNBC or other cancers. Future studies will be required to evaluate this drug in preclinical models.

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Weekly Paclitaxel given concurrently with Durvalumab has a favorable safety profile in triple-negative metastatic breast cancer.

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