Immunotherapeutics in breast cancer will likely not be limited to late-stage triple-negative breast cancer. Earlier lines, combination regimens, and expansion into different disease subtypes should become part of this emerging landscape, according to Hope S. Rugo, MD, FASCO, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.
Hope S. Rugo, MD, FASCO
Clinical evidence of immune responsiveness to checkpoint inhibition in triple-negative breast cancer is being solidified by a growing body of data. However, the efficacy of these agents in breast cancer will not stop with this subtype, predicted Dr. Rugo.
“Immunotherapy has clearly come of age in breast cancer,” Dr. Rugo said at the 2020 Miami Breast Cancer Conference.1 “Its role in HER2-positive and estrogen-receptor positive disease is actively being explored. We have a lot of exciting trials.”
Importance of Tumor-Infiltrating Lymphocytes
With a better understanding of breast cancer biology, the historical view of this malignancy as having low immunogenic potential began to change. Discussing the tumor immune microenvironment, Dr. Rugo noted the importance of tumor-infiltrating lymphocytes. The concentration of these key determinants of tumor immunogenicity varies by subtype, with high concentrations seen most often in triple-negative breast cancer, followed by HER2-positive, and then estrogen receptor–positive tumors.
These differences are associated with response. The fact that the concentration of tumor-infiltrating lymphocytes is predictive of disease-free and overall survival in untreated node-negative triple-negative breast cancer and in HER2-positive breast cancer “is quite remarkable,” Dr. Rugo commented. In fact, some breast cancer experts maintain that tumor-infiltrating lymphocytes should become part of the evaluation of early-stage triple-negative breast cancer, she said. “Of course, at present, we have no way to put that information into practice.”
Anti–PD-1/PD-L1 Agents: Where Is the Benefit?
As Dr. Rugo pointed out, some important lessons have been learned in the use of immunotherapy for breast cancer; the line of therapy, the expression of programmed cell death protein ligand 1 (PD-L1), and the addition of chemotherapy to the checkpoint inhibitor all matter. “Tumors become less immunosensitive or immunologically responsive over time as they garner mutations and have genomic chaos with disease progression… And chemotherapy might improve response, because it makes the tumor look more foreign to the immune system,” she explained.
These factors were evident in IMpassion130, which evaluated atezolizumab plus nab-paclitaxel in patients with previously untreated, metastatic triple-negative breast cancer.2 In the primary analysis of the intent-to-treat population, there was a signal of efficacy with the combination in progression-free survival ((hazard ratio [HR] = 0.80; P = .0025), but not in overall survival.
On further evaluation of the prespecified PD-L1–positive population using the SP142 antibody (with a cutoff of 1% being positive), the benefit in progression-free survival and—although not defined by the study statistical plan—in overall survival, appeared to be limited to the 41% of patients with tumor PD-L1–positive immune cells. Patients with PD-L1–negative tumors derived no benefit from atezolizumab.
In the post hoc analysis presented by Dr. Rugo at the European Society for Medical Oncology (ESMO) Congress 2019,3 in patients with PD-L1–positive tumors by the SP142 assay, the median overall survival was 25 months with atezolizumab/nab-paclitaxel vs 18 months with nab-paclitaxel alone (HR = 0.71; 95% CI = 0.54–0.93). Again, no benefit was shown with atezolizumab in patients with PD-L1–negative disease.
Dr. Rugo commented: “With longer follow-up, the survival improvement in patients who had PD-L1–positive disease was 7 months, which is very impressive…. Regardless of whether you checked the PD-L1 status in the primary or metastatic tissue, progression-free survival and overall survival were similarly improved in patients who received atezolizumab.”
“This is the first treatment to improve survival, other than chemotherapy, for triple-negative, metastatic breast cancer,” Dr. Rugo noted. The U.S. Food and Drug Association approved the combination in March 2019.
Role for Maintenance Checkpoint Inhibition?
Another recent study, SAFIR-02, evaluated the PD-L1 inhibitor durvalumab as maintenance therapy after response to induction chemotherapy or stable disease in patients with triple-negative breast cancer or PD-L1–positive tumors.4 Overall, patients fared no better with durvalumab than with continued chemotherapy, but in patients with triple-negative breast cancer and in those with PD-L1–positive tumors, durvalumab significantly improved overall survival. The median survival was 21 months with durvalumab and 14 months with maintenance chemotherapy (HR = 0.54; P = .0377) in the triple-negative breast cancer cohort and 26 months vs 12 months, respectively, in the PD-L1–positive cohort (HR = 0.42; P = .0552).
“The role of immunotherapy in HER2-positive and estrogen receptor–positive disease is actively being explored. We have a lot of exciting trials.”— Hope S. Rugo, MD, FASCO
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“In the groups of patients who had triple-negative or PD-L1–positive breast cancer (most of whom had triple-negative disease), there seemed to be a marked, really quite dramatic, improvement in overall survival,” Dr. Rugo noted. “These numbers are small, but it is encouraging that there may be a role for maintenance immunotherapy.”
Studies indicate that the expression of both PD-L1 and tumor-infiltrating lymphocytes is reduced as tumors progress from early- to late-stage disease. Initiating immunotherapy early—even in the neoadjuvant setting—may be the best use of these agents, but studies of this approach have yielded inconsistent results.
The recent KEYNOTE-522 trial evaluated conventional neoadjuvant therapy plus pembrolizumab in 1,174 patients with newly diagnosed triple-negative breast cancer.5 Patients were randomly assigned to four cycles of pembrolizumab or placebo plus paclitaxel/carboplatin followed by an additional four cycles of pembrolizumab or placebo plus doxorubicin or epirubicin and cyclophosphamide, followed after surgery by adjuvant pembrolizumab or placebo.
For the primary endpoint—pathologic complete response (ypT0/Tis ypN0) in the first 602 patients—a significant advantage was shown with pembrolizumab/chemotherapy (64.8% vs 51.2%; P = .00055). In patients with node-positive disease, the difference vs placebo/chemotherapy was even greater—20.6%—while dropping to 6.3% among those with node-negative disease. “It does suggest the more cancer you have, potentially the more you need immunotherapy to boost the chemotherapy response,” Dr. Rugo stated.
With short follow-up (15 months), event-free survival is trending toward pembrolizumab/chemotherapy (91.3%) vs chemotherapy/placebo (85.3%; HR = 0.63). Although more pembrolizumab-treated patients discontinued treatment, “they still saw a dramatic difference in pathologic complete response…. So, some exposure to immunotherapy is better than none,” noted Dr. Rugo.
In the GeparNuevo study, patents with triple-negative breast cancer received neoadjuvant durvalumab or placebo every 4 weeks plus nab-paclitaxel followed by standard epirubicin/cyclophosphamide.6 The study also included a “window phase” in which durvalumab or placebo was given for 2 weeks, followed by a core biopsy, and then nab-paclitaxel. A benefit for durvalumab was seen only in the window cohort, where the pathologic complete response rate was 61.0% vs 41.4% (P = .035) before the start of chemotherapy.
The neoadjuvant NeoTRIP trial also did not demonstrate a pathologic complete response benefit in patients with early high-risk or locally advanced triple-negative breast cancer receiving atezolizumab plus chemotherapy followed by surgery and adjuvant chemotherapy.7 However, in the I-SPY2 trial, pembrolizumab (given with paclitaxel) “graduated” for efficacy in HER2-negative cohorts.8
Dr. Rugo commented on these inconsistent results: “My take is that anthracyclines and disease stage are key factors in determining benefit from neoadjuvant checkpoint inhibitor therapy. And PD-L1 status may not matter when the immune system is intact.”
Another factor associated with immunotherapy outcomes after neoadjuvant therapy may be the concentration of tumor-infiltrating lymphocytes. A recent analysis of 2,210 patients with early-stage triple-negative breast cancer treated with chemotherapy showed that those with high concentrations of tumor-infiltrating lymphocytes had very good long-term outcomes, particularly those with negative lymph nodes.9 Such information could help to select patients who will need immunotherapy to improve their outcomes. “We may be able to separate out groups of patients using these and other factors,” Dr. Rugo said.
There are numerous phase III trials of programmed cell death protein 1 (PD-1)/PD-L1 inhibitors in triple-negative breast cancer in the neoadjuvant, adjuvant, and metastatic settings, using a variety of chemotherapy backbones to identify optimal combinations. One particularly interesting study, the phase II adaptive TONIC trial, found the highest response rates occurred after induction with doxorubicin (35%) or cisplatin (23%) followed by nivolumab/doxorubicin.10 This approach was also associated with an upregulation of immune-related genes involved in PD-1/PD-L1 and T-cell cytotoxicity pathways. The clinical and translational data suggest that short-term doxorubicin and cisplatin may induce a favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in triple-negative breast cancer. “These are very exciting data and an intriguing idea…that a bit of chemo may change outcomes,” Dr Rugo commented. Similar studies using chemotherapy induction are underway.
There is also excitement over the potential for poly (ADP-ribose) polymerase inhibition to enhance immune surveillance through multiple mechanisms. Dr. Rugo is Principal Investigator of the phase III KEYLYNK-009 trial (ClinicalTrials.gov identifier NCT04191135), which is evaluating induction chemotherapy with gemcitabine/carboplatin and pembrolizumab and then maintenance with the same drugs or with olaparib and pembrolizumab. Finally, studies are incorporating AKT inhibitors, including a phase II study of paclitaxel/atezolizumab plus ipatasertib (NCT03800836). This trial produced a “dramatic” waterfall plot, regardless of abnormalities in AKT or PIK3CA. A phase III study has been planned.
DISCLOSURE: Dr. Rugo disclosed relevant relationships with Pfizer, Merck, Novartis, Eli Lilly, Genentech, OBI Pharma, Odonate Therapeutics, Daiichi Sankyo, Eisai, Seattle Genetics, MacroGenics, Immunomedics, Amgen, Mylan, AstraZeneca, and Puma Biotechnology.
1. Rugo HS: Immunotherapy comes into its own for breast cancer: Updates and new directions. 2020 Miami Breast Cancer Conference. General session. Presented March 6, 2020.
2. Schmid P, Adams S, Rugo HS, et al: Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379:2108-2121, 2018.
3. Rugo HS, Loi S, Adams S, et al: Performance of PD-L1 immunohistochemistry assays in unresectable locally advanced or metastatic triple-negative breast cancer: Post-hoc analysis of IMpassion130. ESMO Congress 2019. Abstract LBA20. Presented September 28, 2019.
4. Dalenc F, Garberis I, Filleron T, et al: Durvalumab compared to maintenance chemotherapy in patients with metastatic breast cancer: Results from phase II randomized trial SAFIR02-IMMUNO. 2019 San Antonio Breast Cancer Symposium. Abstract GS3-02. Presented December 12, 2019.
5. Schmid P, Cortes J, Pusztai L, et al: Pembrolizumab for early triple-negative breast cancer. N Engl J Med 382:810-821, 2020.
6. Loibl S, Untch M, Burchardi N, et al: A randomized phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: Clinical results and biomarker analysis of GeparNuevo study. Ann Oncol 30:1279-1288, 2019.
7. Gianni L, Huang CS, Egle D, et al: Pathologic complete response to neoadjuvant treatment with or without atezolizumab in triple negative, early high-risk and locally advanced breast cancer: NeoTRIPaPDL1 Michelangelo randomized study. 2019 San Antonio Breast Cancer Symposium. Abstract GS3-04. Presented December 12, 2019.
8. Nanda R, Liu MC, Yau C, et al: Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: An analysis of the ongoing phase II adaptively randomized I-SPY2 trial. JAMA Oncol. February 13, 2020 (early release online).
9. Loi S, Drubay D, Adams S, et al: Tumor-infiltrating lymphocytes and prognosis: A pooled individual patient analysis of early-stage triple-negative breast cancers. J Clin Oncol 37:559-569, 2019.
10. Voorwerk L, Slagter M, Horlings HM, et al: Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity of PD-1 blockade: The TONIC trial. Nat Med 25:920-928, 2019.