Hyperprogression after nivolumab for melanoma: A case report

Introduction

It is estimated that 2%–5% of patients with melanoma present with distant metastatic disease. Those patients who were present with distant metastatic melanoma have a poor prognosis, with a reported median survival time of six to eight months. ¹ While new approvals of immunotherapeutic and targeted agents have implemented in patients with more treatment options for the initial management of stage IV disease, many of these agents present unusual restrictions.

Nowadays, immune checkpoint inhibitors (ICIs) such as nivolumab are used in the treatment of many different types of cancer. ² The approval of nivolumab was based on the results of Checkmate-037, a phase 3 randomized, controlled, open-label study of nivolumab versus investigator’s choice chemotherapy in patients with advanced melanoma who previously received ipilimumab. ³ Nivolumab was approved for the treatment of advanced melanoma in Turkey in April 2017.

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Figure 1.

PET/CT scan images before (on the left) and after (on the right) the nivolumab therapy.

On the other hand, the activities of ICIs are different from those of cytotoxic agents; therefore, patients’ responses to them are unique. Pseudoprogression and hyperprogressive (HP) disease have been reported in patients prescribed with ICIs ⁴ ; specifically, the hyperprogression has to date been reported in especially lung and head and neck cancers but also in melanoma. ⁵

Pseudoprogression is a temporary enlargement of the tumor or metastatic sites before regressing in size ⁶ and it happens in almost 2%–6% of patients treated with immunotherapy, depending on the criteria used to define the condition. It can occur with any of the immunotherapy agents. It was first described in three patients with melanoma who received ipilimumab, ⁷ and pseudoprogression is an important clinical entity because the continuation of the drug in these patients prolongs survival.

But then, a new pattern of progression has been recently described. Some patients on immunotherapy may experience an accelerated paradoxical progression of the tumor with worsening clinical status, which appears to negatively impact survival. This phenomenon has been termed hyperprogression. HP was defined as twofold increase of the expected tumor growth rate (which is an estimation of the increase in tumor volume over time) in patients with disease progression between baseline and first assessment by response evaluation criteria in solid tumors (RECIST) criteria at eight weeks; it was correlated with advanced age at treatment and worse oncological results such as median overall survival. ⁸

Here, we present a patient with advanced melanoma who was prescribed nivolumab after ipilimumab and dabrafenib plus trametinib, whereupon she experienced rapid progression following the administration of this ICI.

Case report

A 25-year-old woman presented to hospital on April 2014 with a recent diagnosis of malignant melanoma of the right arm. The patient underwent excision of the melanoma which demonstrated superficial spreading melanoma with the depth of invasion approximately 6.3 mm. Ulceration was present with no satellitosis. Lymphovascular invasion was also present. The patient underwent wide local excision with right axillary lymph node dissection on May 2014 and metastasis was detected in three lymph nodes. After the surgical intervention, adjuvant interferon treatment has started. In the second month of adjuvant treatment, cervical and left supraclavicular metastatic lymphadenopathies (LAPs) were detected. BRAF mutation testing was positive for V600E mutation and positron emission tomography/computed tomography (PET/CT) was confirmed metastatic disease. Because of the absence of visceral organ metastases and the presence of disease leading to LAP involvement, ipilimumab was preferred instead of BRAF inhibitor. Four cycles of ipilimumab were administered and then she was followed up.

The patient who had stable disease after ipilimumab was admitted to the hospital with the complaint of abdominal distention in October 2017. PET/CT showed ascites, peritoneal implants, left supraclavicular and cervical metastatic LAPs and progression. Melanoma metastasis was confirmed by the pathological sampling of the ascites, and since BRAF V600E mutation was positive, dabrafenib plus trametinib was started. In the third month of treatment, a complete response was observed with PET/CT.

In August 2018, she complained of a headache and multiple metastatic lesions were detected in brain magnetic resonance imaging. Palliative whole brain radiotherapy was performed, and PET/CT showed the progression of metastatic lesions in peritoneal implants, intra-abdominal metastatic LAPs, ascites fluid, and bilateral adnexal lesions. Her Eastern Cooperative Oncology Group (ECOG) performance score was 1, and as the fourth-line treatment, nivolumab (240 mg every 14 days) was started at this stage. After the fourth dose of nivolumab administration, the patient’s general condition deteriorated, ascites fluid increased, bilateral massive pleural effusion developed, and lactate dehydrogenase (LDH) value was increased approximately five-fold compared to before treatment, she had an epileptic seizure due to the progression of brain metastases. After the clinical progression was evident in the second month of treatment, PET/CT was performed and peritoneal carcinomatosis, bilateral pleural effusion, and multiple metastatic foci in the cranium showed marked progression. The picture shows the comparison of PET/CT images performed before and after nivolumab treatment and demonstrates the dramatic HP disease (Figure 1). Nivolumab was discontinued due to hyperprogression, and cisplatin and dacarbazine were initiated.

Discussion

We report HP disease in a young woman with advanced melanoma who was treated with nivolumab. She received nivolumab after palliative whole brain radiotherapy and her disease progressed rapidly. She had also been treated with anti-CTLA and BRAF/MEK inhibitors, respectively, before nivolumab.

In recent years, immune checkpoint inhibitors have revolutionized the standard treatment of many solid tumors, especially melanomas, with a significant improvement in the overall survival for some patients. ICIs function differently from cytotoxic agents, and pseudoprogression and HP disease are the specific sequelae of these inhibitors. In addition to these positive oncological outcomes, recent evidence suggests that treatment with ICIs may backfire in a subset of patients, leading to rapid tumor development, a response opposite to that expected. ⁹

Champiat et al. described the hyperprogression pattern in patients treated with anti-PD-1/PD-L1 agents. ⁸ They did not observe any difference in the rate of HP across the different histologies of cancers including melanoma, non-small cell lung, head and neck, colorectal, urothelial, ovarian, biliary tract carcinomas, and lymphomas. HP may develop with both anti-PD-1 and anti-PD-L1 agents. Also, the number and type of previous lines of treatment, as well as PD1/PDL1 expression, are not predictive factors for HP. When we look at the emerging data from the literature patients with HP tend to be elderly, with low tumor volume and slow-growing initial disease at baseline. This phenomenon of disease progression acceleration is not specific for anti-PD-1/PD-L1 agents and was sometimes observed with other targeted therapies. ¹⁰ Kanjanapan et al. reported that HP disease due to immunotherapy is more common in women, which is in line with our case. ¹¹

Kobari et al. reported three renal cell carcinoma patients who suffered HP disease after nivolumab. ¹² All three patients were older than 60 years and either patients died due to hyperprogression.

The case that we present is not compatible with the literature as a young patient with high volume advanced melanoma that HP disease occurred after nivolumab administration. Palliative whole brain irradiation was performed before ICI therapy that could be a risk factor for HP. Ogata et al. have reported HP disease in the irradiation field after a single dose of nivolumab for a gastric cancer patient. ¹³ The mechanism of HP disease is not clear. Ogata et al. hypothesize that radiotherapy causes the production of tumor antigens that alter the immune environment that may facilitate rapid progression within the irradiation field. In our case, HP disease was also detected in the brain that was irradiated before anti-PD-1 treatment.

Hatano et al. reported two cases that have HP disease after treatment with another ICI agent pembrolizumab for urothelial carcinoma. ¹⁴ One of these patients was treated with definitive radiotherapy for bladder cancer six months before the pembrolizumab administration. Although radiotherapy was administered a few months before anti-PD-L1 treatment, it may be a potential risk factor in the development of hyper-progressive disease in lung metastases that are not in the irradiation field, similar to our case.

The HP disease with ICIs remains an essentially undiscovered entity. More studies are urgently needed to understand why some patients rapidly progress after treatment and predicting which patient will experience this undesired result. Also, clinicians should be aware of the possibility of HP disease during the immunotherapy that may result in discontinuation of treatment.