First-line famitinib regimen active in advanced triple-negative breast cancer
The addition of famitinib to first-line camrelizumab and nab-paclitaxel appeared active among patients with immunomodulatory subtype advanced triple-negative breast cancer, according to results presented at the virtual ASCO Annual Meeting.
The regimen also exhibited a manageable toxicity profile, results of the prospective, single-arm, phase 2 FUTURE-C-PLUS trial showed.
“To our knowledge, this is the first prospective study to combine antiangiogenic, immune checkpoint inhibitors and chemotherapy in advanced triple-negative breast cancer,” Zhi-Ming Shao, MD, PhD, of Fudan University Shanghai Cancer Center in China, said during a presentation. “The confirmed objective response rates ... [are] the highest [observed to date in this treatment setting]. PFS improvement is promising.”
Triple-negative breast cancer offers limited therapeutic targets and is associated with poor prognosis. However, molecular subtyping and precision treatment can extend survival, Shao said.
The combination of camrelizumab (Jiangsu Hengrui Medicine) — an anti-PD-1 immune checkpoint inhibitor — and paclitaxel protein-bound particles for injectable suspension (Abraxane, Celgene), commonly called nab-paclitaxel, has demonstrated promising antitumor activity among patients with immunomodulatory subtype metastatic triple-negative breast cancer. Results of the FUTURE trial showed a 52.6% ORR among heavily pretreated patients.
Antiangiogenic agents have been shown to enhance response to immune checkpoint inhibitors, according to study background.
Shao and colleagues conducted the prospective, single-arm phase 2 FUTURE-C-PLUS trial to assess the efficacy and safety of a novel triplet combination of famitinib (Jiangsu Hengrui Medicine) — a tyrosine kinase inhibitor that targets VEGFR-2, PDGFR and c-kit — plus camrelizumab and nab-paclitaxel as first-line treatment for patients with immunomodulatory subtype advanced triple-negative breast cancer.
Researchers enrolled 48 adults (median age, 50 years; range, 18-70) with treatment-naive unresectable locally advanced or metastatic triple-negative breast cancer. All patients had immunomodulatory subtype disease, defined as CD8-positive by immunohistochemistry.
All patients had an ECOG performance status of 0 (37.5%) or 1 (62.5%); eligibility criteria allowed patients who received prior neoadjuvant chemotherapy to enroll provided they had a treatment-free interval of at least 6 months.
Nearly half (47.9%) of the cohort had at least three metastatic sites (lung, 50%; bone, 39.6%, only lymph node or soft tissue, 29.2%; liver, 20.6%; brain, 6.3%).
Patients received 200 mg camrelizumab via IV on days 1 and 15; nab-paclitaxel dosed at 100 mg/m2 via IV on days 1, 8 and 15; and 20 mg oral famitinib daily.
Treatment continued in 28-day cycles until disease progression, unacceptable toxicity or patient withdrawal. Unless patients experienced intolerable toxicity, they received at least six cycles of nab-paclitaxel.
ORR according to RECIST version 1.1 served as the primary endpoint. PFS, OS, duration of response and safety served as secondary endpoints.
Shao and colleagues also used targeted sequencing with a 484-gene panel to explore predictive biomarkers.
Forty-six patients had at least one post-baseline tumor assessment. As of data cutoff on April 30, 23 patients remained on treatment.
Median follow-up was 11.5 months.
Researchers reported a confirmed ORR of 81.3% (95% CI, 70.2-92.3) in the intention-to-treat population (n = 48) and 84.8% (95% CI, 74.4-95.2) in the per-protocol population (n = 46). Median time to response was 1.8 months (95% CI, 1.8-2).
In the intention-to-treat population, five patients (10.4%) achieved complete response, 34 (70.8%) achieved partial response, five (10.4%) had stable disease and two (4.2%) experienced disease progression.
PFS data had not matured by the time of analysis. However, researchers reported a 9-month PFS rate of 60.2% (95% CI, 43.2-77.3) and a 10-month PFS rate of 53.5% (95% CI, 37.6-69.3).
“Biomarker analysis of genomic events showed somatic mutations of baseline BACA1, KAT6A and PKD1 detected by next-generation sequencing panels could potentially predict response to therapy,” Shao said.
Median treatment exposure to each drug was eight cycles. Researchers observed no unexpected adverse events, and they characterized the triplet combination as relatively well-tolerated.
Forty-six patients (95.8%) experienced any-grade treatment-related adverse events, 24 (50%) experienced grade 3 or grade 4 events, and two (4.2%) experienced serious adverse events.
The most common grade 3 or grade 4 adverse events included neutropenia (33.4%), anemia (10.4%), febrile neutropenia (10.4%) and thrombocytopenia (8.4%).
Researchers reported no treatment-related deaths. Three patients (6.3%) discontinued treatment due to adverse events. Researchers reported 14 treatment interruptions due to adverse events — four (8.3%) with camrelizumab, six (12.5%) with nab-paclitaxel and four (8.3%) with famitinib.
The ongoing randomized phase 2 FUTURE-SUPER trial is designed to evaluate the efficacy and safety of multiple targeted treatments — including famitinib with PD-1 therapy and nab-paclitaxel — vs. traditional chemotherapy for patients with unresectable locally advanced or metastatic triple-negative breast cancer.
“Results ... are eagerly awaited,” Shao said.
Perspective
Back to TopIn recent years, we have seen important developments for our patients with metastatic triple-negative breast cancer. On one hand, we have checkpoint blockade plus chemotherapy for PD-L1-positive tumors. On the other, we have the first antibody-drug conjugate — sacituzumab govitecan (Trodelvy, Immunomedics) — for heavily pretreated patients.
These developments are critically important, but they come with new research questions, many of them regarding immuno-oncology (IO).
Everybody is waiting for biomarkers beyond PD-L1 or to use on top of PD-L1. Also, many studies are still focusing on whether we can make a cold triple-negative breast cancer hot, especially for those PD-L1-negative tumors because — in general — triple-negative breast cancer tumors are cold. Many research questions also are focusing on combination treatments, whether it be IO plus IO, IO plus an antibody-drug conjugate, or targeted treatment. However, there is still room for other approaches in metastatic triple-negative breast cancer.
In the FUTURE-C-PLUS trial, researchers used only CD8 count higher than 10% to select immunogenic triple-negative breast cancers. Treatment consisted of a triplet regimen — an anti-PD-1 agent, nab-paclitaxel and a relatively broad TKI. Not many trials follow this approach.
The 81% response rate was impressive. That is one of the strengths of this relatively small trial, and it definitely is worth follow-up. I also like the selection. Researchers used simple CD8 staining to select patients with immunogenic triple-negative breast cancer.
Still, we have questions. Validation definitely is required in larger cohorts, and I am glad to see a randomized version of this trial is ongoing.
What about the cutoff of CD8? Is 10% really the best cutoff to select patients with immunogenic disease? Is the impressive ORR related to triplet treatment, or is it driven by the fact researchers really were able to select patients with immunogenic triple-negative breast cancers?
Finally, I think it is time to investigate chemotherapy-free regimens for immunogenic triple-negative breast cancer. Can we leave out the taxane and simply give PD-1 blockade with anti-VEGF treatment, as is done now for renal cell carcinoma?
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Chen L, et al. Abstract 1007. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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