Expert Highlights Immunotherapy/Chemotherapy Combos in TNBC

Lisa Carey, MD

The efficacy of combination therapy with a checkpoint inhibitor and chemotherapy has been proved in the triple-negative breast cancer (TNBC) space, and the additive and early toxicity may be worth the survival benefit, Lisa A. Carey, MD, said in a presentation during the 2018 ESMO Congress.

Results of the phase III IMpassion130 trial, which were presented during the meeting, demonstrated that the addition of atezolizumab (Tecentriq) to nab-paclitaxel (Abraxane) reduced the risk of progression or death by 38% versus nab-paclitaxel alone in patients with PD-L1—positive metastatic TNBC.¹

“This is clearly a positive trial. It’s safe to say that we anticipate approval of the first noncytotoxic therapy in metastatic TNBC,” said Carey, who is the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research, chief of hematology/oncology, physician-in-chief, North Carolina Cancer Hospital, and associate director of Clinical Sciences at Lineberger Comprehensive Cancer Center in Chapel Hill.

TNBC has remained a challenging breast cancer subtype to target because of its heterogeneity, mutability, and lack of targets, Carey explained.

“Triple-negative breast cancer is not a disease; it is a ‘gimish’ of many diseases,” she said. “It’s histologically heterogenous, molecularly heterogenous, and now what we are increasingly appreciating is that it is immunologically heterogenous.”

Moreover, there are TNBC subgroups with high, intermediate, and low levels of tumor-infiltrating lymphocytes (TILs), the primary of which is associated with response to chemotherapy. Regarding immunological heterogeneity, there are 4 molecular phenotypes detected via mRNA profiling: basal-like immune-activated, basal-like immune-suppressed, mesenchymal, and luminal androgen receptor. Immune-activated phenotypes, Carey said, carry a better prognosis and are likely to have better pathological complete responses (pCRs) to neoadjuvant chemotherapy.

There are also implications for immune-directed therapy. Single-agent PD-1/PD-L1 inhibitors have shown the highest levels of activity in treatment-naïve patients with PD-L1—positive TNBC, with avelumab (Bavencio), pembrolizumab (Keytruda), and atezolizumab.

“If you do achieve response, remember metastatic TNBC tends to have a rapid evolution and does not have a very long duration of response when they respond to chemotherapy. So we are seeing response [to immunotherapy, but] there [are] just not enough of them. How do we get these numbers higher?” Carey asked.

In efforts to increase these responses across breast cancer subtypes, combinatorial strategies with immunotherapy are ongoing—some of which include PARP inhibitors, MEK inhibitors, HER2-directed therapy, CDK4/6 inhibitors, vaccines, adenosine modulators, IDO inhibitors, and other immune checkpoint modulators.

Combining checkpoint inhibitors with chemotherapy may be effective because chemotherapy functions to release antigens that stimulate immunogenicity and effector T cells, reduce regulatory T cells, increase major histocompatibility complex class I and type I interferon, and make the tumor microenvironment more favorable for immune intervention, Carey explained.

Phase Ib findings of the atezolizumab/nab-paclitaxel regimen were reported at the 2015 San Antonio Breast Cancer Symposium. Data showed that upfront treatment with atezolizumab/nab-paclitaxel resulted in a confirmed objective response rate (ORR) of 66.7% in patients with metastatic TNBC.² The combination was evaluated across several lines of treatment regardless of PD-L1 status for those with metastatic disease. In the second-line setting, the confirmed ORR was 25%, and in the third line and beyond, the ORR was 28.6%. The ORR was 41.7% across the full trial.

In a 2-year overall survival (OS) follow-up of the phase Ib findings, the ORR was 39.4% (95% CI, 22.9%-57.9%), and the median duration of response was 9.1 months (95% CI, 2.0-20.9 months).³ This was highest in the PD-L1—positive and first-line settings, with ORRs of 54% and 41%, respectively.

“There are a couple of interesting things about this,” said Carey. “It did lead to the IMpassion130 study, but they did try to get serial biopsies. In a subset of patients, they had a lead-in phase of chemotherapy alone for 2 weeks prior to initiating the checkpoint inhibitor. They didn’t find in [this] induction phase much of an effect on the biomarkers they were looking at in terms of the tumor microenvironment. They also didn’t see any decrement in what they expected to see once atezolizumab was added by the existence of chemotherapy.”

Aside from IMpassion130, data of immunotherapy with chemotherapy have reported out with one other regimen: pembrolizumab and eribulin (Halaven) in the ENHANCE1/KEYNOTE-150 study, in which treatment with pembrolizumab plus eribulin demonstrated a 26.4% ORR for patients with metastatic TNBC.⁴

In the open-label study, the ORR with the combination for untreated patients with metastatic TNBC (n = 65) was 29.2% (95% CI, 18.6%-41.8%). In a cohort of patients pretreated with 1 to 2 therapies (n = 41), the ORR was 22.0% (95% CI, 10.6%-37.6%). Across all treatment arms, there were 3 complete responses to the combination (2.8%).

In IMpassion130, results of the primary progression-free survival (PFS) analysis in the PD-L1—positive population demonstrated a clinically meaningful median PFS of 7.5 months (95% CI, 6.7-9.2) with atezolizumab/nab-paclitaxel and 5.0 months (95% CI, 3.8-5.6) with chemotherapy (HR, 0.62; 95% CI, 0.49-0.78; P <.0001). In the intent-to-treat (ITT) population, the median PFS with atezolizumab/nab-paclitaxel and nab-paclitaxel alone was 7.2 months (95% CI, 5.6-7.5) and 5.5 months (95% CI, 5.3-5.6), respectively (HR, 0.80; 95% CI, 0.69-0.92; P = .0025).

At a 12.9-month follow-up, an interim OS analysis of the PD-L1—positive population showed a clinically meaningful improvement with added atezolizumab at 25.0 months versus nab-paclitaxel alone at 15.5 months (HR, 0.62; 95% CI, 0.45-0.86). In the ITT population, this benefit was not statistically significant.

In terms of safety, most all-grade adverse events (AEs) were similar between arms. The most common grade 3/4 AEs with atezolizumab/nab-paclitaxel and nab-paclitaxel were neutropenia (8% vs 8%), decreased neutrophil count (5% vs 3%), peripheral neuropathy (6% vs 3%), fatigue (4% vs 3%), and anemia (3% vs 3%), respectively. There were 3 deaths on the atezolizumab arm and 1 on the chemotherapy arm. Moreover, dose interruptions or reductions occurred in 47% of those on atezolizumab versus 40% of those on nab-paclitaxel alone; discontinuations occurred in 16% and 8%.

Some immune-related AEs were higher in the atezolizumab arm compared with those in the nab-paclitaxel arm, such as rash (34% vs 26%), hypothyroidism (17% vs 4%), hyperthyroidism (4% vs 1%), and pneumonitis (3% vs <1%), respectively.

“The additive toxicity early may be worthwhile if it allows a higher proportion of patients to have extended chemotherapy-free duration on an immune checkpoint inhibitor alone as well as survival advantage,” said Carey.

However, following this study, Carey said, there are a number of questions, such as which patient population is most appropriate to receive atezolizumab/nab-paclitaxel, what the duration of chemotherapy should be, how AEs should be managed, and what other immunotherapy/chemotherapy combinations might work in this setting. She also inquired about using this approach in the curative setting.

For example, the randomized phase II TONIC trial evaluated chemotherapy or radiation therapy followed by nivolumab (Opdivo) in patients with metastatic TNBC who received ≤3 prior lines of therapy. The sequence of this approach, Carey explained, is to make the tumor microenvironment more favorable before being treated with a checkpoint inhibitor.

The trial was designed with a “pick a winner” strategy to move forward in clinical trials, with induction cohorts of doxorubicin, cisplatin, radiotherapy, cyclophosphamide, or no induction. The ORR was 20%, with cisplatin (23%) and doxorubicin (35%) showing the highest responses.⁵

“What they concluded is that you can consider induction chemotherapy, particularly with doxorubicin or cisplatin as a promising potential agent,” Carey explained. “This is not something to be done conventionally, but it is very intriguing.”

The strategy is also being explored in the neoadjuvant setting. In one of the several arms of the I-SPY 2 trial, investigators evaluated neoadjuvant pembrolizumab at 200 mg every 3 weeks for 4 cycles plus paclitaxel at 80 mg/m² weekly for 12 cycles in patients with 3 breast cancer subtypes, including TNBC. Patients then went on to receive doxorubicin at 60 mg/m² and cyclophosphamide at 600 mg/m² for 4 cycles prior to surgery.

In the TNBC cohort, results showed that the pCR in the pembrolizumab arm was 0.60 (95% CI, 0.43-0.78) versus 0.20 (95% CI, 0.06-0.33) in the control arm.⁶

While the data are exciting, Carey said, she explained that they are an estimation of an intermediate endpoint, and grade 3 or higher adrenal insufficiency was detected in approximately 7% of patients, along with other immune-related AEs.

Finally, the GeparNuevo study investigated the PD-L1 inhibitor durvalumab (Imfinzi) in combination with nab-paclitaxel plus epirubicin/cyclophosphamide (EC) in 174 patients with TNBC who were stratified by low, intermediate, and high TILs. Patients received durvalumab or placebo as a “window” trial, with two-thirds of patients given window exposure prior to receiving nab-paclitaxel/EC. The primary endpoint was pCR.

Data showed that the durvalumab arm had a pCR of 53.4% versus 44.2% with placebo (adjusted OR, 1.53; 95% CI, 0.82-2.84; P = .287), although this was not statistically significant.⁷ In the window subset (n = 117), however, the ORRs were 61.0% and 41.4% for durvalumab and placebo, respectively (P = .052).

“It does raise the question of whether induction with an immune checkpoint inhibitor made into a larger multi-polychemotherapy backbone in the early breast cancer setting augments effectiveness of the approach,” concluded Carey. “This again calls into question the fact that not only are our combinations not entirely clear, [but] the duration is not entirely clear and the timing isn’t clear, and these are all things we should be looking at in the upcoming years.”&ensp;

References

1. Schmid P. IMpassion130: Results from a global, randomised, double-blind, phase 3 study of atezolizumab (atezo) + nab-paclitaxel (nab-P) vs placebo + nab-P in treatment-naive, locally advanced or metastatic triple-negative breast cancer (mTNBC). In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA1_PR.
2. Adams S, Diamond J, Hamilton E, et al. Safety and clinical activity of atezolizumab (anti-PDL1) in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer. Presented at: San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract P2-11-06.
3. Adams S, Diamond JR, Hamilton E, et al. Atezolizumab plus nab-paclitaxel in the treatment of metastatic triple-negative breast cancer with 2-year survival follow-up [published online October 19, 2018]. JAMA Oncol. doi: 10.1001/jamaoncol.2018.5152.
4. Tolaney SM, Kalinsky K, Kaklamani V, et al. Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract PD6-13.
5. Kok M, Voorwerk L, Horlings H, et al. Adaptive phase II randomized trial of nivolumab after induction treatment in triple negative breast cancer (TONIC trial): final response data stage I and first translational data. J Clin Oncol. 2018;36(suppl; abstr 1012). doi: 10.1200/JCO.2018.36.15_suppl.1012.
6. Nanda R, Liu MC, Yau C, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): results from I-SPY 2. J Clin Oncol. 2017;35(suppl; abstr 506). doi: 10.1200/JCO.2017.35.15_suppl.506.
7. Loibl S, Untch M, Burchardi N, et al. A randomized phase II neoadjuvant study (GeparNuevo) to investigate the addition of durvalumab, a PD-L1 antibody, to a taxane-anthracycline containing chemotherapy in triple negative breast cancer (TNBC). J Clin Oncol. 2017;35(suppl; abstr 3062). doi: 10.1200/JCO.2017.35.15_suppl.3062.