Immunotherapies Spark Excitement in Triple-Negative Breast Cancer Treatment
THE USE OF IMMUNOTHERAPY approaches in triple-negative breast cancer (TNBC) has resulted in diverse breakthroughs that leverage immune checkpoint inhibitors (ICIs). Expanded use of ICIs has led to the identification of different molecular subtypes that can help develop individualized treatment plans. Investigators in numerous trials are exploring immunotherapy in combination with existing treatment modalities for TNBC.
A 2024 San Antonio Breast Cancer Symposium poster session focused on innovative immunotherapy approaches in TNBC.1 The session featured poster presentations summarized by Heather McArthur, MD, MPH; and Thomas Grinda, MD, MSc.
T he phase 3 KEYNOTE-355 trial (NCT02819518) demonstrated that in patients with advanced TNBC whose tumors expressed PD-L1 with a combined positive score (CPS) of 10 or more, adding pembrolizumab (Keytruda) to chemotherapy led to significantly longer overall survival (OS) than chemotherapy alone.2 “This benefit was only observed in patients who had PD-L1–positive tumors as defined by a CPS of greater than or equal to 10,” said McArthur, a professor in the Department of Internal Medicine, UT Southwestern Medical Center, and clinical director, breast cancer, and Komen Distinguished Chair in Clinical Breast Cancer Research at Harold C. Simmons Comprehensive Cancer Center in Dallas, Texas, during her session. “We have learned from the application of immunotherapy that the earlier we apply these strategies [in the course of the disease], the more likely they are to succeed. First-line approaches are critically important.”
The first poster in the session was from the phase 2 SPARK study (NCT04734262), which evaluated the combination of tislelizumab-jsgr (Tevimbra) with sitravatinib (MGCD516), with or without nab-paclitaxel (Abraxane), in patients with untreated locally recurrent or metastatic TNBC.3 Tislelizumab is a monoclonal antibody directed against PD-1, and sitravatinib is a spectrum-selective tyrosine kinase inhibitor (TKI). Primary end points were overall response rate (ORR) and treatment-related adverse events (TRAEs). Secondary end points were duration of response (DOR), disease-control rate (DCR), and progression-free survival (PFS).
McArthur focused on cohort C, which included patients (n = 37) who received all 3 agents. “The majority of responses are partial responses, but the net ORR is 75.7% with a DCR of 97.3%,” McArthur said. Although cross-study comparisons are discouraged, McArthur did point out that in KEYNOTE-355, the DCR was 56%.
Data showed a median PFS of 10.6 months (95% CI, 7.9-15.8) in all evaluable patients. Among patients with CD8+ disease or CD8–disease, respectively, the median PFS was 15.8 months and 9.1 months. Additionally, the median PFS was 12.3 months for patients with a PD-L1 CPS of 1 or higher and 10.6 months for those with a PD-L1 CPS of less than 1. The median OS was not reached at the time of analysis. At 1 year, the OS rate was 91.0% (95% CI, 74.6%-97.0%).
TRAEs were reported in 97.3% of patients, and 43.2% experienced grade 3 or higher TRAEs, the investigators noted. In particular, 8% of patients experienced palmar-plantar erythrodysesthesia; 11% had an elevated alanine aminotransferase level; and 3% of patients had low white blood counts, low neutrophils, elevated aspartate aminotransferase levels, urinary tract infections, or hypertension.
COMPLEMENT Trial
The second poster was a review of the phase 2 COMPLEMENT trial (NCT05174832), which evaluated cisplatin, nab-paclitaxel, and pembrolizumab in patients with previously untreated locally recurrent inoperable or metastatic TNBC.4 After undergoing this triplet therapy, patients clinically benefiting from the induction were randomly assigned to receive pembrolizumab with or without olaparib (Lynparza) in the maintenance phase.
On the May 31, 2024, data cutoff date, investigators reported that 52 patients had been enrolled. Twenty patients (38%) had a PD-L1 CPS of 10 or higher, and 32 patients (62%) had a CPS of less than 10. Four patients had a germline BRCA1/2 mutation.
At initial early-stage diagnosis, 41 patients (78.8%) had TNBC; 11 patients (21.2%) had hormone receptor positive disease that became TNBC at distant recurrence.4 Patients were randomly assigned evenly to the 2 arms. At the induction stage, the ORR was 86.5%, the median DOR was 60%, and the median time to response was 1.5 months.4 Preliminary results showed patients with conversion to TNBC obtained less clinical benefit from this maintenance strategy than patients without conversion (6.6 vs 12.3 months).
“The data look encouraging,” McArthur said. “It’s interesting to note that patients with conversion to TNBC, [ie,] those who initially have hormone receptor–positive disease, seem to derive less benefit from this maintenance strategy than those who were consistently triple negative. [That’s demonstrated by] the doubling of progression-free survival.”
BRIA-IMT Regimen
The third poster spotlighted the BRIA-IMT regimen, an allogeneic whole cell–based cancer vaccine (SV-BR-1-GM) in combination with ICIs that was explored in a phase 1/2 study (NCT03328026).5 Specifically, the regimen consisted of SV-BR-1-GM, retifanlimab-dlwr (Zynyz), and low-dose local pegylated interferon-α. “The combination elicited an overall survival benefit among [patients with] heavily pretreated metastatic breast cancer,” McArthur said.
The 54 patients who were enrolled had undergone a median 6 lines of prior therapy. Forty-four percent previously received an antibody-drug conjugate (ADC), 20% previously received immune therapy, and 63% had previously received a CDK4/6 inhibitor.
“A clinical benefit was observed in all subtypes of breast cancer and was potentially impressive in the HER2-positive cohort, although, notably, this was only observed in 2 patients in that cohort,” McArthur said.
Adverse events were mostly grade 1 and 2, with the most common being fatigue (18.5% of patients for both grade 1 and 2), injection site reaction (29.6% grade 1; 3.7% grade 2), and nausea (22% grade 1; 9.3% grade 2).
Regarding patients with intracranial metastasis (n = 8), the median OS was 13.7 months, median number of prior lines of therapy was 5, median number of prior lines of radiation was 3, and median number of prior surgeries was 2. “It seems that the vaccine, either as monotherapy or in combination with immunotherapy, had some intracranial activity, which is encouraging,” McArthur said. “These preliminary results will be confirmed in the ongoing randomized phase 3 pivotal registration trial NCT06072612.”
MUC-1 Vaccine Tecemotide
The final poster reviewed by McArthur involved the MUC-1 vaccine tecemotide, which was added to standard neoadjuvant systemic therapy in the phase 2 ABCSG (Austrian Breast & Colorectal Cancer Study Group) trial.6 The study evaluated the safety and efficacy of tecemotide in patients with early breast cancer.
In the trial, 400 patients in the intent-to-treat population were randomly assigned to receive standard of care plus tecemotide (n = 200) vs standard of care (n = 200). The safety analysis (n = 396) included 195 patients treated with the addition of tecemotide and 201 with standard of care alone.
The primary end point was residual cancer burden after surgery. Follow-up was available for 72% of patients, most of whom received chemotherapy (82%) and letrozole (Femara; 18%) in the neoadjuvant setting.
Previously, investigators had reported no difference in the residual cancer burden with and without tecemotide in endocrine and chemotherapy-treated subgroups. “Further, the addition of the vaccine did not affect overall pathologic complete response rates, MUC-1 expression, or tumor- infiltrating lymphocyte content,” McArthur said.
In this 7-year follow-up study, the exploratory end points favored standard of care plus tecemotide, justifying the need to further evaluate this strategy.
McArthur noted that strategies that target other elements of the tumor microenvironment beyond those mediated by PD-L1 also warrant further study. “Overall, PARP inhibitors with or without ICIs are an effective maintenance strategy for metastatic TNBC after platinum-based induction,” McArthur said. “Modern vaccine strategies show promise in both the advanced and early stage settings.”
Bispecific Antibodies
During his presentation,7 Thomas Grinda, MD, MSc, highlighted evaluations of ivonescimab,8 PM8002/BNT327,9 and AK10510 in the TNBC setting. In a phase 2 safety and efficacy study, adult patients were randomly assigned to receive 20 mg/kg of ivonescimab plus 90 mg/m2 of paclitaxel or 100 mg/m2 of nab-paclitaxel until disease progression or unacceptable toxicity.8 Ivonescimab is a tetravalent bispecific antibody targeting PD-1 and VEGF.
Primary end points were incidence and severity of adverse events and ORR. Secondary end points included DCR, DOR, and PFS. At data cutoff on September 30, 2024, 36 patients with locally advanced, unresectable or metastatic TNBC were enrolled in the study. Notable baseline characteristics of the cohort include a median age of 54.6 years (range, 35.4-73.3), 50% of patients had an ECOG performance status of 0 and 50% had an ECOG performance status of 1, 1 patient had brain metastases, 7 patients had liver metastases, and the majority (83.3%) had a PD-L1 CPS score of less than 10.8
The most common any-grade TRAEs with incidence greater than 20% were decrease in white blood cell count (69.4%), decrease in neutrophil count (55.6%), and increases in alanine aminotransferase and aspartate aminotransferase levels (50% each). Most common grade 3 or greater TRAEs were decrease in white blood cell count (22.2%), decrease in neutrophil count (19.4%), and increases in alanine aminotransferase and aspartate aminotransferase levels (5.6% each).8
Grinda, an assistant professor of medicine at Université Paris-Saclay and a medical oncologist in the Department of Medicine at Gustave Roussy in Villejuif, France, looked at the 3 posters collectively.
When reviewing outcomes, the ivonescimab trial8 demonstrated an ORR of 80.0% (95% CI, 63.1-91.1), the PM002/BNT327 trial9 had an ORR of 73.8% (95% CI, 58.0-86.1), and the AK105 trial10 had an ORR of 75.0% (95% CI, 58.8%-87.3%), he noted.
Median PFS for the 3 posters was 9.36 months (95% CI, 6.24-not evaluable), 13.5 months (95% CI, 9.4-19.3), and 10.6 months (95% CI, 7.59-10.69), respectively. “Significant antitumor activity and low primary resistance ORR and PFS seem independent of PD-L1 expression,” Grinda said.
Regarding safety, there were no incidences of TRAEs leading to discontinuation in the ivonescimab trial, 9.5% that led to discontinuation in the PM8002/BNT327 trial, and none in the AK105 trial. Any-grade decreased neutrophil counts were seen in 56%, 85%, and 51% of patients, respectively. Grade 3/4 decreased neutrophil counts were reported in 19%, 20%, and 21% of patients, respectively.
Grade 3/4 anemia was reported in 3%, 5%, and 2% of patients, respectively. Anygrade hepatoxicity has been reported in 50%, 28%, and 51% of patients, respectively, and grade 3/4 hepatotoxicity has been reported in 5.6%, less than 5%, and 10%, respectively.
“Toxicities have been mainly hematologic and hepatic so far,” Grinda said.
“Triplet combinations of taxanes, anti–PD-L1, and anti-VEGF are promising,” Grinda said. “We need comparative studies evaluating OS to confirm this triplet effect.”
REFERENCES
1. Poster spotlight 3: highlights on novel therapeutics. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. Accessed January 15, 2025.
2. Cortes J, Rugo HS, Cescon DW, et al; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387(3):217-226. doi:10.1056/NEJMoa2202809
3. Liu X, Sui X, Xu Y, et al. Tislelizumab plus sitravatinib and nab-paclitaxel in patients with untreated locally recurrent or metastatic triple negative breast cancer (TNBC): updated efficacy and safety results. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. PS3-01. Accessed January 16, 2025.
4. Gong C, Tao Z, Wang B, et al. Induction of cisplatin/Abraxane/pembrolizumab followed by pembrolizumab ± olaparib maintenance in triple-negative metastatic breast cancer patients (COMPLEMENT) – a randomized, open-label, phase II study. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. PS3-02. Accessed January 16, 2025.
5. Chumsri S, Nangia C, Barve M, et al. Overall survival results of BRIA-IMT allogenic whole cell-based cancer vaccine. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. Abstract PS3-04.
6. Singer CF, Hlauschek D, Pfeiler G, et al. Vaccination with MUC-1-targeting tecemotide improves survival of patients receiving neo-adjuvant chemotherapy for early breast cancer: results from the prospective randomized ABCSG 34 trial. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. Abstract PS3-03.
7. Poster spotlight 3: targeted powerhouses: the role of bispecific antibodies, TKIs, and ADCs in Breast Cancer. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. December 11, 2024. Accessed January 15, 2025.
8. Ouyang Q, Wang X, Tian C, et al. Evaluation of the safety and efficacy of ivonescimab in combination with chemotherapy as first-line treatment for triple-negative breast cancer. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. PS3-05. Accessed January 16, 2025.
9. Wu J, Zhang J, Tong Z, et al. Interim overall survival of patients with locally advanced or metastatic triple-negative breast cancer treated with first line PM8002/BNT327 in combination with nab-paclitaxel in Phase Ib/II study. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. PS3-08. Accessed January 16, 2025.
10. Sun T. A prospective phase 2 study on efficacy and safety of AK105, anlotinib combined with nab-paclitaxel (nab-P) as a first-line therapy in patients(pts) with advanced triple-negative breast cancer (TNBC). Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. PS3-06. Accessed January 16, 2025.
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