Ipilimumab Combined with Cytotoxic Chemotherapy in Metastatic Melanoma
Ipilimumab (IPI), a fully human anti-CTLA-4 monoclonal antibody, is approved as a single agent for patients with metastatic melanoma (MM) on the basis of increased overall survival compared with an experimental tumor vaccine (glycoprotein 100).1 Longer-term follow-up of patients with MM has demonstrated that patterns of response to IPI are heterogeneous and significantly different compared with chemotherapy and other immunotherapies.2 While objective response and stable disease can be observed within expected time frames, responses have also been documented up to months after IPI initiation. In some cases, response or stable disease with IPI were preceded by apparent disease progression. In short, it may take more time to observe a radiographically detectable change in tumor size with IPI compared with traditional chemotherapy.2
For patients with rapidly progressing BRAF wild-type MM, treatment alternatives include dacarbazine, temozolomide, paclitaxel, and carboplatin combined with paclitaxel (CP).3 Hypothesizing that cytoreduction by CP might provide time for IPI response, Jamal and colleagues (ASCO 2014; Abstract 9066) conducted a randomized phase 2 study of IPI plus CP in patients with unresectable stage III or IV MM. In this trial, 30 patients who received either no prior treatment or 1 BRAF-targeted regimen received IPI (3 mg/kg every 3 weeks x 4) either CP (AUC 6 + 175 mg/m2 every 3 weeks x 5) either concurrently (Arm A) or delayed by 1 week (Arm B). Tumor assessments were conducted at weeks 8, 16, and 24.
The 30 patients in this trial included 24 cutaneous, 2 mucosal, 3 ocular, and 1 unknown primary melanoma. Their median age was 55 years. Six of the
8 BRAF-mutated patients received prior vemurafenib. Twenty-five patients (83%) received all 5 cycles of CP and 28 patients (93%) completed IPI induction. Two patients died prior to week 16 of disease progression. Three patients discontinued CP in light of toxicity. The median follow-up was 24 weeks (range, 8-24).
Efficacy data for the 25 patients who received IPI + CP are summarized in the Table. Preliminary immune marker analyses showed that an abundance of tumor inflammatory cells in pretreatment tissue samples are not predictive of response.
Table: Efficacy Endpoints in Phase 2 Trial of IPI + CP
|Endpoint||All Patients Receiving IPI + CP [n = 30]||IPI + CP, Arm A (concurrent administration) [n = 10]||IPI + CP, Arm B (delayed administration) [n = 20]|
|Overall response rate*||13% (mWHO) 27% (irRC)||20% (mWHO) 20% (irRC)||10% (mWHO) 30% (irRC)|
|Disease control rate||37% (mWHO) 57% (irRC)||60% (mWHO) 70% (irRC)||25% (mWHO)a 50% (irRC)|
|12-month overall survival||67%||NR||NR|
*Responses are reported using modified World Health Organization (mWHO) response criteria, as well as immune-related response criteria (irRC). The irRC were defined in an attempt to capture the unique response patterns observed with ipilimumab in advanced melanoma beyond those described by Response Evaluation Criteria in Solid Tumors (RECIST) or WHO criteria.4
No treatment-related deaths occurred during this trial of IPI + CP in patients with advanced melanoma. Severe (grade 3/4) adverse events (AEs) regardless of causality were observed in 63% of patients. CP-related grade 3/4 AEs occurred in 47% of patients, including hepatotoxicity, electrolyte imbalances, myelosuppression, and infections. Febrile neutropenia occurred in 2 of 30 patients (7%). Five of 30 patients (17%) received corticosteroids for an immune-related AE: grade 3 colitis (n = 2), grade 2 endocrinopathy (n = 2), and grade 2 rash (n = 1).
On the basis of these preliminary findings, amal and colleagues concluded that the combination of IPI and CP is active in patients with BRAF wild-type melanoma whose disease is progressing rapidly. Safety results suggest manageable toxicity when CP is added to IPI, with most patients completing the full course of treatment.
- Yervoy (ipilimumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; December 2013.
- Saenger YM, Wolchok JD. The heterogeneity of the kinetics of response to ipilimumab in metastatic melanoma: patient cases. Cancer Immunity. 2008; 8, 1-7.
- NCCN Guidelines. Melanoma. Version 4.2014. May 2014.
- Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412-7420.