Merkel cell carcinoma (MCC) is a rare but clinically aggressive cancer with a high mortality rate. In recent years, antibodies blocking the interactions among PD-1 and its ligands have generated durable tumor regressions in patients with advanced MCC. However, there is a paucity of data regarding effective therapy for patients whose disease is refractory to PD-1 pathway blockade. This retrospective case series describes a heterogeneous group of patients treated with additional immune checkpoint blocking therapy after MCC progression through anti-PD-1. Among 13 patients treated with anti-CTLA-4, alone or in combination with anti-PD-1, objective responses were seen in 4 (31%). Additionally, one patient with MCC refractory to anti-PD-1 and anti-CTLA-4 experienced tumor regression with anti-PD-L1. Our report – the largest case series to date describing this patient population – provides evidence that sequentially-administered salvage immune checkpoint blocking therapy can potentially activate anti-tumor immunity in patients with advanced anti-PD-1-refractory MCC and provides a strong rationale for formally testing these agents in multicenter clinical trials. Additionally, to the best of our knowledge, our report is the first to demonstrate possible anti-tumor activity of second-line treatment with a PD-L1 antibody in a patient with anti-PD-1-refractory disease. Electronic supplementary material The online version of this article (10.1186/s40425-019-0661-6) contains supplementary material, which is available to authorized users.
Bisphosphonates reduce the incidence of skeletal-related events (fractures, pain, hypercalcemia) in patients (pts) with bone metastases from breast cancer. By inhibiting osteoclast function and subsequent bone turnover they may inhibit the growth of bone (and other) metastases. Their role in preventing or delaying the development of bone (or other) metastases in pts with early breast cancer is uncertain. Three previous trials of oral clodronate have given mixed results. The largest trial (placebo-controlled) and a smaller open-label trial suggested that oral clodronate benefitted pts with improved bone metastases-free survival (BMFS) and overall survival (OS), but a third open-label study showed no benefit with an apparent detrimental effect on survival. Studies of IV zoledronate in open-label trials in early breast cancer have also shown mixed results: the AZURE trial in pts with node positive breast cancer showed no benefit in disease-free survival (DFS) or OS with a possible effect in pts aged over 60. The ABCSG-12 trial in GnRH (plus tamoxifen or anastrozole) treated women with early breast cancer showed a small DFS benefit for those receiving IV zoledronate but no BMFS or OS benefit. Methods: B-34 is a prospective, randomized, double-blind, phase III clinical trial in pts with stage 1, 2 or 3 breast cancer assessing oral clodronate 1600mg daily for 3 years compared to placebo given alone or in addition to adjuvant chemo- or hormone therapy. Stratification is by age (<50, +50), number of positive nodes (0, 1–3, 4+) and ER/PR status. The primary end-point is DFS. Secondary endpoints are the incidence of skeletal metastases, OS, relapse-free survival, incidence of non-skeletal metastases, and incidence of skeletal morbid events. Results: 3323 patients were accrued — 1662 in Group A and 1661 in Group B. As of March 31, 2011, 54 pts were declared ineligible: 23 in Group A and 31 in Group B. The average time on study is 101.3 months. Patient characteristics were evenly distributed throughout both groups. Approximately 75% of pts in each group had negative axillary lymph nodes and some 78% in each group were ER and/or PR positive. About 64% of pts were age 50 or over. Oral clodronate was generally tolerable, toxicities observed being mainly due to the concomitant systemic chemotherapy. One pt in Group A had a 1 mm area of osteonecrosis on the palatal taurus. Compliance, as expected with trials of oral medications, has been a problem. 1910 pts completed 3 years of therapy. Event rates were slower than anticipated. This final analysis assesses a total of 598 events in the two arms. Conclusions: This trial is the largest placebo-controlled study of an oral bisphosphonate in patients with early breast cancer and will provide further information on the role of bisphosphonates in breast cancer management. Supported for NSABP by NCI U10CA12027, −37377, 69651, 69974; and Bayer Schering Pharma Oy; for ECOG by U10CA021115; for NCCTG by U10CA25224; for SWOG by U10CA38926. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S2-3.
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