A new frontier in treatment of advanced melanoma: Redefining clinical management in the era of immune checkpoint inhibitors

ABSTRACT

Immune checkpoint inhibitors have revolutionized treatment of advanced cutaneous melanoma. This group of novel therapeutic agents differs from other systemic treatments and has necessitated a new approach for several fundamental aspects of clinical practice in oncology. Marked differences in outcomes associated with immune checkpoint inhibitors compared with other systemic therapies has required a new paradigm for prognostication in the setting of advanced melanoma. Distinct patterns of tumor response have required new norms for disease monitoring. A unique spectrum of toxicity is associated with use of immune checkpoint inhibitors which can be severe and refractory. Patients and clinicians must be informed regarding immune-related adverse events, yet in the published literature, there is substantial variability in reporting. As immune checkpoint inhibitors gain a prominent role in cancer treatment, standardization of adverse event reporting will be vital to ensure validity of evidence and to promote safe clinical practice.

Treatment of advanced cutaneous melanoma has changed dramatically in recent years. This highly aggressive form of skin cancer, if not surgically resectable, has been associated with poor prognosis.¹ Historically, high dose interleukin-2 was offered to selected patients for a small chance of durable remission despite the risk of significant, even life-threatening toxicity.² Dacarbazine, a cytotoxic chemotherapy agent, was the standard treatment of many years despite a lack of evidence suggesting survival benefit.³ Several novel therapies including molecularly-targeted oral agents and infusional immune checkpoint inhibitors (ICIs) have largely replaced chemotherapy in current clinical practice. Development of ICIs has been among the most important breakthroughs in cancer treatment in the 21^st century. Yet, this new class of therapeutic agents has challenged the oncology community to redefine fundamental aspects of melanoma treatment including prognostication, disease monitoring and management of toxicity.

Immune evasion, a hallmark of malignancy, is necessary for a cancer to proliferate. Mechanisms by which cancer cells coexist with the host immune system have been characterized. After an infectious insult, immune modulating inhibitory pathways dampen T-cell activity, thus preventing autoimmunity.⁴ Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) down-regulate T-cell response in lymphoid tissue and the tumor microenvironment, respectively.^5,6 Tumor cells can hijack these coregulatory mechanisms to avoid attack. Monoclonal antibodies against CTLA-4 (ipilimumab and tremelimumab) and PD-1 (nivolumab and pembrolizumab) interfere with these coregulatory pathways thereby promoting T-cell activation with anti-cancer effect. Collectively, these agents are classified as ICIs.

Efficacy of ICIs is proportional to mutational burden in cancers since tumors with many neoantigens are more likely to stimulate host immune response.⁷ Relative to other cancers, melanoma carries a high mutational burden, as do lung cancer, bladder cancer and renal cell carcinoma.⁸ ICIs have shown efficacy in all of these cancer types.^9-12 CTLA-4 and PD-1 inhibitors, along with other novel ICIs which target the ligand to PD-1, are rapidly being tested across a wide variety of primary tumor types and use of these drugs in clinical practice is expanding. Even for cancers with low mutational burden, current studies are exploring combining ICIs with potentially synergistic treatments with the aim to increase immunogenicity, thereby optimizing activity of the ICIs. Immunotherapy with ICIs is poised to become a pillar of cancer care.

Much of the excitement around ICIs relates to the potential for durable remission in many patients with advanced melanoma, a disease previously considered to be rapidly fatal. In fact, around 20% experience long-term remission with ipilimumab (CTLA-4 inhibitor).¹³ PD-1-directed agents and the combination of CTLA-4 and PD-1 inhibition show promise in early survival analyses of randomized controlled trials (RCTs),^9,14,15 and there is hope that a greater proportion of patients will experience long-term survival. This has challenged physicians to develop a new approach to prognostication. Previously, for metastatic melanoma, systemic therapy was given with palliative intent and at best, oncologists hoped to offer prolongation of survival on the order of several months. Now, oncologists can discuss a somewhat more optimistic outlook since many more patients will respond to ICIs compared with chemotherapy.¹⁶ Yet, a minority of patients will achieve prolonged remission, and since predictors of response are not well established, all patients must now struggle with great uncertainty when planning for the future.

In addition to the new challenges in prognostication, monitoring status of disease for patients treated with ICIs also differs compared with other systemic therapies. Assessment of tumor size with cross-sectional imaging such as computed tomography is a mainstay of monitoring the status of a solid malignancy. The Response Evaluation Criteria In Solid Tumors (RECIST criteria) were developed to provided a standardized framework for defining response or progression on therapy in clinical trials.¹⁷ ICIs have demonstrated variable patterns of response. In many cases, tumors transiently increase in size before regressing, a phenomenon called pseudo-progression.¹⁸ Oncologists must consider symptoms and biochemical markers in addition to early imaging results to determine disease status. If pseudo-progression is suspected, continuation of treatment may be beneficial. However, in the event of true progression, transitioning to another active therapy should not be delayed. This can be a difficult distinction in the clinical setting. An unprecedented number of immunotherapy trials are in process and inconsistency in interpreting response is a concern.

The variable response patterns with use of ICIs has necessitated reassessment of imaging norms for measuring response. Recently, proposed immune-related response evaluation criteria (iRECIST) have been published.¹⁹ In the proposed framework, growth of a target lesion on imaging is not immediately classified as progression, rather, repeat assessment at an interval of 4–8 weeks must be performed to confirm continued growth. While this guideline has not been validated, it represents international consensus for a standardized approach among stakeholders in drug development. This is an important step toward ensuring validity in the growing body of evidence relating to ICIs.

One of the most striking differences between ICIs and other systemic cancer treatments is the unique toxicity profile. Side effects from ICIs most often result from immune attack on normal host tissues. The spectrum of auto-immune phenomena that can occur following use of ICIs constitute immune-related adverse events (irAEs). Toxicities including colitis, hypophysitis, pneumonitis, hepatitis and dermatitis are well established consequences of ICIs,²⁰ but PD-1-directed agents seem to confer lower risk compared with CTLA-4 inhibitors.¹⁶ With more widespread use of ICIs, irAEs have been documented involving almost any organ system.

Chemotherapy toxicity such as nausea, or mucositis is temporally related to administration of the cytotoxic drug and usually self-limited in duration. Conversely, irAEs can have delayed onset and a refractory clinical course. If not identified and managed promptly, these autoimmune events can be life-threatening.²⁰ It is incumbent on the treating clinician to monitor vigilantly for irAEs and to consider treatment-related toxicity in the event of any new symptoms. For example, colitis is one of the more common irAEs with use of ipilimumab.²⁰ Diarrhea from colitis can be severe and often requires high dose oral or parenteral steroids tapered slowly to control bowel inflammation. In refractory cases, infliximab, a monoclonal antibody against tumor necrosis factor α, has been used. Rarely, surgical intervention may be required for severe colitis.²⁰ Inadequate treatment can have dire consequences with fatalities reported from colonic perforation.

Clinicians and patients must be educated regarding irAEs not only for safe use of ICIs, but also to facilitate informed consent for therapy. Since most patients do not experience long-term remission, the balance of risks and benefits associated with ICIs must be considered in treatment decisions. Therefore, clear reporting of irAEs in publication of clinical trials is essential. Reporting of toxicity is variable in the oncology literature.²¹ A recent systematic review focused on irAEs associated with ICIs highlights deficiencies in communication of harms.²² Although improved documentation was identified in more recent publications in high-impact journals, generally irAE reporting was of insufficient quality. Notably, timing of onset, management and reversibility of irAEs were poorly reported. The review authors called for standardized reporting of irAEs to facilitate clinical decision making.

Relying solely on chemotherapy toxicity grading systems such as the Common Terminology Criteria for Adverse Events (CTCAE) is a barrier to high quality reporting in ICI trials since immune toxicities differ clinically from chemotherapy side effects. Additionally, standardization is lacking regarding the nature of adverse events included in publications. Some trial investigators report only treatment-related adverse events, while others report all toxicities. In some articles, only adverse events occurring with a frequency exceeding a minimum threshold are reported. Thus, rare events may be excluded from primary publications even if associated with significant morbidity or mortality. A recent systematic review of the literature and network meta-analysis of RCTs of first-line treatments of advanced BRAF-mutated melanoma included a safety analysis.¹⁶ Only a small number of trials could be included in the pooled analysis due to inconsistency in reporting of adverse events in primary trials. Few trials presented treatment-related adverse events, which is a clinically important outcome. Improving and standardizing reporting of irAEs should be prioritized as ICIs gain clinical importance.

Inconsistency in reporting of irAEs also threatens comparative analyses including economic evaluations. ICIs are costly and present a significant financial burden to patients and health care organizations. Cost effectiveness is an important consideration, particularly when multiple effective treatment options are available, as is the case for advanced BRAF-mutated melanoma. Economic evaluation requires assessment of costs associated with management of treatment-related toxicities. Sometimes rare, but costly adverse events can impact cost effectiveness, and therefore, thorough reporting in the literature is imperative.

Use of ICIs for advanced melanoma represents a new frontier in oncology since several fundamental aspects of clinical practice are being redefined including prognostication and disease monitoring. Importantly, the toxicities associated with ICIs are unique with respect to onset, management and reversibility. These events can be severe and refractory; thus, informing patients and clinicians about irAEs is important for risk-benefit evaluation and for safe administration of therapy. Variability in reporting of irAEs threatens the validity of the ICI-related literature, and negatively impacts informed decision-making in the clinic. As the oncology community continues to explore the great potential of ICIs in cancer care, standardized, high-quality reporting of irAEs will be of utmost importance.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.