O’Shaughnessy Spotlights Key Updates in Triple-Negative Breast Cancer

The treatment landscape of triple-negative breast cancer (TNBC) has undergone substantial growth in 2020, said Joyce A. O’Shaughnessy, MD, who noted that updates in the metastatic and neoadjuvant settings have added to the utilization of new standards of care.

During a 2020 Institutional Perspectives in Cancer webinar on breast cancer, O’Shaughnessy, cochair of Breast Cancer Research and chair of breast cancer prevention research at Baylor-Sammons Cancer Center of Texas Oncology, as well as the 2016 Giant of Cancer Care^® winner in Community Outreach, highlighted some of the most exciting updates in TNBC that emerged in 2020.

Frontline Immunotherapy

At the European Society for Medical Oncology (ESMO) Virtual Congress 2020, the final overall survival (OS) data from the phase 3 IMpassion130 trial (NCT02425891) demonstrated a clinically meaningful benefit for patients with PD-L1– positive metastatic TNBC who received first-line atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) versus placebo plus nab-paclitaxel.¹ Although OS was not statistically significant in the intention-to-treat (ITT) population, patients with PD-L1–positive TNBC by immunohistochemistry had a median OS of 25.4 months (95% CI, 19.6-30.7) with the addition of atezolizumab compared with 17.9 months (95% CI, 13.6-20.3) with placebo, translating to 3-year OS rates of 36% and 22%, respectively (stratified HR, 0.67; 95% CI, 0.53-0.86).

“Survival in IMpassion130 has really held up and has become the standard of care in the PD-L1[–positive] population,” said O’Shaughnessy. “We have to know PD-L1 status when our patients recur with metastatic [TNBC].”

Conversely, the phase 3 IMpassion131 trial (NCT03125902) failed to show a survival advantage with paclitaxel plus atezolizumab versus paclitaxel plus placebo in the ITT or PD-L1–positive population.² In September 2020, the FDA issued an alert that practitioners should not substitute paclitaxel protein-bound with paclitaxel in clinical practice.³

Additionally, the phase 3 KEYNOTE-355 trial (NCT02819518) showed a progression-free survival (PFS) advantage with pembrolizumab (Keytruda) plus several chemotherapy partners in the ITT population of patients with TNBC, as well as in PD-L1–positive (combined positive score [CPS] ≥1) patients.4 Moreover, the addition of pembrolizumab translated to a PFS benefit for patients with a PD-L1 CPS score of 10 or greater compared with chemotherapy alone (9.7 vs 5.6 months, respectively; HR, 0.65; 95% CI, 0.49- 0.86; P = .0012).

During the 2020 San Antonio Breast Cancer Symposium (SABCS), findings from subgroup analyses of the KEYNOTE355 trial showed that frontline pembrolizumab plus chemotherapy induced clinical benefit across patient subgroups, including those with PD-L1 expression by combined positive score compared with chemotherapy alone.⁵

In November 2020, the FDA granted an accelerated approval to pembrolizumab in combination with chemotherapy for the treatment of patients with locally recurrent, unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥ 10), based on findings from the KEYNOTE-355 trial.

Neoadjuvant Therapy

In the preoperative setting, results of the randomized phase 3 IMpassion031 trial (NCT03197935) showed improvements in pathologic complete response (pCR) rates with atezolizumab plus nab-paclitaxel, followed by atezolizumab plus doxorubicin Adriamycin and cyclophosphamide (AC), with subsequent surgery and atezolizumab, versus nab-paclitaxel plus placebo, followed by AC plus placebo, prior to surgery and observation in patients with TNBC whose primary tumor measured larger than 2 cm.⁶

Notably, the benefit was observed in the ITT population (pCR, 57.6% vs 41.1%, respectively) and was seen irrespective of PD-L1 status (positive, 68.8% vs 49.3%, respectively; negative, 47.7% vs 34.4%, respectively).

These findings were corroborated by results of the KEYNOTE-522 trial (NCT03036488), which evaluated a similar schema with pembrolizumab. In KEYNOTE-522, the pCR rates were 64.8% with pembrolizumab plus chemotherapy versus 51.2% with placebo plus chemotherapy in the ITT population; 68.9% versus 54.9%, respectively, in the PD-L1–positive population; and 45.3% versus 30.3%, respectively, in the PD-L1–negative population.⁷ Notably, patients with positive nodes achieved an absolute benefit of 20.6% with the addition of pembrolizumab (64.8% vs 44.1%, respectively; node negative, 64.9% vs 58.6%, respectively).

Additionally, the negative findings of the phase 3 NeoTRIP trial (NCT02620280) of nab-paclitaxel and carboplatin with or without atezolizumab shed light on the potential need to include doxorubicin in neoadjuvant strategies.⁸

“[The NeoTRIP] regimen lacked doxorubicin, which can favorably impact the immune microenvironment and make the tumor cells more immunogenic. It is thought that that may explain why NeoTRIP was negative but [IMpassion031 and KEYNOTE-522] were positive,” O’Shaughnessy said.

PARP Inhibitors

The PARP inhibitors olaparib (Lynparza) and talazoparib (Talzenna) have been welcome additions to the treatment armamentarium for patients with deleterious or suspected deleterious germline BRCA-mutant, HER2-negative, metastatic breast cancer, explained O’Shaughnessy. In TNBC, findings from the phase 3 OlympiAD (NCT02000622) and EMBRACA (NCT01945775) trials, evaluating the agents respectively, showed PFS benefits with the PARP inhibitors compared with physician’s choice of chemotherapy.^9,10

However, OS benefit was not found to be statistically significant in either trial.^11,12 Additionally, extended follow-up of the OlympiAD trial confirmed that the differences observed in the survival curves with olaparib versus chemotherapy were not statistically significant in the overall population.¹³ No benefit was observed irrespective of tissue receptor subtype, prior chemotherapy, or prior exposure to platinum-based chemotherapy regimens.

“We do want to be using the PARP inhibitors as soon as we can in the metastatic, germline BRCA[-mutant], HER2-negative population, whether [tumors are] triple negative or [estrogen receptor] positive,” explained O’Shaughnessy. “We want to get germline BRCA analyses on all our patients, regardless of age and family history, if they have HER2-negative breast cancer.”

Regarding safety, patients on olaparib had more anemia, vomiting, nausea, fatigue, headache, and cough compared with patients on chemotherapy. Mainly hematologic toxicities were observed with talazoparib in the EMBRACA trial, including anemia, neutropenia, and thrombocytopenia.

Additionally, findings from the randomized phase 3 BROCADE3 trial (NCT02163694) showed that veliparib, coadministered with carboplatin and paclitaxel, increased PFS in women with hormone receptor–positive breast cancer and TNBC who harbored a germline BRCA1/2 mutation.¹⁴

Patients who stopped chemotherapy after a mean of 11 cycles and continued on veliparib as monotherapy had a 36-month PFS rate of 26% compared with 11% of patients who remained on the control regimen (HR, 0.705; 95% CI, 0.566-0.877; P = .002). As such, the results suggest that maintenance veliparib confers a PFS benefit for patients versus chemotherapy, said O’Shaughnessy.

Sacituzumab Govitecan

In April 2020, the FDA granted an accelerated approval to sacituzumab govitecan-hziy (Trodelvy), a novel Trop-2– directed antibody-drug conjugate (ADC), for the treatment of patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease.

The approval was based on findings from a phase 1/2 trial that demonstrated an objective response rate of 33.3% by local assessment and a median duration of response of 7.7 months with the agent.¹⁵

Trop-2 is ubiquitously expressed on TNBC cells, which allows sacituzumab govitecan to be used more widely, O’Shaughnessy explained.

Results of the confirmatory phase 3 ASCENT trial (NCT02574455), which were presented virtually during the ESMO Virtual Congress 2020, revealed that sacituzumab govitecan induced an absolute PFS benefit of 3.9 months compared with physician’s choice of treatment (5.6 vs 1.7 months; HR, 0.41; 95% CI, 0.32-0.52; P < .0001).¹⁶ Additionally, the ADC led to an absolute OS benefit of 5.4 months versus physician’s choice of treatment (12.1 vs 6.7 months; HR, 0.48; 95% CI, 0.38-0.59; P < .0001).

Regarding safety, 4.7% of patients on sacituzumab govitecan experienced an adverse event that led to treatment discontinuation. Moreover, no severe cardiotoxicity, grade 3 or greater neuropathy, or grade 4 or greater interstitial lung disease events were observed.

Furthermore, during the 2020 SABCS, data from a subgroup analysis of the ASCENT trial were presented virtually, showing that sacituzumab govitecan increased ORR and PFS compared with chemotherapy among patients with metastatic TNBC who had stable brain metastases.¹⁷ A biomarker analysis of the trial revealed that sacituzumab govitecan induced clinical benefit compared with physician’s choice of therapy for patients with metastatic TNBC, irrespective of Trop-2 expression.¹⁸ Patients with median or high Trop-2 scores derived greater efficacy from the ADC.

Currently, sacituzumab govitecan is being evaluated in the ongoing SASCIA trial (NCT04595565) for patients with HER2- negative early-stage breast cancer who have had at least 16 weeks of taxane-based neoadjuvant chemotherapy versus physician’s choice of treatment.¹⁹ Pending positive results, this trial could bring the novel ADC into the curative setting for patients, O’Shaughnessy concluded. 

References

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