Rare cancers make top advance of the year
Progress in the treatment of rare cancers has been named Advance of the Year by the American Society of Clinical Oncology (ASCO).
In its latest annual report, ASCO highlighted five remarkable achievements in rare cancers that are considered to hold ‘real promise’ for patients. Identification and regulatory approval of new therapeutic options for these difficult-to-treat cancers in the past year were made possible mostly through federally funded research. [J Clin Oncol 2019, doi: 10.1200/JCO.18.02037]
First treatment for anaplastic thyroid carcinoma in 50 years
For patients with BRAF-mutated anaplastic thyroid carcinoma (ATC), the BRAF inhibitor/MEK inhibitor combination of dabrafenib plus trametinib was approved by the US FDA in 2018 based on results of a single-arm phase II trial.
The dabrafenib/trametinib combination – the first treatment approved for ATC in almost 50 years – demonstrated an overall response rate (ORR) of 69 percent in 16 patients with previously treated, locally advanced or metastatic, BRAF-mutated ATC in the open-label trial. At the time of data reporting, seven patients were experiencing ongoing responses. While median progression-free survival (PFS) and median overall survival (OS) were not reached, estimated 12-month PFS and OS rates were 79 percent and 80 percent, respectively. [J Clin Oncol 2018;36:7-13]
“Before this study, no chemotherapy prolonged survival or improved quality of life for patients with ATC. This new combination therapy has now become the standard of care,” noted authors of the ASCO report.
In the study’s safety population of 100 patients with seven rare tumour histologies, common adverse events (AEs) associated with dabrafenib/trametinib treatment were fatigue (38 percent), pyrexia (37 percent), and nausea (35 percent).
Sorafenib improves PFS in desmoid tumours
In the international phase III Alliance A091105 trial, sorafenib demonstrated a significant improvement in PFS vs placebo in patients with desmoid tumours, a rare type of sarcoma that had often been managed with off-label treatments previously.
Among 87 patients with unresectable, progressive or symptomatic disease, 1-year PFS rate was 87 percent in those randomized to receive sorafenib vs 43 percent in the placebo arm. Median PFS was not reached in the sorafenib arm vs 9.4 months in the placebo arm (hazard ratio [HR], 0.14; 95 percent confidence interval [CI], 0.06 to 0.33; p<0.0001). [J Clin Oncol 2018, doi: 10.1200/JCO.2018.36.15_suppl.11500]
The protocol allowed crossover from placebo to sorafenib upon disease progression. About one-third of sorafenib recipients experienced grade 3/4 AEs, which were primarily rash, hypertension, fatigue and pain.
177Lu-Dotatate approved for midgut NETs
In 2018, the US FDA also approved lutetium-177 (177Lu)-Dotatate, a radionuclide-octreotide analogue, for the treatment of adults with midgut neuroendocrine tumours (NETs). The approval was based on results of the international phase III GENEBIOLuNet trial in 229 patients with advanced midgut NETs.
At 20 months, estimated PFS rate was 65.2 percent in patients randomized to receive 177Lu-Dotatate, compared with 10.8 percent in those receiving octreotide long-acting repeatable (LAR). Median PFS was not reached in the 177Lu-Dotatate group vs 8.4 months in the octreotide LAR group (HR, 0.21; 95 percent CI, 0.13 to 0.33; p<0.001). [N Engl J Med 2017;376:125-135]
Treatment with 177Lu-Dotatate was also associated with improved OS (14 deaths vs 26 deaths; p=0.004) and response rate (18 percent vs 3 percent; p<0.001) vs octreotide LAR.
Grade 3/4 neutropenia, thrombocytopenia and lymphopenia occurred in 1 percent, 2 percent and 9 percent of patients in the 177Lu-Dotatate group, respectively, vs no patients in the control group.
Trastuzumab improves PFS in uterine serous carcinoma
In patients with uterine serous carcinoma, a rare and aggressive endometrial cancer, trastuzumab added to carboplatin and paclitaxel significantly improved PFS vs chemotherapy alone in a randomized phase II trial.
Among 61 patients with stage III/IV or recurrent HER2-positive disease, median PFS was 12.6 months in the trastuzumab plus chemotherapy arm, compared with 8 months in the chemotherapy alone arm (HR, 0.44; 90 percent CI, 0.26 to 0.76; p=0.005). The corresponding median PFS for patients with stage III/IV disease undergoing primary treatment (n=41) was 17.9 months vs 9.3 months (HR, 0.40; 90 percent CI, 0.20 to 0.80; p=0.013), while that for patients with recurrent disease (n=17) was 9.2 months vs 6 months (HR, 0.14; 90 percent CI, 0.04 to 0.53; p=0.003). Toxicity was similar between the two treatment arms. [J Clin Oncol 2018;36:2044-2051]
Pexidartinib promising for tenosynovial giant cell tumour
Tenosynovial giant cell tumour (TGCT) is a rare neoplasm of the joint/tendon sheath that occurs generally in working-age adults, with no approved systemic therapy currently available. In the global phase III ENLIVEN trial in 120 adult patients with symptomatic TGCT, ORR was 39.3 percent in those randomized to receive the colony-stimulating factor 1 (CSF-1) inhibitor pexidartinib, compared with 0 percent in those receiving placebo. [J Clin Oncol 2018, doi: 10.1200/JCO.2018.36.15_suppl.11502]
After a median follow-up of 6 months, no responders had disease progression. Functional outcomes, including pain scores, range of motion and physical function, were also significantly improved with pexidartinib vs placebo.
However, hepatic toxicities were more frequent with pexidartinib, with eight patients in the pexidartinib group discontinuing treatment due to hepatic effects.According to authors of the ASCO report, the general use of CSF-1 inhibitors is not yet recommended due to the occurrence of serious liver toxicities in some study participants. “The use of CSF-1 inhibitors in TGCT holds promise and continues to be investigated in new clinical trials, with toxicity being part of the focus of an ongoing study,” they noted.