Although trastuzumab is considered as a standard of care in metastatic human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer, resistance to the treatment is almost inevitable.1 At the 2017 San Antonio Breast Cancer Symposium (SABCS), an exciting evidence showing that PD-1/PD-L1 immune checkpoint inhibitors might help to overcome trastuzumab resistance was presented by Dr. Sherene Loi, Associate Professor at Peter MacCallum Cancer Centre in Melbourne, Australia.
Immunogenicity of breast cancer: What do we know?
Breast cancer is traditionally not considered as an immunogenic tumor type.2,3 However, relevant tumor-immune interaction has been demonstrated in certain subtypes of breast cancer.2,3 In 2014, Dr. Loi and her colleagues have reported, for the first time, an association between higher levels of tumor-infiltrating lymphocytes (TILs) and increased trastuzumab benefit in HER2-positive breast cancers.3 This generates an interest in the use of PD-1/PD-L1 immune checkpoint inhibitors to overcome trastuzumab resistance in the HER2-positive subset of breast cancers. “We believe that immune evasion is a part of the biological resistance to trastuzumab in patients with this disease [HER2-positive breast cancer],” said Dr. Loi.4
“Prior studies from our group have shown that antitumor immunity is important for improved outcomes in patients with advanced HER2-positive breast cancer,” continued Dr. Loi. “Trastuzumab itself has been shown to have immune-mediated mechanisms of action, and preclinical studies have suggested that immune-mediated mechanisms of trastuzumab resistance can be overcome with checkpoint inhibition combinations.”4-6
PANACEA: Pembrolizumab plus trastuzumab in trastuzumab-resistant HER2-positive advanced breast cancer
PANACEA, sponsored and managed by the International Breast Cancer Study Group (IBCSG) in collaboration with the Breast International Group (BIG), is a phase Ib/II trial evaluating the safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER2-positive advanced breast cancer.7 Fifty-eight patients with centrally confirmed HER2-positive breast cancer and documented disease progression on prior trastuzumab-based therapies were recruited.4,7 Other inclusion criteria were Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, tumor biopsy sample less than 1 year, and measurable disease per RECIST 1.1.4,7 There was no limit on the number of prior system therapies.4,7
No dose limiting toxicities were observed in the phase Ib part of the trial, in which sixu PD-L1-positive patients received 2 or 10mg/kg pembrolizumab plus the standard dose of trastuzumab every 3 weeks.4,7 In phase II, 52 patients received 200mg pembrolizumab plus the standard dose of trastuzumab every 3 weeks for 24 months or until disease progression (40 patients were PD-L1-positive; 12 patients were PD-L1-negative).4,7
PANACEA: Clinical benefits in PD-L1-positive cohorts
In the PD-L1-positive cohort, the trial met its primary endpoint with an objective response rate (ORR) of 15% and disease control rate (DCR) of 25%.4,7 The median duration of disease control (complete response [CR], partial response [PR], or stable disease [SD] ≥6 months) was 11.1 months and the median duration of response was 3.5 months.4,7 Five (10.8) patients continued to have no disease progression at the time of reporting.4,7 In contrast to the benefits shown in the PD-L1 positive cohort, no responses were observed in the PD-L1-negative cohort.4,7
Intriguingly, higher levels of stromal TILs (sTILs) were associated with better response and disease control in the PD-L1-positive cohort (Figure 1).7 The analysis, however, also revealed that the median level of TIL infiltration in the metastatic lesion was only 1%. “This is 20 times less than what we observe in primary HER2-positive breast cancer,” said Dr. Loi.8
In patients with sTILs ≥5%, the ORR and DCR were 39% and 47%, respectively.7 Comparatively, both the ORR and DCR were only 5% in patients with sTILs <5%. Concerning the use of sTILs ≥5 as a potential predictive marker, “an [sTILs level] of 5% provides high sensitivity, high negative predictive value, and potentially high reproducibility amongst pathologists,” suggested Dr. Loi.6
In the PD-L1-positive cohort, the median progression-free survival (PFS) and overall survival (OS) were 2.7 months and 16.1 months, respectively.7 The corresponding 12-month rates were 13% and 65%.7 As seen in Figure 2, “there is a tantalizing suggestion of [raising the] tail on the [survival] curve… Obviously, this requires further follow-up, and the numbers are small,” commented Dr. Loi.7,9
Safety was also evaluated across 58 patients, with fatigue as the most commonly reported treatment-related adverse event (AE) (21%), followed by diarrhea (14%) and arthralgia (14%).7 No cardiac events were reported in the trial.7 Any grade immune-related AEs were reported in 11 patients (19%).7 The most common immune-related AEs were hyper-/hypo-thyroidism (6.9%) and pneumonitis (6.9%).7 “These frequencies are consistent with what has been reported in other solid tumor types with pembrolizumab,” said Dr. Loi.
“Observations suggest that the PD-1/PD-L1 pathway plays an important role in the trastuzumab resistance that we see in patients with metastatic HER2-positive breast cancer, and the PANACEA study provides proof-of principle evidence that pembrolizumab can help to reverse this,” said Dr. Loi. “Moreover, the quantification of TILs seems to be a meaningful way for us to identify those who would benefit most from an immunotherapeutic approach.”10
Anti-tumor immune microenvironment might be affected by multiple lines of treatment
Similar with the findings in PANACEA, retrospective studies of most solid tumor types have demonstrated that there is a correlation between a higher level of TILs and clinical benefits, indicating the central role of T cells in antitumor immunity.11 Yet, it remains unclear why some patients respond to PD-1/PD-L1 immune checkpoint inhibitors, but others do not.
Considering that multiple lines of treatment might impact the anti-tumor immune microenvironment, Dr. Loi suggested that PD-1/PD-L1 immune checkpoint inhibitors, such as pembrolizumab, might be more effective if used in the earlier lines of therapy. “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… that reduces your chance of responding to pembrolizumab, for example, as a monotherapy.”8
“We do not 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 are going to have of existing effective antitumor immunity that can be reactivated with the addition of pembrolizumab,” elaborated Dr. Loi.8
“However, as you can see, there are some patients who still maintain a degree of antitumor immunity even after many lines of treatment and can still experience durable benefit from this treatment.” Although further studies are warranted, Dr. Loi suggested that “PD-1 inhibition is likely to become part of the treatment armamentarium of HER2-positive disease in the future.”4,8
1. Lavaud P, Andre F. Strategies to overcome trastuzumab resistance in HER2-overexpressing breast cancers: focus on new data from clinical trials. BMC Med. 2014;12:132.
2. Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31(7):860-7.
3. Loi S, Michiels S, Salgado R, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014;25(8):1544-50.
4. SABCS 2017: Combination of Pembrolizumab and Trastuzumab Shows Early Promise for Patients With Trastuzumab-Resistant Breast Cancer. The ASCO Post. 2017 (Accessed February 2, 2018, at http://www.ascopost.com/News/58327).
5. PANACEA: pembrolizumab overcomes trastuzumab resistance for some. MDedge. 2017 (Accessed February 2, 2018, at https://www.mdedge.com/oncologypractice/article/154126/breast-cancer/panacea-pembrolizumab-overcomes-trastuzumab-resistance).
6. Pembrolizumab/Trastuzumab Active in HER2-Positive Breast Cancer. OncLive. 2017 (Accessed February 2, 2017, at http://www.onclive.com/conference-coverage/sabcs-2017/pembrolizumabtrastuzumab-active-in-her2positive-breast-cancer).
7. Loi S, Giobbie-Hurder A, Gombos A, et al. Phase Ib/II study evaluating safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER2-positive advanced breast cancer: results from the PANACEA study (IBCSG 45-13/BIG 4-13/KEYNOTE-014). 2017 San Antonio Breast Cancer Symposium; San Antonio, TX, USA; December 5-9, 2017; Abstract GS2-06.
8. Pembro Boosts Treatment Impact in Advanced Breast Cancer. Medscape. 2017 (Accessed February 2, 2018, at https://www.medscape.com/viewarticle/889729#vp_2).
9. SABCS 2017: Immunotherapy shows early promise for patients with trastuzumab-resistant breast cancer. ecancerconferences. 2017 (Accessed February 2, 2018, at http://ecancer.org/conference/966-sabcs-2017/video/6537/immunotherapy-shows-early-promise-for-patients-with-trastuzumab-resistant-breast-cancer.php).
10. PANACEA Press Release San Antonio Breast Cancer Symposium 2017. International Breast Cancer Study Group (IBCSG) Press Release. 2017 (Accessed February 2, 2018, at http://www.ibcsg.org/News/Pages/PressRelease.aspx).
11. Lanitis E, Dangaj D, Irving M, et al. Mechanisms regulating T-cell infiltration and activity in solid tumors. Ann Oncol. 2017;28(suppl_12):xii18-xii32.