Oligometastatic Melanoma Treated by Metastasectomy in Combination with Immune Checkpoint and BRAF Inhibitors: A Case Series

Background

Historically, the treatment for metastatic melanoma had been relegated to palliative measures. Early therapies improved patient quality of life; however, median survival remained unaffected. Studies are showing that surgical excision with the combination of immune checkpoint inhibitor (ICI) therapy is having better outcomes than systemic therapy alone [1]. In patients who presented with resectable metastases, complete re-section resulted in a median survival of 15 to 20 months and a 5-year survival rate of approximately 20% [2–5]. The Southwest Oncology Group (SWOG) 9430 study described a 4-year overall survival rate of 31% in patients with fully resected disease [6]. However, with ICI therapy, treatment of stage III and IV melanoma has improved.

The development of ICI and targeted therapies has revolutionized the treatment of metastatic melanoma. Ipilimumab, an anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, improved overall survival in patients with metastatic melanoma [7,8]. In 2014, the Food and Drug Administration approved nivolumab and pembrolizumab for treatment of patients with metastatic melanoma who had progressed on ipilimumab or a BRAF-inhibitor. Both nivolumab and pembrolizumab showed superior efficacy when compared with chemotherapy [9,10]. Pembrolizumab had superior progression-free survival, overall survival, and response rates, compared with ipilimumab [11,12]. Thus, physicians have options when developing a treatment plan for patients with metastatic melanoma.

There are factors that make it difficult to choose an optimal treatment. For one, data from randomized control trials comparing ICI and targeted therapies in patients with BRAF mutations remain lacking. The knowledge of a primary site of disease has a possible influence on response. Studies have shown that patients with melanoma of an unknown primary site can have better outcomes with the use of ICI than can those with a known primary site [13].

Establishing those patients with highest risk of incurring distant metastases is challenging, and guidelines are mixed on using serum biomarkers, such as lactate dehydrogenase and S100 calcium-binding protein b, or others, that have low specificity in newly diagnosed metastatic melanoma, like melanoma inhibitor activity or vascular endothelial growth factor. There is emerging evidence regarding the use of circulating tumor DNA as a serial, noninvasive test for tumor mutational analysis, staging, and prognostication [14].

The extent of metastasis plays an important role in choosing an effective treatment strategy. Systemic pharmacologic therapy is the mainstay of treatment for widely metastatic disease [15]. However, metastasectomy is showing promising results for progression-free and overall survival in oligometastatic disease. The definition of oligometastatic disease can be variable. The general principle describes a limited burden of metastases, limited to no more than 5 metastatic regions [16]. We focus on patients with oligometastatic disease within these parameters, understanding that such a definition has yet to be formalized for melanoma.

The advent of targeted and immunotherapies has prompted the re-evaluation of the role of metastasectomy [17]. The most effective treatment for oligometastatic melanoma is likely a multimodal approach, involving both medical and surgical interventions. A recent study showed that surgical resection of distant metastases in patients who responded to ICI had a 5-year overall survival rate of 90% [18]. Furthermore, a meta-analysis performed by Wankhede et al showed that patients who received curative metastasectomies have a significantly lower risk of death than patients who did not have curative metastasectomies [19]. In a time when we are seeing more effective systemic therapies for malignant melanoma, curative metastasectomies are leading to better overall survival for resistant metastases [20,21]. This case series aims to support the argument for curative metastasectomy in patients with oligometastatic melanoma who have responded to ICI and/or BRAF inhibitor therapy.

Case Reports

Metastasectomy After Oligoprogression on ICI and BRAF Inhibitor Therapy

CASE 1: A 52-year-old man presented with a skin lesion on his mid-back in November 2018 (Figure 1). Wide resection revealed melanoma with an ipsilateral axillary lymph node metastasis. The pathology report confirmed a BRAF V600K-positive, stage T4b N2b melanoma that included metastasis to the bone, liver, and spleen.

Therapy with ipilimumab and nivolumab was initiated in March 2019. Restaging computed tomography (CT) in June 2019 showed a pulmonary embolism, resolving a left axillary lymph node, increasing right axillary lymph nodes, bone metastasis, and liver lesions. After cycle 3 was held due to colitis, he was restarted on nivolumab monotherapy in June 2019. A restaging CT scan in August 2019 showed a mixed response, as the right axillary lymph nodes and liver metastases increased in size, while the left axillary lymph nodes decreased. Encorafenib and binimetinib were initiated in August 2019, with a restaging CT scan in September 2019 showing a partial response diffusely. Due to a transaminitis, nivolumab was started in lieu of encorafenib and binimetinib. Serial CT imaging revealed no progression of disease, until a positron-emission tomography (PET)/CT scan in November 2020 showed a hypermetabolic intra-abdominal, mesenteric nodal mass (as shown in Figure 2). The patient was deemed a surgical candidate for curative metastasectomy during his tumor board discussion. In December 2020, he underwent surgical resection of the small bowel and mesenteric nodal mass, confirming malignant melanoma supported by S100+ and HMB45+ tumor cells (Figure 3). He continued on nivolumab monotherapy and was disease-free after 24 months. The follow-up with circulating tumor DNA remained negative at the time of this report.

CASE 2: A 51-year-old man presented with right axillary lymphadenopathy, which showed BRAF V600E-positive melanoma on biopsy in 2013 (Figure 4).

The patient was started on vemurafenib followed by high-dose interleukin-2 and showed stable disease until therapy was stopped due to rash. Vemurafenib was re-initiated after progression of disease but stopped due to rash. In October 2014, dabrafenib was initiated. CT imaging in June 2015 revealed multiple small lung nodules. Further imaging in September 2015 showed a new soft tissue gallbladder lesion, leading to the discontinuation of dabrafenib. The patient transitioned to pembrolizumab. Magnetic resonance imaging (MRI) in January 2016 indicated an increase in the size of his gallbladder metastasis. A laparoscopic cholecystectomy was performed as a day procedure and had negative margins (Figures 5, 6). Follow-up imaging continued to show stable lung nodules. The patient underwent stereotactic body radiotherapy for his lung lesions in August 2016. PET/CT in February 2017 was negative for active disease.

The patient received his last cycle of pembrolizumab in March 2018 and remained in active surveillance without active disease for a total of 54 months, until March 2021. At that time, he presented with abdominal pain and was found to have a pancreatic head mass on CT imaging. Pancreatic adenocarcinoma was diagnosed via endoscopic ultrasound biopsy. His oncologic care was taken over by his gastrointestinal oncology specialist, who directly updated the patient’s melanoma specialist. The patient received mFOLFIRINOX followed by FOLFIRI maintenance until discovery of liver metastases were confirmed as pancreatic in origin. He received gemcitabine and nab-paclitaxel before transitioning to comfort measures and died in January 2023. There were no biopsies of metastatic lesions that showed melanoma.

CASE 3: A 53-year-old woman presented in February 2019 with an erythematous rash that progressed to subcutaneous nodules (Figure 7). A single 0.4-cm skin punch biopsy was performed but likely did not reach deep enough to capture the tumor. A CT scan in October 2019 revealed a lung mass and adrenal masses. PET/CT in November 2019 established the lung lesion and diffuse subcutaneous lesions. Biopsy was notable for BRAF V600K-positive melanoma.

Therapy with ipilimumab and nivolumab was initiated in November 2019. MRI of the brain revealed metastasis, for which the patient received stereotactic radiosurgery in December 2019. PET/CT after cycle 3 in January 2020 showed significant radiologic response. She was transitioned to maintenance nivolumab.

In February 2020, restaging MRI of her brain showed interval development of an intrasellar mass, suspicious for pituitary metastasis, as well as a 7-mm nodular enhancing focus in the right posterior temporal lobe. A subsequent restaging MRI of the brain in May 2020 showed interval resolution of her previously noted brain metastases. There was no evidence of active disease. This continued until imaging in October 2020 revealed a small bowel mass, with mesenteric lymphadenopathy (as shown in Figure 8). The patient underwent surgical excision of the 4.7-cm small bowel mass. The pathology report revealed malignant melanoma, supported by lesional cells testing diffusely positive for SOX10 and patchy positive for Melan A (Figure 9). She continued on nivolumab monotherapy, without disease progression for 10 months, before developing a hypermetabolic, anterior rib lesion of unclear etiology. There was no evidence of further progression of her disease for an additional 3 months until her death. The cause of her death was not made known to her medical team but was suggested to be unrelated to her malignancy.

CASE 4: A 34-year-old man presented in December 2017 with left axillary fullness (Figure 10). Biopsy results indicated a regressed melanocytic lesion. PET/CT and brain MRI revealed no distant disease. Axillary dissection and subsequent pathology in March 2018 confirmed stage IIIc N3b and BRAF V600E- and TP53-positive malignant melanoma.

Therapy with nivolumab monotherapy was initiated in May 2018. A restaging CT scan in July 2018 revealed a new right perinephric mass and subcutaneous chest wall mass. PET/CT in August 2018 showed a hypermetabolic lesion to right upper lobe of the lung, an active right retroperitoneal lymph node, and right chest wall lesion. Encorafenib and binimetinib were started. PET/CT in October 2018 indicated a mixed response, with an increase in the right chest wall mass, while showing resolving retroperitoneal and cardiophrenic lymph nodes. Resection of the right axillary lymph node and chest wall nodule returned positive for melanoma, with 1 of 7 nodes with rare SOX10-positive cells (Figure 11). From November to January 2019, the patient experienced persistent epigastric pain and diarrhea. The gastroenterology team performed a small bowel enteroscopy and colonoscopy in January 2019. A jejunal biopsy was positive for melanoma. Dabrafenib and trametinib were started. Restaging imaging indicated a good response, until PET/CT in May 2019 revealed an increasing small bowel mass and persistent small cardiophrenic lymphadenopathy (as shown in Figure 12). In May 2019, pembrolizumab was added off-cycle to dabrafenib and trametinib before transition to pembrolizumab monotherapy in June 2019. A restaging CT scan in August 2019 exhibited an increasing small bowel mass and pericardiac lymph node. He was transitioned to ipilimumab and nivolumab in August 2019.

In September 2019, he underwent a small bowel resection. The pathology report confirmed malignant melanoma. A restaging CT scan in December 2019 showed a small bowel lesion and intra-abdominal lymphadenopathy with soft tissue and pulmonary lesions. PET/CT appreciated a new small bowel lesion but less prominent pericardiac lymphadenopathy. In January 2020, dabrafenib and trametinib were restarted and continued through July 2020. The patient completed his last cycle of nivolumab before active surveillance in July 2021. He was disease-free at 39 months. The follow-up with circulating tumor DNA remains negative.

CASE 5: An 82-year man presented with an irregularly shaped forearm lesion (Figure 13). A shave biopsy of the forearm lesion revealed a malignant melanoma. A left axillary sentinel lymph node excision confirmed metastatic melanoma, involving 2 out of 4 lymph nodes, with focal capsular invasion present. A left axillary lymph node dissection revealed BRAF-negative, NRAS-positive melanoma in November 2009. After CT imaging revealed concerning lesions, a biopsy of the lung and bone lesions revealed metastatic disease in September 2011.

He started on ipilimumab in 2011 and had completed 4 cycles by January 2012, when a restaging CT revealed no active disease. A new left axillary lymphadenopathy was discovered in September 2015, with PET/CT indicating a left axillary lesion in October 2015. He started on pembrolizumab. A left axillary dissection was performed in February 2016. PET/CT in May 2016 showed multiple, small soft tissue lesions. He restarted ipilimumab in June 2016. A restaging CT scan in August 2016 revealed a decrease in disease burden. PET/CT in December 2016 showed an increase in her left axillary lymphadenopathy and a small bowel lesion. By March 2017, the axillary lymph-adenopathy had resolved, but the small bowel lesion increased (as shown in Figure 14).

In April 2017, he underwent a small bowel resection. The pathology report confirmed malignant melanoma, staining positive for S100 and MiTF (Figure 15). Restaging CT scans have shown no active disease. At the time of this report, he had been disease-free through the last imaging in November 2022, for a total of 67 months.

CASE 6: A 72-year-old man presented with a painless left parotid mass (Figure 16). A left parotid gland lymph node was biopsied in June 2020. The pathology report was consistent with BRAF-negative melanoma.

PET/CT in July 2020 revealed a right-lower-lobe mass, consistent with melanoma on biopsy (Figure 17). Pembrolizumab was initiated in August 2020. A unilateral radical left neck dissection was performed, with the pathology report confirming malignant melanoma, supported by SOX10-positive staining. In September 2020, the patient underwent a right-lower-lobe wedge resection, with pathology was consistent with treated metastatic melanoma (shown in Figure 18).

The patient has continued on pembrolizumab, without signs of disease recurrence. His last imaging was performed in November 2022, giving him a disease-free state for 27 months from his neck dissection.

CASE 7: A 75-year-old man with a history of metastatic prostate cancer in 1999 and melanoma surgically removed from his left facial cheek in 2001 presented with a lung lesion (Figure 19).

PET/CT in February 2019 revealed a 2.7-cm right-lower-lobe lung mass, concerning for primary pulmonary malignancy. A follow-up PET/CT scan in May 2019 redemonstrated this lesion (as shown in Figure 20). July 2019, brain MRI was negative. CT revealed a stable pulmonary lesion. A CT-guided core biopsy of the lung lesion demonstrated metastatic melanoma, supported by positive immunohistochemical staining for SOX10, Melan A, and S100 (focal). Targeted next-generation sequencing was negative for mutations in BRAF, CKIT, and NRAS. In August 2019, right-lower-lobe lobectomy was performed, confirming a 3.5-cm metastatic melanoma with 10% necrosis and 13 lymph nodes, negative for malignancy (Figure 21).

After 17 cycles of pembrolizumab, the patient was transitioned to active surveillance in October 2020. He continues to be disease-free at 40 months, based on imaging.

Discussion

METASTASECTOMY AFTER OLIGOPROGRESSION ON ICI AND BRAF INHIBITOR THERAPY:

In these cases, patients developed oligoprogression of metastatic, BRAF-positive melanoma while undergoing ICI and BRAF inhibitor therapy. The order of therapies was different as the patient in case 1 started on ICI therapy before transitioning to BRAF inhibitor therapy, whereas the opposite was true in case 2. Both conferred a therapeutic response prior to oligoprogression.

The decision was made to surgically remove the progressing metastasis and monitor each patient’s response. At the time of this report, both remained with no active disease following their metastasectomies, as the patient in case 1 is now 24 months disease-free, while the patient in case 2 is 67 months from his last known melanoma lesion.

In previous approaches, progression of metastases could characterize a therapy as failed and relegate a patient to palliative measures. In this case series, surgery remained a curative option for patients who had oligoprogression while otherwise responding well to ICI or BRAF inhibitor therapy. Performance status and the technical aspects of surgery should be considered, because it is possible that a simple laparoscopic cholecystectomy can have significant treatment effects for a patient, as shown in case 2. Thus, treatment teams should include surgeons in the care of similar patients with oligoprogression to provide the best possible outcomes.

GASTROINTESTINAL METASTASECTOMY AFTER ICI AND/OR BRAF INHIBITOR THERAPY:

In cases 3, 4, and 5, patients received ICI and/or BRAF inhibitor therapy for metastatic melanoma with gastrointestinal lesions. These patients demonstrated a good response to pharmacologic therapy, while showing no active disease after metastasectomy.

Gastrointestinal metastases have been particularly difficult to treat in the past for many reasons. For one, abdominal surgeries can often take a large toll on the patient, especially when the patient has such debilitating health problems as metastatic melanoma. The patient’s performance status could preclude them from being an operative candidate. Furthermore, a risk in gastrointestinal metastases is uncontrolled gastrointestinal bleeding. Many patients died due to bleeding from gastrointestinal metastases, because of limited treatment options.

Recent studies show that intra-abdominal metastasectomy in combination with effective systemic therapies improves median survival (32 vs 9.5 months) [27]. These cases highlight examples of how effective treatment of metastatic melanoma can be for patients with gastrointestinal metastases, with the use of ICI and/or BRAF inhibitor therapy in combination with metastasectomy. These patients had significant responses to pharmacologic therapy. This narrowed their metastatic burden. Small bowel resection removed the gastrointestinal metastases, the risk of bleeding from these sites, and provided a curative option.

METASTASECTOMY AFTER ICI THERAPY IN BRAF-NEGATIVE MELANOMA:

In case 6, the patient underwent metastasectomy after responding well to ICI therapy. This case is consistent with previous studies that reveal improved survival for patients receiving metastasectomy after first responding well to ICI therapy [18,26]. One aspect of this case that differs from our other patients is the patient’s BRAF-negative status. The outcome for this patient was similar to our others, as he remained disease-free. This suggests that metastasectomy can be a viable curative therapy regardless of this BRAF mutation status.

METASTASECTOMY PRIOR TO ICI THERAPY IN BRAF-NEGATIVE MELANOMA:

Case 7 involves a patient with metastatic melanoma who underwent metastasectomy prior to directed pharmacologic therapy. The patient underwent a right-lower-lobe resection of a suspicious lesion. The pathology report revealed the lesion to be metastasis of a previously known melanoma, due to the unknown nature of the primary cancer. He began ICI therapy after metastasectomy. This case suggests that the timing of surgical intervention can be flexible in patients with oligometastatic melanoma who ultimately respond well to ICI therapy. It is possible that these patients have positive outcomes with metastasectomy prior to pharmacologic therapy that are similar to the outcomes of those who receive pharmacologic therapy first.

Conclusions

This case series continues the findings of recent studies, showing survival benefit for patients with oligometastatic melanoma who received curative metastasectomy after a good response to ICI and/or BRAF inhibitor therapy. At the time of this report, our first and third subgroups continued to show no evidence of disease after curative metastasectomy. Meanwhile, the second subgroup suggests patients with oligometastatic melanoma involving the gastrointestinal system benefit from metastasectomy. Surgical removal of suspect lesions could prevent uncontrolled gastrointestinal bleeding and have evidence of survival benefit. Finally, our fourth subgroup demonstrated that the timing can be flexible in the right context. In the recent past, the patients in this case series could have been described as having unresectable melanomas, given the overall burden of disease. Here, however, ICI and/or BRAF inhibitor therapy combined with metastasectomy provided a possible curative option for such patients.

The extent to which we can expand our approach to metastasectomies warrants further investigation. It is clear that conversations with surgical specialists should be started at patient presentation. Metastasectomy prior to pharmacologic therapy can be effective in the right context. An expanded study on this possibility looking at location of metastasis, extent of disease, and genetic makeup of disease should be accounted for. Patient selection at this time should be limited to those with oligometastatic disease (no more than 5 metastatic regions), those who have or are expected to respond well to ICI and/or BRAF inhibitor therapy, and patients with a performance status conducive to surgical intervention (ECOG 1 or better).

This case series reiterates survival benefit for patients who received metastasectomy after exhibiting good response to ICI therapy. ICI and/or BRAF inhibitor therapy combined with metastasectomy provides a possible curative option for patients who may have previously been relegated to palliative-focused care. By using a multimodal approach with oncologists and surgeons, we can challenge our understanding of what constitutes a resectable cancer and improve overall survival for patients with oligometastatic melanoma.