Selumetinib is well tolerated, and is active in the treatment of recurrent low-grade serous carcinoma. The median PFS was 11 months, with PFS >6 months in 63% of patients. In exploratory analyses, response to Selumetinib did not appear to be related to RAS/RAF mutational status. These results are appealing because LGSC have been increasingly recognized as more chemoresistant than HGSC, with the majority of patients (88%) having positive second-look surgery.10,12,15–17
. Persistent disease after primary chemotherapy was the only factor associated with shorter OS time.10
Primary peritoneal carcinoma (PPC) is histologically indistinguishable from epithelial ovarian cancer, and has similar clinical characteristics, patterns of spread, response to treatment, and survival rates.16,18
Low-grade serous PPC also appears to have similar clinical characteristics as low-grade serous ovarian cancer. At the completion of primary treatment consisting of maximal surgical cytoreductive effort followed by adjuvant chemotherapy, 66·7% of low-grade serous PPC patients were noted to have persistent or progressive disease. The 5-year PFS was 16%, yet the five-year OS was 69%.16
In the recurrent setting, the chemo resistance of LGSC is even more profound. An evaluation of 58 patients from the University of Texas MD Anderson Cancer Center with recurrent LGSC who received 108 separate chemotherapy regimens (“patient-regimens”), revealed four responses—(one complete and three partial); for an overall RR (ORR) of 3·7% (11). The median time to progression was 29 weeks.12
This is in stark contrast with data from previous reports of ovarian cancer trials, which predominantly involved patients with HGSC.19,20
In platinum-sensitive disease HGSC patients treated with a taxane-platinum drug combination, RRs ranged from 66% to 90%, with median PFS durations of nine to 19 months.21,22
In phase III studies of women with platinum-resistant/refractory disease, reports on several chemotherapeutic agents produced RRs in the range of 15%-30%.12,23,24
PFS durations generally ranged from 2–6 months. These cytotoxic chemotherapies carry associated toxicity. Twenty nine percent of patients experienced grade 3–4 toxicity. 12,23,24
Thirty eight percent of patients receiving gemcitabine, 71% of topotecan patients, and 19% of pegylated liposomal doxyrubicin patients experienced grade 3 or 4 toxicities. The majority of grade 3–4 toxicities were hematologic for topotecan and gemcitabine 77% and 38% respectively and palmar-plantar erythrodysesthesia and stomatitis 22% and 9%, respectively, for pegylated liposomal doxyrubicin (PLD). Fatigue (grade 2, 3, or 4) also is higher with gemcitabine and topotecan compared with PLD. This compares to the 6% G4 toxicity overall, with one(2%) G3-4 hematologic toxicity observed in the current study. There was a 25% grade 3 gastrointestinal toxicity and 17% grade 3 dermatologic toxicity observed however these were tolerable and manageable.
The chemoresistant nature of recurrent LGSC to cytotoxic chemotherapy makes effective alternative molecular therapies of paramount importance. The poor observed RR of recurrent LGSC patients in the MD Anderson cohort was in the most favorable setting, 53% of patients having received only one prior cycle of chemotherapy. While there was no control group specifically in the current trial and cross trial comparisons can be fraught with statistical imprecision, in the current trial the majority of patients (57%) had three or more prior chemotherapy regimens compared to 25% in the MD Anderson cohort.12
Despite this heavily pretreated condition, the disease stability rate of 65% and median PFS of 11 months is substantially improved over that observed with the MD Anderson cohort of 60% and 7.3 months, respectively. The activity of Selumetinib in recurrent LGSCs confirms the importance of targeting the MAPK pathway in this subset of patients.
At the time this study was planned, a high frequency of BRAF and KRAS mutations in LGSCs had been observed, and our hypothesis that MAPK inhibition would be a potentially active therapeutic intervention was based on this observation. Our results suggest that Selumetinib is an active agent, but not necessarily because of BRAF or KRAS mutational activation per se, as determined by limited archival specimen analysis. Given the current regulatory trends and recommendations for clinical trial design that are moving in a more restrictive direction this was an important and potentially provocative decision. The decision to allow patients with and without BRAF or KRAS mutational activation proved to be appropriate. Unless the evidence for limiting eligible patient populations is compelling, trial design must allow the hypothesis to be adequately tested clinically. A limitation of our correlative study is that the concordance of BRAF or KRAS mutational activation between primary and recurrent/metastatic disease has not been adequately studied. Additionally, if significant tumor heterogeneity exists and the mutation containing cells account for less than 10% of the specimen it is possible that a mutation was not detected.
Given the robust activation of the MAPK pathway in LGSCs, molecular targeting of this pathway provides a logical treatment option for patients with this disease. Additionally, both the angiogenesis pathway and the IGF/insulin axis are attractive molecular targets also worth exploring in LGSC in combination with MAPK inhibitors. In the current study Selumetinib exhibits considerable activity in recurrent low-grade serous tumors. The 15% RR is 4X that observed for cytotoxic chemotherapy in the setting of recurrent low-grade serous tumors. The regimen also has considerable less toxicity when compared to cytotoxic regimens with a 6% incidence of grade 4 toxicities which is substantially less than the 18%–71% rate observed for cytotoxic agents. Additionally, Selumetinib displayed a robust disease stability rate with a median PFS of 11 months, and 63% of patients experiencing a PFS >6 months duration. These results warrant further evaluation of inhibitors of the MAPK pathway in LGSCs.