Efficacy of Ipilimumab and Nivolumab Rechallenge in a Long-Term Melanoma Survivor: A Case Report

Abstract

Patient: Female, 40-year-old

Final Diagnosis: Malignant melanoma

Symptoms: Change in size and symmetry of mole • FDG avid soft tissue recurrence

Clinical Procedure: —

Specialty: Oncology

Objective: Unusual clinical course

Background

The combination of anti-CTLA4 and anti-PD-1 immune checkpoint inhibitors (ICIs) has replaced chemotherapy as the most effective first-line therapy for advanced-stage melanoma, associated with a median overall survival of 72 months. Irrespective of BRAF status, ipilimumab-nivolumab (IPINIVO) is the most effective first-line approach but treatment-limiting toxicities are twice as common as with other ICIs. In recurrent disease, rechallenging with the same dual therapy has not shown great efficacy, although rechallenge with ipilimumab (anti-CTLA-4) is not well studied. Reported studies were limited by small sample sizes and populations with recurrence <24 months after initial therapy.

Case Report

We present a 40-year-old woman with a history of resected stage IIIc, BRAF wild-type melanoma, previously treated in the adjuvant setting with low-dose IPINIVO (1: 3 mg/kg ipilimumab: nivolumab), with systemic progression in the peritoneum 7 years later, showing nodularity and ulceration at the original site with progressive abdominal and pelvic pressure. The patient was rechallenged with standard-dose IPINIVO (3: 1 mg/kg iplimumab: nivolumab) and achieved excellent clinical response despite multiple treatment-delaying toxicities: grade 2 cytokine release syndrome after cycle 1 and grade 2 pneumonitis and grade 3 colitis after cycle 2, managed with high-dose prednisone. The patient remains on maintenance nivolumab with ongoing radiographic and clinical response for over 18 months.

Conclusions

There are limited data on the benefit and safety of IPINIVO with rechallenge in patients who achieved initial PFS longer than 2 years, warranting further research in populations with resistant disease. Long-term safety data from rechallenge responders are needed.

Introduction

Before the advent of immune checkpoint inhibitors (ICIs), IL-2, dacarbazine, and dabrafenib chemotherapy were approved for treatment of metastatic melanoma [1–3]. The overall survival benefit was estimated at 2–10% [1,2,4].

In the past two decades, improved understanding of T cell regulatory function and the roles of CTLA-4, PD-1, and LAG-3 transformed cancer treatment [5]. CTLA-4, expressed on activated T cells in the tumor microenvironment, competes with CD28 on T cells to bind to antigen-presenting cells. This function limits co-stimulatory signaling to prevent premature T cell activation. It also inhibits Akt pathway activation to reduce co-stimulatory ligand availability [6]. PD-1 is expressed on activated T cells, binding to PD-L1 and PD-L2 ligands expressed in the tumor microenvironment, which promotes downstream inhibition of signaling molecules important for T cell proliferation and cytokine production [7]. Similarly, LAG-3, expressed in exhausted T cells, binds with ligands in the tumor microenvironment to suppress T cell activation [8]. These T cell receptors are checkpoints that limit T cell function, helping cancer cells evade immune attack.

Among patients with advanced melanoma, therapies targeting these receptors have extended survival by several years for many, with overall survival exceeding 50% [9]. Ipilimumab (anti-CTLA-4) was approved by the FDA in 2011 after results of a phase III trial in which patients with unresectable stage 3 or 4 melanoma received ipilimumab 3 mg/kg every 3 weeks for up to 4 treatments versus glycoprotein 100 vaccine alone improved overall survival from 6.4 months to 10 months [10]. Subsequently, pembrolizumab (anti-PD-1) and nivolumab (anti-PD-1) were both approved by the FDA in 2014 [11,12].

Several studies have since explored ipilimumab in combination with anti-PD-1 therapy, revealing superior outcomes with enhanced overall survival compared to ipilimumab monotherapy [13–16]. In 2022, the FDA approved the combination of nivolumab-relatlimab (anti-PD-1-anti-LAG-3) after a phase 3 trial revealed fixed-dose nivolumab (480 mg) and relatlimab (160 mg) had longer progression-free survival at 10.2 months compared with nivolumab monotherapy at 4.6 months at 3-year follow-up [17].

The associated toxicities of all immunotherapies include allergic reactions (hives, facial edema, difficulty breathing), rashes, pneumonitis, colitis, hepatitis, and endocrinopathies [18]. Close monitoring is required as severe grades of these toxicities are dose-limiting.

Despite the overall improvement in melanoma management with ICIs, resistance to immunotherapy poses a challenge. Proposed mechanisms of resistance include loss of antigen expression that differentiates melanoma cells from non-cancer cells, impaired MHC expression from defects in IFNy signaling, insufficient T cell infiltration, and abnormal lipid metabolism [19,20]. In recurrent disease, reinduction with the same ICI has not shown great efficacy, although rechallenge with ipilimumab is not well studied. When investigated, it was mostly applied to populations with median recurrence-free survival of less than 2 years, with only 1 study including a small number of patients with late progression [21–24]. Moreover, reinduction with monotherapy or combination therapy in these trials mostly achieved disease stability that was short-lived (less than 6 months) or had disease progression with recurrent toxicities [21–24]. However, recent data revealing significantly longer progression-free survival periods prompts the question as to whether, in patients with delayed recurrence, resistance can be bypassed by rechallenging with the combination of ipilimumab-nivolumab (IPINIVO).

Case Report

A 40-year-old woman with history of stage IIIc malignant melanoma of the back, in remission for 7 years, was found to have FDG-avid soft tissue recurrence near the primary surgical site on surveillance PET CT. She was initially seen in consultation at age 33 years due to a change in the size and symmetry of a pre-existing mole on her back, with pathology revealing 1.5 mm thickness without ulceration, lymphovascular invasion, and 1 mitosis/mm². A right axillary sentinel node biopsy was positive for metastatic disease; no extranodal extension was observed on pathology. She was effectively treated with wide surgical excision and 6 months of adjuvant combination therapy with low-dose IPINIVO (1: 3 mg/kg ipilimumab: nivolumab) (Figure 1) [25]. At the time of recurrence, it was unclear whether the new findings represented nodal spread or subcutaneous metastasis. PET imaging reported an FDG-avid 1.6×1.0 cm subcutaneous nodule overlying the left infraspinatus muscle (SUV max 11.5). The patient underwent wide local excision, with pathology revealing multifocal disease in the subcutaneous tissue and dermis, BRAF wild-type, with the largest tumor deposit measuring 13.5 mm. Genomic sequencing of the tissue indicated a high tumor mutational burden (12 mut/Mb).

Figure 1.

Schematic of patient treatment course. Red – progression of disease on treatment; Blue – regression of disease on treatment; Purple – recurrence-free survival period.

After tumor board discussion, she began adjuvant nivolumab therapy (480 mg every 4 weeks) for an anticipated 12-month course. After 4 cycles administered between 6/15/23–9/7/23, a repeat PET CT on 10/15/23 revealed local metastatic recurrence in the subcutaneous left upper back, not appreciable on exam, with no evidence of distant metastases.

Treatment transitioned to combination nivolumab-relatlimab (anti-LAG-3) dosed at 480 mg-160 mg (Figure 1). She received a total of 4 cycles between 10/16/23 and 1/11/24, with the course complicated by wound dehiscence and distant metastases (Figure 2). After cycle 1, the patient self-detected new nodularity at the primary site. She received cycle 2 and underwent radical resection in the same week (11/20/23). On 1/4/24, 2 weeks after cycle 3 and 6 weeks after surgical resection, she presented to the emergency department with wound dehiscence and drainage from the surgical site. A wound vac was placed but she continued to experience slow persistent bleeding from the site with an increase in wound cavity size and new nodularity in the surgical bed and margins. To slow the bleeding, she underwent 40 Gy/10 fractions radiation therapy. During this time, she also began experiencing abdominal discomfort and pelvic pressure. Systemic staging revealed distant metastases to the lungs and peritoneal cavity with small ascites (Figure 2).

Figure 2.

Change in clinical and radiographic disease on immunotherapy. (A) On nivolumab-relatlimab; (B) Peritoneal metastases on nivolumab-relatlimab; (C) Lung metastasis on nivolumab-relatlimab; (D) After cycle 1 of ipilimumab-nivolumab; (E) Regression of peritoneal metastases after cycle 1 of ipilimumab-nivolumab; (F) Regression of lung metastasis after cycle 1 of ipilimumab-nivolumab; (G) One month after cycle 4 of ipilimumab-nivolumab; (H) After 1 year on maintenance nivolumab.

Given the rapid disease progression and limited available treatment options, the patient was rechallenged with standard-dose IPINIVO (3: 1 mg/kg ipilimumab: nivolumab), completing 4 cycles between 2/15/24 and 8/19/24, with excellent clinical and radiographic response (Figure 1). Four weeks after cycle 1, repeat imaging revealed marked improvement in the many nodules noted throughout the peritoneal cavity and the 2 cm right basilar lung mass, nearing complete resolution (Figure 2). The treatment course was complicated by multiple treatment-delaying toxicities. Following reinduction with cycle 1, the patient was hospitalized with grade 2 cytokine release syndrome which improved with intravenous fluids, high-dose steroid taper, and a 5-day antibiotic course. Eight weeks after cycle 1, the patient received cycle 2. About 2 weeks after the infusion, she was diagnosed with grade 2 pneumonitis for which a high-dose steroid taper was initiated. Nearing completion of the steroid taper, the patient was hospitalized for severe diarrhea proven to be grade 3 colitis which improved with a high-dose steroid regimen tapered over 8 weeks. Cycle 3 was administered 10 weeks after cycle 2 and cycle 4 was administered 6 weeks after cycle 3, delayed due to antibiotic treatment of wound cellulitis. Presently, she remains on maintenance nivolumab (240 mg every 2 weeks) without evidence of disease progression (Figure 1). The most recent imaging showed stability of known sub-6 mm pulmonary nodules, with no definite evidence of FDG-avid malignancy on PET CT.

Discussion

At the time of the patient’s initial diagnosis, chemotherapy was the standard of care. Alternative immunotherapies were accessible to patients through clinical trials and overall survival information was not available. In 2011, ipilimumab received FDA approval for treatment of advanced-stage melanoma, noting longer progression-free survival compared to standard therapy, offering new hope for curative management in late-stage disease [26]. By 2015, the standard of care shifted to ICIs as further FDA approval was given for nivolumab, pembrolizumab and subsequently for combinations ipilimumab-nivolumab and nivolumab-relatlimab [17,18,25,27–30].

Despite the significant improvement in progression-free survival, reaching 50% from 5%, ICI resistance remains a challenge, with estimates as high as 40–70% of patients experiencing primary resistance and 30–40% experiencing progression after initial response [9,31]. For patients who experience ICI failure, guidelines advise treatment with alternative agents including various ICIs, BRAF/MEK inhibitors, targets against MAP kinase, and combination carboplatin-paclitaxel [31,32]. Other chemotherapies including dacarbazine, temozolomide, and fotemustine may be prescribed with palliative intent [32].

It is believed that low tumor mutational burden, insufficient antigen presentation and T cell priming, and factors related to tumor angiogenesis are drivers of resistance [9,19,20]. Research has shown that the loss of interferon gamma signaling interferes with the rejuvenation and infiltration of tumor-infiltrating lymphocytes mediating resistance [26]. Longer overall survival was observed in cancers with high tumor mutational burden defined as ≥10 mut/Mb, but an overall benefit was still seen in patients with disease with low tumor mutational burden [33,34]. It was also determined that the migration and invasion of melanoma cells is controlled by the epithelial-mesenchymal transition mediated by MFAP2, an extracellular matrix protein, through activation of the Wnt/b-catenin signaling pathway [35]. Mutations in tumor cells favoring activation of this pathway may contribute to drug resistance.

Evidence suggests that the reinduction of ICIs has a <30% response rate due to acquired resistance [21]. Suggested targets to overcome resistance include inhibition of aberrantly active JAK1/2, which enables downstream suppression of interferon, as well as intratumoral injection of Toll-like receptor 9 agonists that act synergistically with anti-PD-1 therapy to engage T cells [26]. Investigation into azacitidine and carboplatin as a primer to avelumab (anti-PD-L1) therapy with the goal to re-establish sensitivity to ICIs revealed a median progression-free period of 18 weeks with 10% overall response rate, but use of azacitidine and carboplatin with the FDA-approved ICIs for melanoma has not been reported, to our knowledge, in patients with this disease [36]. The use of anti-VEGF with pembrolizumab in patients with PD1 resistance achieved partial response in cases of mucosal melanoma and prevented disease progression in cases of ocular melanoma [37].

Additional trials have explored IL-2 or IL-12 in combination with immune checkpoint therapy [38–41]. In combination with tumor vaccine, high-dose IL-2 was shown to improve 5-year survival to 40% from 13% if IL-2 was delivered alone [42].

Others have applied tumor-infiltrating lymphocyte (TIL) therapy to reinvigorate the immune response in the tumor microenvironment [43,44]. Through extraction and ex vivo growth of autologous lymphocytes found within the tumor microenvironment, TIL therapy offers the administration of a more robust and tailored immune attack. In its early application, TIL and IL-2 applied to 20 patients with metastatic melanoma achieved an objective response rate of 60% in IL-2-naïve patients and 40% in IL-2-exposed patients [45]. A more recent larger analysis of 153 patients with high tumor mutational burden who previously failed a median of 3 prior therapies with at least 80% having anti-PD-1 and anti-CTLA-4 treatment revealed an overall response rate of 31%, with median progression-free survival of 4.1 months and overall survival of 13.9 months [46]. Administration of ipilimumab with TIL therapy in 13 patients with metastatic melanoma achieved 38.5% objective response at 12 weeks, with median progression-free survival of 7.3 months [43]. These reports show a promising alternative for patients with limited options.

When comparing the administration of alternate ICIs after primary resistance to either anti-PD1 or anti-CTLA-4, it was determined that treatment with anti-PD-1 in those with resistance to anti-CTLA-4 had an objective response rate of 43% and a disease control rate of 53%, while those with initial anti-PD-1 resistance had an objective response rate of <18% and a disease control rate of 25% when treated with anti-CTLA-4 [9]. For both groups, the median time to progression was under 6 months. The difference between groups may be related to evidence that anti-CTLA-4 treatment increases tumor lymphocyte infiltration; therefore, even if resistance occurs, those with anti-CTLA-4 exposure may have altered tumor microenvironments favoring immunologic response to repeat ICI therapy [9]. This may help explain our patient’s favorable response to rechallenge with anti-CTLA-4 compared to her disease progression with anti-PD-1 and anti-LAG-3 treatment.

Further research into potential biomarkers and predictive indicators for responders to ipilimumab rechallenge is necessary. In our case, the patient’s high tumor mutational burden and prolonged recurrence interval may be favorable indicators to consider when evaluating a patient for reinduction. However, evaluation of the tumor microenvironment may elucidate other favorable indicators, as shown by a recently published risk model that included tumor mutational burden and microenvironment features to help guide ICI prescribing [34].

Case reports are not intended to be presented as practice-changing and cannot provide any definitive guidelines for future treatment recommendations but can offer data to promote investigation in larger cohorts. Follow-up on long-term safety in rechallenge responders is required.

Conclusions

As research continues to increase our understanding of ICIs, it would be beneficial to investigate whether rechallenge with standard-dose ipilimumab-nivolumab can bypass disease resistance in patients with delayed recurrences. Larger, multicenter, randomized trials evaluating overall response rate and progression-free survival with ICI reinduction may establish a new approach to management of drug-resistant melanoma.