ASCO 2020 Heralds a Handful of Influential Data Across Breast Cancer Settings

Joyce A. O'Shaughnessy, MD

The 2020 ASCO Virtual Scientific Program delivered a number of important updates to the field of breast cancer, explained Joyce A. O'Shaughnessy, MD, chair of Breast Cancer Research and the Celebrating Women Chair in Breast Cancer at Baylor-Sammons Cancer Center, Texas Oncology.

During the 2020 ASCO Direct Highlights^TM webcast, a program developed by Physicians’ Education Resource^® (PER®), LLC, O’Shaughnessy, who is also chair of The US Oncology Network, and 2016 Giant of Cancer Care^® in Community Outreach, discussed these developments that span the neoadjuvant, adjuvant, and metastatic settings.

Neoadjuvant Setting

Arguably one of the most important trials to evaluate preoperative endocrine therapy in postmenopausal patients with estrogen receptor (ER)–positive, HER2-negative breast cancer was the phase 3 ALTERNATE trial, said O’Shaughnessy.

In the trial, investigators measured the percentage of patients with a Preoperative Endocrine Prognostic Index (PEPI) 0 score following 6 months of preoperative endocrine therapy, defined by pathologic T1/2 and pathologic N0 disease, Ki-67 score of less than or equal to 2.7%, and ER positivity.

Patients who had a Ki-67 greater than 10% 2 to 4 weeks after starting endocrine therapy and those who did not have a PEPI 0 score after surgery were switched to chemotherapy. Patients with a PEPI 0 score following surgery continued on endocrine therapy for an additional 4.5 years.

The results showed that the PEPI 0 score was similar whether patients received anastrozole (17.7%, n = 434), fulvestrant (Faslodex; 21.8%; n = 431), or anastrozole plus fulvestrant (20.0%, n = 434). This translated to an endocrine-sensitive disease rate of 18.6% (97.5% CI, 14.6%-23.2%), 22.7% (97.5% CI, 18.4%-27.6%), and 20.5% (97.5% CI, 16.3%-25.2%), respectively.¹

“This trial gives us license to utilize preoperative endocrine therapy and will tell us whether patients can forego chemotherapy because they’re going to do so well without it,” said O’Shaughnessy.

Adjuvant Setting

In the phase 3 KAITLIN trial, patients with early-stage HER2-positive node-positive or high-risk node-negative (T2+) breast cancer received 3 to 4 cycles of anthracyclines followed by a randomization to standard 12 weeks of taxane chemotherapy plus trastuzumab (Herceptin) and pertuzumab (Perjeta; AC-THP) versus ado-trastuzumab emtansine (T-DM1; Kadcyla) plus pertuzumab for 1 year (AC-KP).

The results showed that AC-KP did not lead to an improvement in invasive disease-free survival (iDFS) versus AC-THP in the node-positive population (HR, 0.97; 95% CI, 0.71-1.32; P =.8270) nor the intent-to-treat population (ITT; HR, 0.98; 95% CI, 0.72-1.32), failing to meet the coprimary end points of the trial.²

“There’s no real role right now for T-DM1 in the curative setting for women with early-stage HER2-positive breast cancer outside of the KATHERINE trial,” said O’Shaughnessy.

Also presented were long-term results of the phase 3 MINDACT trial which evaluated the 70-gene assay MammaPrint as guidance for adjuvant chemotherapy in patients with early-stage, ER–positive, HER2-negative breast cancer.

The design was such that patients with clinically and genomically low-risk disease received endocrine therapy alone, patients with clinically and genomically high-risk disease received chemotherapy and endocrine therapy, and patients with discordant clinical and genomic risk were randomized to receive chemotherapy plus endocrine therapy versus endocrine therapy alone.

Updated findings showed that endocrine therapy alone led to a 5-year rate of distant metastasis-free survival (MFS) of 95.1% (95% CI, 93.1%-96.6%) in clinically high-risk and genomically low-risk patients, confirming the primary positive results of the trial.³

Moreover, investigators showed a 2.6% absolute difference in distant MFS among clinically high-risk and genomically low-risk patients who received chemotherapy (92.0%; 95% CI, 89.6%-93.8%) versus not (89.4%; 95% CI, 86.8%-91.5%). Further analysis showed that patients 50 years of age or younger who received chemotherapy derived a 5% benefit in distant MFS at 8 years (93.6%; 95% CI, 89.3%-96.3%) versus those who did not (88.6%; 95% CI, 83.5%-92.3%). No difference was seen among patients older than 50 years, suggesting that chemotherapy can be safely omitted in postmenopausal women.

“It’s possible that this age dependent effect of chemotherapy benefit is due to chemotherapy-induced ovarian function suppression,” said O’Shaughnessy. “If we optimize the endocrine therapy using an LHRH analogue with either tamoxifen or an aromatase inhibitor, premenopausal patients will not get additional benefit from chemotherapy.”

Overall, the findings provide important information in further support of the use of the 70-gene assay in guiding treatment de-escalation in clinically high risk and genomically low-risk patients, said O’Shaughnessy.

Metastatic Disease

In the metastatic setting, O’Shaughnessy highlighted the results of the phase KEYNOTE-355 trial, which evaluated pembrolizumab (Keytruda) plus chemotherapy versus placebo plus chemotherapy in previously untreated patients with locally recurrent or metastatic triple-negative breast cancer (TNBC).

In the ITT population, the progression-free survival (PFS) was 7.5 months in the pembrolizumab arm versus 5.6 months in the placebo arm (HR, 0.82; 95% CI, 0.69-0.97). The 1-year PFS rates were 29.8% and 20.9%, respectively. Patients with a PD-L1 combined positive score (CPS) of 10 or greater derived similar benefit from pembrolizumab, with a PFS of 7.6 months (HR, 0.74; 95% CI, 0.61-0.90; P = .0014).⁴

Among patients with a PD-L1 CPS of 10 or greater, the PFS benefit was more pronounced with pembrolizumab, at 9.7 months (HR, 0.65; 95% CI, 0.49-0.86; P =.0012), meeting the prespecified boundary for significance. The 1-year PFS rates were 39.1% and 23.0%, respectively.

Whether an overall survival (OS) benefit will be observed with the combination in the PD-L1–positive population as was observed with the FDA-approved combination of atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) remains to be seen, said O’Shaughnessy.

Notably, patients with a disease-free interval (DFI) less than 12 months did not benefit from the addition of pembrolizumab to chemotherapy (HR, 1.00). Additionally, patients who received gemcitabine and carboplatin derived less benefit from pembrolizumab (HR, 0.77) than those who received a taxane (HR, 0.51). However, the protocol mandated that patients with a DFI less than 12 months had to receive gemcitabine and carboplatin, which is why the data are less impressive in that subgroup, said O’Shaughnessy.

Regarding safety, grade 3 to 5 immune-related adverse events (iRAEs) were reported in 5.2% of patients in the pembrolizumab arm versus 0% in the placebo arm, and there were no iRAEs that led to death in either arm.

When it comes to PARP inhibition, O’Shaughnessy cited the phase 2 TBCRC 048 trial, which evaluated olaparib (Lynparza) in patients with germline (n = 27) or somatic (n = 26) mutations in homologous recombination deficiency (HRD) genes.

The majority of patients were ER positive and HER2 negative, and received a median of 1 prior line of therapy in the metastatic setting. Of these patients, 93% had received prior CDK4/6 inhibition.

In the germline cohort, partial responses (PRs) were seen predominantly among patients with germline PALB2 mutations (82%; n = 11). The median time to response among all patients with germline mutations was 12 weeks (90% CI, 11-20), and the median duration of response (DOR) was 9 months (90% CI, 7.5-NA).⁵

In the somatic cohort, PRs were most common among patients with BRCA mutations (50%; n = 16). Among all patients with somatic mutations, the median time to response was 11 weeks (90% CI, 8-12), and the median DOR was 6.3 months (90% CI, 3-NA).

Although more data are needed to confirm the activity of olaparib in this setting, the results reported therein are worth discussing with patients, said O’Shaughnessy.

Though not practice-changing, the results of the phase 2 PARSIFAL trial demonstrated that endocrine-sensitive patients with metastatic ER–positive, HER2-negative breast cancer can receive fulvestrant or letrozole in combination with palbociclib (Ibrance) without sacrificing

PFS. The median PFS was 27.9 months and 32.8 months in the ITT population, respectively (HR, 1.13; 95% CI, 0.89-1.45). Similar rates of PFS were seen in patients with visceral disease versus not and recurrent disease versus de novo disease, regardless of endocrine therapy partner.⁶

“Most patients prefer all-oral therapy, and then we can utilize the fulvestrant in the second-line setting either by itself or in combination with everolimus or alpelisib (Piqray) as appropriate,” said O’Shaughnessy.

The phase 3 ECOG-ACRIN 2108 trial helped settle the debate regarding the value of early local therapy in patients with de novo metastatic disease with an intact primary tumor, explained O’Shaughnessy. The design was such that patients who did not have progressive distant disease following 4 to 8 months of systemic therapy continued systemic therapy or received early local treatment.

At a median follow-up of 54 months, the median OS was 54 months (HR, 1.09; 90% CI, 0.80-1.49; log-rank P =.63), showing no benefit with local regional therapy. Similar results were seen when broken down by subtype, explained O’Shaughnessy, who added that women with TNBC who received local therapy experienced worse OS versus those in the continued systemic therapy arm (HR, 3.50; 95% CI, 1.16-10.57). However, the rate of locoregional progression was 25.6% in the continued systemic therapy arm versus 10.2% in the early local therapy arm.⁷

“Based on available data, local regional therapy for the primary tumor should not be offered to women with stage IV breast cancer with the expectation of a survival benefit,” said O’Shaughnessy. “When systemic disease is well-controlled with systemic therapy, but the primary site is progressing, local regional therapy may be considered.”

The field also saw the results of the phase 2 BYLieve trial, which evaluated alpelisib plus fulvestrant in PIK3CA-mutated hormone receptor–positive, HER2-negative advanced breast cancer that progressed on prior CDK4/6 inhibition. The results showed that 50.4% of patients were alive and progression free at 6 months (n = 61),⁸ which was comparable to the 44.4% of patients who were alive and progression free at 6 months in the SOLAR-1 trial, explained O’Shaughnessy.

“These data really cement alpelisib as a standard of care for all PIK3CA-mutant patients who are progressing on CDK4/6 inhibitors,” said O’Shaughnessy.

The most notable data pertaining to patients with brain metastases came from the subset analysis of the phase 2 HER2CLIMB trial. Preliminary results from the trial showed that tucatinib (Tukysa) plus trastuzumab (Herceptin) and capecitabine led to a 46% reduction in the risk of progression or death (n = 480) and a 34% reduction in the risk of death (n = 612) in patients with previously treated HER2-positive metastatic breast cancer, as well as a 52% reduction in the risk of progression or death in those with brain metastases (n = 291).

In April 2020, the FDA approved the triplet for patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti–HER2-based regimens in the metastatic setting, based on data from the primary HER2CLIMB analysis.

The subset analysis showed that at 1 year, the rate of central nervous system (CNS)-PFS was 40.2% (95% CI, 29.5%-50.6%) in the tucatinib arm versus 0% in the control arm, translating to a 68% reduction in the risk of CNS progression or death (HR, 0.32; 95% CI, 0.22-0.48; P <.00001). The median CNS-PFS was 9.9 months (95% CI, 8.0-13.9) with the triplet versus 4.2 months (95% CI, 3.6-5.7) with the doublet.⁹

The 1-year OS rate was 70.1% (95% CI, 62.1%-76.7%) in the tucatinib arm versus 46.7% (95% CI, 33.9%-58.4%) in the placebo arm, translating to a 42% reduction in the risk of death (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months (95% CI, 15.5 to not evaluable [NE]) versus 12.0 months (95% CI, 11.2-15.2) in the tucatinib and placebo groups, respectively.

Among patients with active brain metastases, the risk of CNS progression or death was reduced by 64% with the addition of tucatinib, which showed a CNS-PFS rate of 35.0% (95% CI, 23.2%-47.0%) at 1 year versus 0% in the placebo arm (HR, 0.36; 95% CI, 0.22-0.57; P <.0001). The median CNS-PFS in patients with active brain metastases was 9.5 months (95% CI, 7.5-11.1) with tucatinib versus 4.1 months (95% CI,2.9-5.6) with placebo.

The risk of death was reduced by 51% with the addition of tucatinib in patients with active brain metastases (HR, 0.49; 95% CI, 0.30-0.80; P = .004). At 1 year, the OS rate was 71.7% (95% CI, 61.4%-79.7%) in the tucatinib arm versus 41.1% (95% CI, 25.5%-56.1%) in the placebo arm, and the median OS was 20.7 months (95% CI, 15.1-NE) and 11.6 months (95% CI, 10.5-13.8), respectively.

The confirmed intracranial objective response rate (ORR-IC) in patients with measurable intracranial disease was 47% (95% CI, 33.7%-61.2%) in the tucatinib arm versus 20% (95% CI, 5.7%-43.7%) in the placebo arm (P = .03). The median duration of intracranial response was 6.8 months (95% CI, 5.5-16.4) versus 3.0 months (95% CI, 3.0-10.3) in the tucatinib and placebo arms, respectively.

“This raises the question of whether we should do a brain MRI in the second-line setting, find patients with brain metastasis, and preferentially treat them with tucatinib,” said O’Shaughnessy. “I probably think the answer is yes.”

References

1. Ma CX, Suman VJ, Leitch AM, et al. ALTERNATE: Neoadjuvant endocrine treatment (NET) approaches for clinical stage II or III estrogen receptor-positive HER2-negative breast cancer (ER+ HER2- BC) in postmenopausal (PM) women: Alliance A011106. J Clin Oncol. 2020;38(15 suppl):504. doi:10.1200/JCO.2020.38.15_suppl.504

2. Harbeck N, Im SA, Barrios CH, et al. Primary analysis of KAITLIN: A phase III study of trastuzumab emtansine (T-DM1) + pertuzumab versus trastuzumab + pertuzumab + taxane, after anthracyclines as adjuvant therapy for high-risk HER2-positive early breast cancer (EBC). J Clin Oncol. 2020;38(15 suppl):500. doi:10.1200/JCO.2020.38.15_suppl.500

3. Cardoso F, van’t Veer L, Poncet C, et al. MINDACT: Long-term results of the large prospective trial testing the 70-gene signature MammaPrint as guidance for adjuvant chemotherapy in breast cancer patients. J Clin Oncol. 2020;38(15 suppl):506. doi:10.1200/JCO.2020.38.15_suppl.506

4. Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J Clin Oncol. 2020;38(15 suppl):1000. doi:10.1200/JCO.2020.38.15_suppl.1000

5. Tung NM, Robson ME, Ventz S, et al. TBCRC 048: A phase II study of olaparib monotherapy in metastatic breast cancer patients with germline or somatic mutations in DNA damage response (DDR) pathway genes (Olaparib Expanded). J Clin Oncol. 2020;38(15 suppl):1002. doi:10.1200/JCO.2020.38.15_suppl.1002

6. Llombart-Cussac A, Perez-Garcia JM, Bellet M, et al. PARSIFAL: A randomized, multicenter, open-label, phase II trial to evaluate palbociclib in combination with fulvestrant or letrozole in endocrine-sensitive patients with estrogen receptor (ER)[+}/HER2[-] metastatic breast cancer. J Clin Oncol. 2020;38(15 suppl):1007. doi:10.1200/JCO.2020.38.15_suppl.1007

7. Khan SA, Zhao F, Solin LJ, et al. A randomized phase III trial of systemic therapy plus early localy therapy versus systemic therapy alone in women with de novo stage IV breast cancer: A trial of the ECOG-ACRIN Research Group (E2108). J Clin Oncol. 2020;38(18 suppl):LBA2. doi:10.1200/JCO.2020.38.18_suppl.LBA2

8. Rugo H, Lerebours F, Ciruelos E, et al. Alpelisib. (ALP) + fulvestrant in patients (pts) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermanl growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results. J Clin Oncol. 2020;38(15 suppl):1006. doi:10.1200/JCO.2020.38.15_suppl.1006

9. Lin NU, Murthy RK, Anders CA, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). J Clin Oncol. 2020;38(15 suppl):1005. doi:10.1200/JCO.2020.38.15_suppl.1005