Pembro Boosts Treatment Impact in Advanced Breast Cancer

Liam Davenport

December 07, 2017

SAN ANTONIO ― Adding the anti–programmed death ligand 1 (PD-L1) inhibitor pembrolizumab (Keytruda, Merck) to trastuzumab in trastuzumab-resistant advanced HER2+ breast cancer achieves a clinical benefit and is well tolerated, the results of a phase 1b/2 study suggest.

The PANACEA study, which was reported here at the San Antonio Breast Cancer Symposium (SABCS) 2017, showed that pembrolizumab plus trastuzumab achieved a disease control rate of 25% in patients with PD-L1-positive disease at a median duration of more than 11 months, despite most tumors being poorly immunogenic.

Moreover, treatment response was related to the number of tumor-infiltrating lymphocytes (TILs), offering the possibility of a predictive marker of response in patients with advanced breast cancer.

Lead investigator Sherene Loi, MD, PhD, associate professor at Peter MacCallum Cancer Center in Melbourne, Australia, said in a press release: "We wanted to investigate if immunotherapy approaches can work in patients with advanced HER2-positive breast cancer that is resistant to trastuzumab."

Dr Sherene Loi

She added: "This proof-of-principle study suggests that immune evasion is a mechanism of resistance to trastuzumab and contributes to disease progression in advanced HER2-positive breast cancer."

She believes that, on the basis of their findings, "PD1 inhibition is likely to become part of the treatment armamentarium of HER2-positive disease in the future."

PD1 inhibition is likely to become part of the treatment armamentarium. Dr Sherene Loi

Dr Loi told Medscape Medical News at a press conference for the study that she believes that pembrolizumab could be more effective if it were used in earlier lines of therapy.

She said: "By the time you get to the advanced stage and after multiple lines of treatment, you have low levels of T-cell infiltrate in your metastatic lesion, for whatever reason...so that all reduces your chance of responding to pembrolizumab, for example, as a monotherapy."

She added: "We don't know yet if chemotherapy in addition to pembrolizumab could change the tumor microenvironment, but certainly I think that the earlier the lines you go, the more chance you're going to have of existing effective antitumor immunity that can be reactivated with the addition of pembrolizumab."

Dr Loi also noted: "However, as you can see, there are some patients that still maintain a degree of antitumor immunity even after many lines of treatment and can still experience durable benefit from this treatment."

Virginia Kaklamani, MD, codirector of the San Antonio Breast Cancer Symposium and leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center, Texas, added: "One of the things that is unique about this study is that we're beginning to identify a subset of patients within a subset that we already test, such as HER2+, that may benefit more from immunotherapy compared to others.

"With the triple-negative patient population, we're still struggling to find that subset, and all of the studies that are now being done are looking at all triple-negative breast cancer patients."

Discussing the current study after the press conference, Dr Kaklamani said that it showed that pembrolizumab is an experimental option in this advanced HER2+ patient population.

"It's not approved in breast cancer, but there's a lot of studies that are now being done with pembrolizumab in all types of breast cancers, and this [trial] is a good signal that we should continue studying it in HER2+ breast cancer."

Study Details

Presenting the study, Dr Loi noted that previous investigations have shown that HER2+ breast cancers have high levels of T-cell infiltration and that TILs are associated with an improved prognosis and response to trastuzumab and chemotherapy.

Moreover, trastuzumab itself has been shown to have immune-mediated mechanisms of action, and preclinical studies have suggested that immune-related mechanisms of resistance to trastuzumab can be overcome with checkpoint inhibition.

The researchers therefore conducted a single-arm phase 1b/2 study with one cohort of PD-L1-positive and another of PD-L1-negative patients. All participants had centrally confirmed HER2+, measurable disease and an ECOG performance status of 0-1.

There was no limit on the number of prior systemic treatments. For patients to be included, disease progression had to have been documented while the patient was being treated with trastuzumab or trastuzumab emtansine (Kadcyla, Genentech).

PD-L1-positive patients in the phase 1b portion of the study were treated with pembrolizumab 2 mg/kg and 10 mg/kg IV plus trastuzumab. In the phase 2 portion, the PD-L1-positive and -negative patients received pembrolizumab 100 mg IV plus trastuzumab.

Of 146 screened patients, six PD-L1-positive patients were enrolled in the phase 1b portion; 40 PD-L1-positive and 12 PD-L1-negative patients were enrolled in the phase 2 portion.

The median age of the patients was 50.5 years, and the median time from the diagnosis of metastatic disease to enrollment was 40 months. Patients were treated for a maximum of 2 years or until disease progression, toxicity, patient withdrawal, or investigator decision.

After a median follow-up of 13.6 months, the objective response rate (ORR) on an intent-to-treat analysis was 15.2% among PD-L1-positive patients. The rate of disease control, defined as complete response, partial response, or stable disease for ≥6 months, was 24%.

None of the patients with PD-L1-negative disease responded to treatment.

Among PD-L1-positive patients, the median duration of disease control was 11 months. Five (10.8%) patients were still receiving treatment and had not experienced disease progression at the time of reporting.

Analysis revealed that the median level of TIL infiltration in the metastatic lesion was 1%. "This is 20 times less than what we observe in primary HER+ breast cancer," Dr Loi said.

"However, we did notice a significantly higher TIL level in the PD-L1-positive cohort and also a significantly higher TIL level in patients who achieved an objective response, as well as in those who achieved disease control. So, higher TIL levels are associated with an increased chance of response."

This finding was underlined when the researchers used a cutoff for stromal TILs of ≥5%. For patients who met this threshold, the ORR was 39%, vs 5% for those with lower TILs. Moreover, the disease control rate was 47% among patients meeting the cutoff, vs 5% among those who did not.

The 5% TIL cutoff was associated with a sensitivity and specificity of 85.7% and 61.8%, respectively, for the ORR, and of 90.0% and 67.7%, respectively, for the disease control rate.

The most common adverse events in the study were fatigue, seen in 12 (21%) patients, followed by diarrhea and arthralgia, both see in eight (14%) patients.

Immune-related adverse events of any grade were observed in 11 (19%) of patients, with six (10) experiencing grade ≥3 events and four (6.9%) having events that led to discontinuation.

This study was sponsored and managed by the International Breast Cancer Study Group in collaboration with the Breast International Group. It was funded by Merck & Co. through a subsidiary. The investigators have disclosed no relevant financial relationships.

San Antonio Breast Cancer Symposium (SABCS) 2017: Abstract GS2-06, presented December 6, 2017.

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