Elizabeth A. Mittendorf, MD, PhD
Multiple ongoing clinical trials are evaluating various immunotherapy strategies for patients with breast cancer, with combinations representing the most potential for future success, according to a talk by Elizabeth A. Mittendorf, MD, PhD, at the 2017 Miami Breast Cancer Conference®.
Multiple clinical trials have assessed monotherapy with the PD-1 inhibitor pembrolizumab (Keytruda), setting the groundwork for future approaches. Additionally, a study has explored the combination of the PD-L1 inhibitor atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane). Phase III studies are currently planned for each of these approaches.
“There are multiple ongoing trials evaluating immunotherapy strategies,” said Mittendorf, from the University of Texas MD Anderson Cancer Center. “Combinations are the likely way forward, and an appropriate strategy will be dictated by the stage of disease.”
Setting the groundwork for future success, studies have demonstrated that breast cancer is immunogenic. It has a moderate mutational load, which is predictive of response. This mutational load varies by histology, with triple-negative breast cancer (TNBC) having the highest burden. Furthermore, prior passive immune strategies, using monoclonal antibodies against HER2, have led to survival benefits, suggesting the immune system plays a role.
To elicit a response, immunotherapy requires the presence of tumor infiltrating lymphocytes (TILs), Mittendorf noted. In a combined analysis from 6 studies that contained 991 patients with breast cancer, 90% of patients had stromal TILs in at least 1% of their tissue samples. The average stromal TIL value was 20%. This is another positive indicator of immunotherapy success, she noted.
“For every 10% increase in TILs there was an increase in relative disease-free survival as well as a decrease in deaths,” said Mittendorf. “TILs have predictive value. Tumors that have significant lymphocyte infiltrate have higher rates of pathologic complete response when patients received neoadjuvant chemotherapy, as compared to when patients have no tumor infiltrate.”
Enough clinical data exist to begin developing a clear path forward for immune checkpoint inhibitors in breast cancer. Mittendorf discussed findings from the phase I KEYNOTE-012 study and the KEYNOTE-028 trials, which explored pembrolizumab across phenotypes. She also described findings for atezolizumab plus nab-paclitaxel for patients with TNBC.
In the KEYNOTE-012 trial, 32 patients with PD-L1–positive heavily pretreated TNBC received intravenous pembrolizumab at 10 mg/kg every 2 weeks. In the updated findings presented at the 2016 San Antonio Breast Cancer Symposium (SABCS), the overall response rate (ORR) was 18.5%, which included 1 complete response (CR; 3.7%) and four partial responses (PR; 14.8%). Additionally, seven patients had stable disease (SD; 25.9%), 1 of which persisted for ≥24 months.
The phase Ib KEYNOTE-028 trial examined pembrolizumab in 25 patients with PD-L1–positive ER-positive/HER2-negative breast cancer. The ORR was 12%, comprising all partial responses and no complete responses. Four patients (16%) had stable disease and the clinical benefit rate (ORR plus stable disease for ≥24 weeks) was 20%.
“Much like what we’ve seen in other tumor types, those who had a response, had a very durable response. The median duration of response has not yet been reached,” said Mittendorf.
The phase III KEYNOTE-119 trial is assessing single-agent pembrolizumab compared with single-agent chemotherapy for patients with metastatic TNBC. This study is ongoing but not currently recruiting patients. The chemotherapy arm consists of capecitabine, eribulin, gemcitabine, or vinorelbine (NCT02555657). Additionally, the phase III SWOG S1418 trial is comparing pembrolizumab with observation for patients with TNBC with >1 cm residual cancer or any lymph node involvement after neoadjuvant chemotherapy (NCT02954874).
“This trial [SWOG] just opened, and I would encourage you to enroll your patients onto this trial,” said Mittendorf.
Looking at response across subtypes, those with TNBC benefited the most from immunotherapy. The key biomarkers of response were PD-L1 expression on the tumor and TILs, mutational load and neoantigens, the microbriome, and the presence of T cells. “These therapies take the brakes off the immune system, so if there are no T cells present, then I am not certain what we would be taking the brakes off,” she added. “We need something to bring those T cells in.”
The primary strategies to augment response to checkpoint inhibition include chemotherapy, radiation, cryoablation, second drugs simulating the innate immune response, and vaccines. In mouse models, there was synergism between anti–PD-L1 therapy and nab-paclitaxel, with better responses noted with the combination compared with monotherapy.
In a phase Ib study, 32 patients with TNBC received concurrent treatment with nab-paclitaxel and atezolizumab across several lines of treatment regardless of PD-L1 status. The ORR was 42% across all patients with metastatic TNBC (95% CI, 22-63). Those treated in the frontline setting (n = 9) had an ORR of 67% (95% CI, 30-93).
The phase III IMpassion130 trial is ongoing for patients with previously untreated metastatic TNBC. This trial is randomizing patients to nab-paclitaxel plus placebo or atezolizumab. The primary endpoint of the study is PFS in the full population and in a PD-L1–positive group. Secondary endpoints include survival, ORR, and duration of response. The target enrollment goal for the trial is 350 patients (NCT02425891).
The phase III NeoTRIPaPDL1 study is looking at the combination of nab-paclitaxel and carboplatin with or without atezolizumab for patients with locally advanced TNBC. Event-free survival will be the primary endpoint of this neoadjuvant trial (NCT02620280).
In addition to the chemotherapy combination approach, studies are also assessing a HER2 peptide vaccine known as nelipepimut-S plus GM-CSF along with trastuzumab or a checkpoint inhibitor, Mittendorf said. Additionally, the peptide vaccine is also being explored for patients with DCIS or in the adjuvant setting.
A phase II study is currently examining nelipepimut-S/GM-CSF plus trastuzumab after neoadjuvant or adjuvant therapy and surgery for patients with HER2-positive breast cancer who did not achieve a pathologic complete response. The primary endpoint of the trial is invasive disease-free survival (NCT02297698).
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