Ipilimumab after progression on anti-PD-1 treatment in advanced melanoma.

AIM: While both efficacy and safety of anti-PD-1 agents seem to be independent of previous treatment with anti-CTLA-4, limited data exist of efficacy and toxicity of ipilimumab after progression on anti-PD-1 therapy. This retrospective analysis describes the efficacy and safety of sequential therapy with ipilimumab in patients with metastatic melanoma who progressed on anti-PD-1 antibody. METHODS: Nine patients who progressed on anti-PD-1 therapy received four cycles of ipilimumab 3 mg/kg every 3 weeks. RESULTS: Two out of nine patients (2/9; 22.2%) showed a partial response, and seven patients (7/9; 77.8%) experienced disease progression. Median progression-free survival was 3.14 months (95% CI: 2.56-3.71), and the median overall survival since the start of anti-PD-1 therapy was 16.8 months (95% CI: 8.1-25.4). Five (5/9; 55.6%) patients experienced grade 3 immune-related adverse events. No grade 4 or 5 adverse events were reported. CONCLUSION: In this small retrospective series of cases, the efficacy of ipilimumab post-anti-PD-1 was similar to that described in the previous reports on ipilimumab.

Serum IGF-I, IGFBP-3, and matrix metalloproteinase-7 levels and acquired chemo-resistance in advanced colorectal cancer.

Insulin-like growth factor-I (IGF-I) is thought to have antiapoptotic and mitogenic properties in colorectal cancer, whereas IGF-binding protein-3 (IGFBP-3) seems to exert a pro-apoptotic effect. Additionally, matrix metalloproteinase-7 (MMP-7), an enzyme with in vitro ability to degrade IGFBP-3, has been shown to be a prognostic factor in advanced colorectal cancer (ACRC). We studied whether chemotherapy treatment for ACRC modulates IGF-I, IGFBP-3, and MMP-7 serum levels. In 41 patients undergoing first-line therapy for ACRC, serum levels of IGF-I, IGFBP-3, and MMP-7 were measured with immunoassays at baseline and every 3 months until progressive disease, or a maximum of five determinations, during a chemotherapy regimen of either FOLFOX or FOLFIRI therapies. Associations were assessed for paired samples, using t-test or Wilcoxon ranks test depending on normality of the variable, verified with Shapiro-Wilk test. An average of four extractions (range 3-5) were done, for a total of 157 determinations. Mean pretreatment values of IGF-I, IGFBP-3, and MMP-7 were 83 (95% CI, 73-92) ng/ml, 2372 (95% CI, 2121-2623) ng/ml, and 10.6 (95% CI, 7.21-13.98) ng/ml respectively. No significant changes in IGF-I were found, but a significant increase in IGFBP-3 serum concentrations was observed during or after chemotherapy treatment without progressive disease, compared with basal levels (P<0.001). A significant decrease in IGFBP-3 to 1983 ng/ml (95% CI, 1675-2292) and a significant increase in MMP-7 levels to 14.6 (7.6-21.7) ng/ml were observed at progression of disease compared with baseline and treatment levels (P<0.001). This study shows that IGFBP-3 and MMP-7 serum levels change during chemotherapy treatment. The increased MMP-7 levels at disease progression support the hypothesis that this protease could play a role in acquired resistance by degrading IGFBP-3.

Phase I trial of neoadjuvant chemoradiotherapy (CRT) with capecitabine and weekly irinotecan followed by laparoscopic total mesorectal excision (LTME) in rectal cancer patients.

BACKGROUND: To analyze the feasibility of capecitabine with weekly irinotecan and concurrent radiotherapy followed by laparoscopic-total mesorectal excision (LTME) in rectal cancer patients. METHODS: Eligible criteria included adenocarcinoma of the rectum staged by endoscopic ultrasonography (u), spiral abdominal and pelvic CT and chest X-ray. Patients received weekly irinotecan 50 mg/m(2) (days 1, 8, 15, 22, 29) and capecitabine (days 1 through 5 for 5 weeks); dose level; (DL) I 250 mg/m(2)/bid; DL II 375 mg/m(2)/bid; DL III 500 mg/m(2)/bid, according to phase I methodology. External beam radiotherapy was delivered up to a total dose of 45 Gy in daily fractions of 1.8 Gy, 5 days a week. LTME was planned 5-7 weeks after CRT. RESULTS: From February 2003 to February 2006, 22 patients were included. Median age was 62 (range 48 to 78). Seven pts were uT3N0 and 15 pts uT3N1. Seven patients were treated at DL I, six at DL II and nine at DL III. Grade 3 adverse events were observed in all levels. The maximum tolerated dose was reached at 375 mg/m(2) (DL II). Conversion rate to open surgery was 5%. Median hospital stay was 6.6 days. One month post-surgical complications were noted in five patients (23%). Median excised nodes were 11 (range 4-21). Pathological complete response was observed in two patients (9%). CONCLUSIONS: LTME after preoperative CRT with CAPIRI is feasible but severe adverse events were found in all levels despite the use of lower dose of capecitabine than previously published.

Pembrolizumab in a BRAF-mutant metastatic melanoma patient following a severe immune-related adverse event with ipilimumab.

Currently, limited data exist on the safety of pembrolizumab in patients with metastatic melanoma who have developed severe immune-related adverse events following treatment with ipilimumab. We report a 45-year-old male patient with BRAF-mutant metastatic melanoma who discontinued treatment with ipilimumab due to treatment-related grade 3 colitis and was subsequently treated with the anti-programmed cell death 1 protein (PD-1) antibody pembrolizumab. He has been on treatment with pembrolizumab for more than 20 months with no major toxicities and has achieved an objective partial response, which is ongoing.

Life-threatening colitis and complete response with ipilimumab in a patient with metastatic BRAF-mutant melanoma and rheumatoid arthritis.

Immune checkpoint inhibitors, such as ipilimumab (an anti-CTLA4 antibody), have become a commonly used therapy in cancer. To date, safety data of patients with underlying autoimmune disease is limited. We present a case of a patient with rheumatoid arthritis who was diagnosed of a BRAF-mutant metastatic melanoma. The patient was treated with ipilimumab and presented with high-grade colitis requiring immunosuppressors. Despite of the immune-related adverse event, no exacerbation of the rheumatoid arthritis was observed and the patient achieved a complete response. This case report contributes to the scarce literature on the use of immune checkpoint inhibitors in patients with an underlying autoimmune condition.