Mixed Response to Immunotherapy in Patients with Metastatic Melanoma

Abstract

Background: Immunotherapy has improved overall survival in metastatic melanoma. Response to therapy can be difficult to evaluate as the traditionally used RECIST 1.1 criteria do not capture heterogeneous responses. Here we describe the clinical characterization of melanoma patients with a clinically defined mixed response to immunotherapy.

Methods: This was a single institution, retrospective analysis of stage IV melanoma patients who received first-line anti-CTLA-4, anti-PD1, or combination anti-CTLA-4/anti-PD1. Therapy response was assessed via clinical definitions, which consisted of cross-sectional imaging combined with clinical exam. Course of disease, clinicopathological characteristics, and management in patients with a mixed clinical response were analyzed.

Results: In 292 patients (anti-CTLA4 = 63; anti-PD1 = 148, anti-CTLA4/anti-PD1 = 81), 103 were responders (35%), 64 mixed responders (22%), and 125 patients had progressive disease (43%). Of patients with a mixed response, 56% eventually had response to therapy (mixed response followed by response, MR-R), while 31% progressed on therapy (MR-NR). MR-NR patients had higher median LDH (p < 0.01), 3 or more organ sites with metastases (p < 0.01), and more frequently had M1d disease (p < 0.01). Mixed responders who underwent surgery (n = 20) had a significantly longer mean OS compared to patients who did not undergo surgery (6.9 years, 95% CI 6.2-7.6 vs. 6.0 years, 95% CI 4.6-7.3, p = 0.02).

Discussion: Mixed response to immunotherapy in metastatic melanoma was not uncommon in our cohort (22%). Clinical characteristics associated with progression of disease after initial mixed response included higher LDH, brain metastases, and ≥ 3 organ sites with metastases. Surgical treatment for highly selected patients with a mixed response was associated with improved outcomes.

Fig. 1

Experimental selection scheme according to clinical classification and RECIST 1.1. Two hundred ninety-two patients with metastatic melanoma were classified by combined clinical/radiographic findings into responder categories: responder (blue), mixed responder (green), and non-responder (red). The black boxes compare RECIST 1.1 categories in a subset of the clinically defined cohorts and demonstrate that the majority of the mixed responders fall into the stable disease (SD) category according to RECIST 1.1. Within the mixed responder cohort, we categorized subsequent response from the time of clinical mixed response

Fig. 2

Overall survival. A Kaplan–Meier overall survival per clinical response categories, and B by RECIST 1.1. A Utilizing our clinical categories, the mixed responders (green) have an intermediate response as compared to responders (blue) and non-responders (red). B The patients with a partial response (PR) and stable disease (SD) by RECIST 1.1 have an intermediate survival as compared to those with a complete response (CR) or progressive disease (PD)

Fig. 3

Clinical mixed response group. A Within the mixed response clinical group, those with a mixed response and subsequent response (MR–R) comprised 59% of the cohort. A subset of these patients had RECIST 1.1 data for comparison: 43% had SD and 57% had a PR by RECIST. B In the subset (9%) of mixed responders with a persistent mixed response, RECIST 1.1 evaluation categorized them as SD (100%). C In the mixed responder subset with eventual progression (MR–NR) (31%), RECIST 1.1 data was available in a subset. These patients were characterized as either SD (78%) or PD (22%)

Fig. 4

Description of mixed responder categories. A Schematic of mixed responders—mixed responders with subsequent responses were more likely to be younger, have BRAF V600E/K mutations, have fewer than 3 sites of disease, low LDH, and no brain metastases. B Kaplan–Meier overall survival curves for mixed responders with subsequent response (MR–R) versus those who subsequently progress (MR–NR)

Fig. 5

Management of mixed responders. A Swimmer plot showing subsequent treatments in mixed responders. MR–R (blue), MR–NR (red), radiation (yellow triangle), surgery (green square). B Surgery in patients with a mixed response. In our cohort, 36% of patients had surgery after being categorized as mixed responders. Of these patients, 50% had visceral metastasectomy, 25% had a subcutaneous metastasectomy, 20% had a lymph node dissection, and 15% had a craniotomy