Δευτέρα, 26 Ιουνίου 2017

IMMUNOTHERAPY IN EARLY BREAST CANCER

Immune checkpoint blockade may have a role in the presurgery treatment of high-risk, early-stage breast cancers, according to results from a phase 2 trial presented here at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting.
Currently, no cancer immunotherapy is approved for use in breast cancer, either metastatic or early-stage disease. But multiple studies are exploring the possibility, including several with pembrolizumab (Keytruda, Merck).
Earlier research in the metastatic setting found that single-agent pembrolizumab had "modest" activity, with a response rate less than 10% among heavily pretreated patients with triple-negative breast cancer (TNBC), said Rita Nanda, MD, a medical oncologist at the University of Chicago in Illinois.
In the new I-SPY 2 trial, the setting is early-stage breast cancer, including TNBC, and pembrolizumab was used as part of a combination therapy.
Lead author Dr Nanda reported that four cycles of neoadjuvant pembrolizumab, when added to conventional chemotherapy, improved estimated pathologic complete response (pCR) rates among 69 patients compared with chemotherapy alone among 180 patients with high-risk, early-stage disease.
pCR was the study's primary endpoint and was defined as no evidence of residual invasive cancer in the breast or lymph nodes.
In the trial, pembrolizumab was studied in three human epidermal growth factor receptor 2 (HER2)–negative biomarker "signatures" (all HER2–, hormone receptor [HR]+/HER2–, HR–/HER2–). The results, which are estimates because of the study's novel "adaptive" randomization, varied by signature.
Table. Estimated pCR Rates 
SignaturePembrolizumab + Standard Chemotherapy (%)Standard Chemotherapy (%)
All HER2–4516
HR–/HER2– (TNBC)6020
HR+/HER2–3413
There was a tripling of the estimated pCR rate in the triple-negative (HR–/HER2–) patients and a near tripling in HR+/HER– patients, emphasized Dr Nanda in her conclusion.
She also told the ASCO audience that pembrolizumab had "graduated" for all 3 HER2– signatures on the basis of these results, which means that there is a greater than 85% predictive probability of success in a 300-patient randomized phase 3 trial.
Priyanka Sharma, MD, a medical oncologist at the University of Kansas in Kansas City, agreed with that move. Phase 3 trials should be pursued, said Dr Sharma, who acted as meeting discussant of the study.
 But she questioned the choice of standard chemotherapy in the trial.
The trial schema called for randomization to 12 weeks of paclitaxel (T) — with or without the experimental pembrolizumab — followed by doxorubicin/cyclophosphamide (AC) every 2 to 3 weeks for four cycles.
Was AC/T "the best neoadjuvant chemotherapy backbone?" wondered Dr Sharma. After all, in I-SPY 2's chemotherapy-alone group, the pCR rate was only 13% to 20% among the various signatures.
Other chemotherapy regimens have shown efficacy in the neoadjuvant setting among patients with TNBC, observed Dr Sharma.
For example, in an early-stage TNBC study comparing a taxane with and without carboplatin followed by AC found a 54% pCR rate in the group with carboplatin vs a rate of only 41% in the no-carboplatin group (J Clin Oncol2014;33:13-21), she said.
Dr Sharma observed that some practitioners believe that the addition of a platinum agent (carboplatin or cisplatin) to neoadjuvant chemotherapy for TNBC is advisable. 
Another expert provided additional context with regard to early-stage TNBC.
"The current standard of therapy is to treat with combination chemotherapy in the neoadjuvant or adjuvant setting. In the neoadjuvant setting, 40% to 50% of patients achieve pCR," said Mateusz Opyrchal, MD, PhD, a medical oncologist at the Roswell Park Cancer Institute in Buffalo, New York.
Asked for comment, Dr Opyrchal also explained the significance of pCR as a measure in this setting. "We know that patients who do not achieve pCR are at much higher risk for recurrence," he said. Other experts have pointed out that, in neoadjuvant studies, pCR is an intermediate endpoint that is important because tumor eradication is desired before surgery proceeds
Overall, the pembrolizumab study results are "encouraging," Dr Opyrchal said, "but larger and randomized studies are needed to discover a true benefit from the combination." 

First Report of Certain Toxicities in Early-Stage Breast Cancer

Dr Nanda reported select adverse events from the trial. Overall, the safety profile among the pembrolizumab-treated patients was consistent with that observed in previously reported studies in the advanced-stage setting.
The pCR advantage came at the cost of some adverse events (pembrolizumab vs control). For example, for all grades, more vomiting (34.8% vs 18.3%), diarrhea (49.3% vs 37.8%), and peripheral motor neuropathy (13% vs 4.0%) occurred in the pembrolizumab group.
Dr Nanda also highlighted that rates of grade 3 to 5 fatigue and nausea were higher in the pembrolizumab-treated patients than in controls (5.8% vs 0.6% and 4.3% vs 0%, respectively).
Among adverse events of "special interest," including immune-related toxicities, the pembrolizumab group, not surprisingly, also fared worse.
For example, the pembrolizumab group had higher rates of hypothyroidism (8.7% vs 0.6%, all grades) and hyperthyroidism (4.3% vs 0%, all grades).
But Dr Nanda gave the most focus to adrenal insufficiency, which was observed in 8.7% (all grades) and 7.2% (grades 3 to 5) of patients in the pembrolizumab group vs none in the control group. Most of the cases presented after completion of AC (10 to 12 weeks after the last pembrolizumab dose), she also observed. "Patients are doing well on replacement therapy,"  said Dr Nanda.
This is the first report regarding the immune-related toxicities in early-stage breast cancer, she also pointed out.
Adrenal insufficiency is a known toxicity of pembrolizumab, but, in patients with metastatic cancer, the rates have been less than 1%, said Dr Nanda.
Because of these toxicities, serial screening of morning cortisol levels has  been incorporated into the trial along with serial thyroid function testing.
Dr Sharma wondered whether, in the early-stage setting, a "more conserved host immune system" is leading to "heightened immune toxicities."

More on I-SPY 2

To date, 13 agents have been studied in multiple concurrent arms and more than 2000 patients have enrolled in I-SPY 2, which stands for Investigation of Serial Studies to Predict Your Therapeutic Response through Imaging and Molecular Analysis 2. Patients are required to have a breast tumor 2.5 cm or greater in diameter on examination or a tumor 2 cm or greater in diameter on breast imaging.
Biomarker assessment, based on HER2 status, HR status, and a 70-gene profile using MammaPrint (Agendia), was performed at baseline to classify patients according to prospectively defined breast cancer subtypes.
In phase 2, the trial is "adaptively randomized," with the goal of efficiently identifying agents to take to phase 3, and it minimizes the number of patients needed to determine efficacy, said Dr Nanda.
A detailed review of the I-SPY 2 trial design and its merits and shortcomings was reported last year by Medscape Medical News.
The trial is supported by multiple pharmaceutical companies as well as private foundations. Dr Nanda and Dr. Opyrchal have disclosed no relevant financial relationships. Dr Sharma has financial ties with multiple drug companies. 
American Society of Clinical Oncology (ASCO) 2017 Annual Meeting. Abstract 506. Presented June 5, 2017.
Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick
For more from Medscape Oncology, follow us on Twitter: @MedscapeOnc

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