Monotherapy with immune checkpoint inhibitors, specifically those targeting programmed death 1 (PD-1), has revolutionized the treatment of metastatic melanoma: approximately 40% of patients achieve a partial or complete response, many of which are durable. However, a subset of patients who initially respond to therapy will progress, leaving the majority of patients in need of an effective second-line approach. While some standard therapies exist, there has been robust interest in utilizing targeted immunotherapy combinations in this population to overcome primary or acquired resistance. Other approaches include treatment with anti–PD-1 agents beyond progression; targeting oligometastatic disease with surgery, radiation, and/or intratumor injections; and the use of other approved systemic therapies. This review summarizes the current available treatment strategies for patients with advanced melanoma when PD-1–directed therapy is not enough.
The use of immune checkpoint blockade has revolutionized the treatment of metastatic melanoma, with dramatic improvements in cancer-related outcomes since the advent of these agents. Long-term survival data demonstrate durable disease control in 20% and 30% of patients receiving the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antagonist ipilimumab and the programmed death 1 (PD-1) inhibitor pembrolizumab, respectively.[1,2] However, a subset of patients—approximately 40% to 45%—experience no response to therapy, with clear de novo resistance (primary resistance). The reasons for primary resistance include inadequate T-cell infiltration into the tumor, as well as immunosuppressive factors within the tumor microenvironment.[3,4] Treatment strategies to overcome these obstacles range from adoptive T-cell therapy to stimulate tumor antigen–specific T cells, to mitogen-activated protein kinase (MAPK) inhibition to improve T-cell trafficking into the tumor.
In contrast to primary resistance, approximately 30% to 40% of patients experience an initial response but ultimately progress months or even years later (acquired resistance). The mechanisms of acquired resistance, like primary resistance, are incompletely understood; however, they include loss of T-cell function through expression of alternative immune checkpoints (such as T-cell immunoglobulin and mucin domain 3 [TIM-3]), disruption of interferon (IFN) gamma signaling via JAK2 mutations,[7,8] and impaired antigen presentation via altered expression of beta-2 microglobulin or major histocompatibility complex molecules.[8-10] Efforts to surmount acquired resistance include PD-1 inhibition coupled with agents targeting additional complementary immune checkpoints, such as TIM-3, CD137, and colony-stimulating factor 1 receptor (CSFR1). Advancements in deconstructing these resistance mechanisms have spurred the development of rational strategies to treat patients who have progressed on anti–PD-1 monotherapy, which will be highlighted in this review.
Post-Progression Continuation of PD-1 Inhibitors
Prior to transitioning to an alternative treatment approach, clinicians can consider continuing the use of PD-1 inhibitors after progression occurs. Whereas disease progression on chemotherapies and tyrosine kinase inhibitors (TKIs) almost uniformly results in treatment discontinuation due to futility of continued therapy, studies demonstrate the possibility of atypical and delayed response with immune checkpoint inhibitor therapy beyond Response Evaluation Criteria in Solid Tumors (RECIST)-defined progression in melanoma.[11,12] Mechanisms to account for these atypical presentations include delayed antitumor response, as well as “pseudoprogression,” in which a transient immune infiltration causes a paradoxical enlargement of the tumor with subsequent shrinkage and clinical benefit that transcends response rate (eg, overall survival (OS) benefit independent of response rate). Two retrospective studies evaluated the benefit of anti–PD-1 antibody therapy past progression in patients with metastatic melanoma.[11,12] Impressive response rates of 19% and 28% were seen in evaluable patients treated beyond progression, with these cases representing 4% and 5% of all patients who had received PD-1 inhibition in these studies, respectively. Notably, delayed responses were rare after 6 months, with these events likely indicative of true progressive disease.
In both studies, there was no increased safety signal for those treated beyond progression. Patients who derived the most benefit from continuation of immune checkpoint inhibitor therapy were more likely to be fit (Eastern Cooperative Oncology Group performance status of 0), with lower levels of lactate dehydrogenase. Though it remains difficult to identify patients who will derive benefit post-progression, in general, clinicians can consider PD-1 continuation with short-term follow-up in certain cases. Ideal candidates include those who appear to be deriving clinical benefit (eg, mixed response, slowed rate of progression, regression in critical areas with growth in non-critical areas), provided that they did not experience rapid progression, tolerated therapy well, are maintaining a good performance status, and would not experience an immediately life-threatening issue due to predicted further progression.
Patients who progress in a limited number of sites (four or fewer) while on immune checkpoint inhibitor therapy often benefit from a comprehensive, multidisciplinary approach—including incorporation of local therapy, such as surgical resection or ablative radiotherapy—to eradicate isolated site(s) of progressive disease and thereby render a more durable response.
Prior to the advent of effective immune checkpoint and targeted therapies, metastasectomy was often the only means of managing progressive disease.[13,14] Studies in the current era of immunotherapy continue to demonstrate improved outcomes of surgical resection in select cases, including in gastrointestinal (GI) tract–only disease, large single brain metastasis, and adrenal metastasis. However, surgery is not feasible in all scenarios, and definitive radiation should be considered in such cases. Radiation therapy provides not only the ability to palliate symptoms, but also to eradicate a resistant subclone when used at definitive doses. One appealing benefit of radiation therapy is its theoretical ability to modulate an immune response and thereby synergize an anticancer effect when used concurrently with immune checkpoint inhibitor therapy. The abscopal effect—a phenomenon in which local radiation therapy is associated with regression of metastatic sites distant from the radiated site—has been reported in patients treated with both radiation therapy and immune checkpoint inhibitor therapy.[18,19] However, it has yet to be prospectively validated.
The safety of radiation therapy in patients receiving immune checkpoint inhibitor therapy has been explored in various studies, with data demonstrating an acceptable safety signal with treatment of various extracranial sites of disease.[20-23] However, when considering the ideal combination of radiation therapy and immune checkpoint inhibitor therapy, there are several variables that require further investigation, including, but not limited to: the ideal dose, optimal timing of radiation therapy, and how much to fractionate. While certain preclinical studies highlight the immunogenic properties of an ablative radiotherapy dose of 15 to 25 Gy in a single fraction, other studies showcase the potential immunosuppressive effects of radiation, particularly of prolonged fractionated radiation therapy, which depletes circulating lymphocytes. Several prospective studies across tumor types have demonstrated that stereotactic body radiation therapy (SBRT), or a hypofractionated method of delivery, may reduce this iatrogenic effect and lead to a more effective antitumor response.[26-28] While the optimal combination regimen is unknown, the available data do demonstrate that immune checkpoint inhibitor therapy with radiation, particularly short-course SBRT, appears to be a safe and potentially synergistic treatment option for the management of melanoma.
Central Nervous System–only progression
Development of intracranial disease is a common cause of morbidity and mortality. Management entails a multidisciplinary discussion, since treatment options vary based on patient- and tumor-specific factors (Figure 1). Surgical resection is often beneficial in cases of a single surgically-accessible metastasis. In cases where surgery is not permissible (eg, poor performance status, medical comorbidities, or metastases in critical locales such as the brain stem), stereotactic radiosurgery has been proven to be a highly effective local therapy. Radiosurgery enables treatment of individual brain metastases using high-dose single-fraction radiation, while sparing the surrounding normal brain and thereby mitigating side effects. Based on the efficacy and acceptable side effect profile of stereotactic radiosurgery, this treatment modality is often pursued in cases of ≤ 4 brain metastases that are ≤ 3 cm in diameter.
The safety and efficacy of cranial radiation therapy with concurrent administration of immune checkpoint inhibitor therapy has become an area of interest. Recent retrospective studies demonstrate an acceptable safety signal,[31,32] with favorable cancer-related outcomes (eg, reduced size of brain metastases and decreased number of new lesions) in patients who received radiation in combination with immune checkpoint inhibitor therapy compared with patients who received radiation alone. A recently published meta-analysis examined a total of 534 patients with a collective 1,570 brain metastases who were treated with immune checkpoint inhibitor therapy and stereotactic radiosurgery; researchers examined the safety and efficacy of a concurrent vs sequential approach, with sequential defined as administration of stereotactic radiosurgery and immune checkpoint inhibitor therapy within 4 weeks of each other. The primary endpoint was the 1-year overall survival rate with a secondary endpoint of radionecrosis incidence. The 1-year OS rate was 64.6% vs 51.6% for concurrent and non-concurrent therapy, respectively. Overall, the incidence of radionecrosis was 5.3%, with rates higher in patients receiving concurrent CTLA-4 antagonists vs PD-1 inhibitors.
In patients with multiple CNS lesions, local therapy options are limited. Strategies for these individuals include alternative systemic agents that penetrate the blood-brain barrier, such as ipilimumab, and combination BRAF/MEK inhibitors in patients harboring an activating BRAF mutation. However, despite achieving high rates of intracranial disease control, the majority of patients have abbreviated progression-free survival (PFS) on targeted agents.[36,37] Notably, although research has been conducted on the efficacy of combination nivolumab and ipilimumab in treatment-naive brain metastases, there are little data on the efficacy of salvage combination therapy in patients who develop CNS disease while on PD-1 inhibitors.
In cases of systemic progression, subsequent treatment selection depends on several factors, such as the molecular features of the tumor, site of progression, and clinical trial availability (Figure 2). The treatments mentioned here—which include standard therapies as well as investigational strategies—are categorized by the presence of injectable disease and BRAF status; the final subgroup highlights additional novel combination regimens under development.
Progression in predominantly injectable disease
Oncolytic viruses. The presence of accessible soft tissue lesions enables the use of injectable agents, such as oncolytic viruses. These innovative treatments, often compromised of wild-type and modified live viruses, favorably modulate the tumor microenvironment by increasing CD8+ T-cell infiltration and upregulating the IFN gamma gene signature.[39,40] Though research on the efficacy of oncolytic virus administration post–PD-1 progression is limited, some data have demonstrated the efficacy of these agents with and without immune checkpoint inhibitors in treatment-naive patients.[39,41,42] Talimogene laherparepvec was the first oncolytic virus to demonstrate efficacy in a phase III clinical trial. It has since been studied in combination with pembrolizumab. In one phase Ib trial (N = 21), combination therapy was generally well tolerated; the overall response rate (ORR) was 62%, with 33% experiencing a complete response. Studies in a PD-1–resistant cohort are underway (ClinicalTrials.gov identifier: NCT02965716).
Positive results have also been seen with an alternative oncolytic virus, CAVATAK, which is a formulation of the naturally occurring virus responsible for the common cold (CVA21). The phase Ib MITCI study investigated the efficacy and safety of intratumoral CAVATAK with ipilimumab in both PD-1–naive and post–PD-1 cohorts (N = 13). Although the number of patients enrolled was small, combination therapy resulted in an ORR of 38%, with a disease control rate (DCR) of 88%, higher than expected for the CTLA-4 antagonist alone, especially since 54% of the group had previously received ipilimumab.
Toll-like receptor (TLR) agonists. TLRs are pattern recognition receptors that, via activation, initiate the innate and adaptive immune response. Due to their ability to enhance immune response, intratumoral administration of different TLR agonists has been incorporated into anticancer treatment strategies. Recent studies—particularly those involving the intratumoral TLR9 agonists SD-101 and CMP-001—have demonstrated encouraging preliminary results in treatment-naive and refractory patients with advanced melanoma. In a phase Ib trial comprised of patients resistant to anti–PD-1 therapy, CMP-001 in combination with pembrolizumab demonstrated an ORR of 22%. Furthermore, the phase Ib study of combination SD-101 and pembrolizumab demonstrated an ORR of 78% in treatment-naive patients, and an ORR of 15% in anti–PD-1 resistant cases. An increase in the expression of an IFN signature gene was detected in post-treatment biopsies in both clinical studies. The dose expansion phase of both trials is ongoing (ClinicalTrials.gov identifiers: NCT02680184 and NCT02521870).
Ipilimumab. Several studies have evaluated the role of ipilimumab after PD-1 monotherapy, with data demonstrating similar response rates in the post–PD-1 and treatment-naive settings. Notably, the response to PD-1 inhibition, or lack thereof, does not predict for subsequent response to ipilimumab. One of the earliest studies establishing the efficacy of post–PD-1 ipilimumab was CheckMate 064. This randomized phase II study examined the safety and efficacy of a planned switch from nivolumab to ipilimumab, or the reverse sequence, in patients with metastatic melanoma. Although the rates of grade 3 to 5 treatment-related adverse events were similar in each cohort (50% vs 43%), the antitumor response rate (41% vs 20%) and 12-month OS rate (76% vs 54%) favored the nivolumab followed by ipilimumab arm. While the majority of patients had not progressed on nivolumab, these data established ipilimumab as a viable treatment option after anti–PD-1 monotherapy (though notably with substantial toxicity rates).
This finding of a post–PD-1 ipilimumab benefit was recapitulated in a multicenter retrospective study exploring the benefit of ipilimumab monotherapy and combination ipilimumab/nivolumab after PD-1 progression. Though the ORR was higher in the combination arm than with ipilimumab monotherapy (21% vs 16%), the DCR favored ipilimumab monotherapy (42% vs 33%), with 1-year OS rates comparable between the groups (54% vs 55%). Based on these data, unless a patient requires a rapid response, ipilimumab monotherapy offers similar antitumor efficacy, with a lower risk of ≥ grade 3 treatment-related adverse events (50% vs 59%).[47,48]
Inhibition of the MAPK pathway. Mutations in the BRAF gene are present in approximately 50% of newly diagnosed melanomas and lead to constitutive activation of the MAPK pathway. Successful inhibition of this pathway with combination BRAF and MEK inhibitors significantly altered the treatment paradigm of BRAF-mutant unresectable disease. Although the National Comprehensive Cancer Network recommends immune checkpoint inhibitors as first-line therapy for this patient population, MAPK inhibitors remain an important treatment option for these patients. Importantly, the timing of BRAF-directed therapy (before or after immunotherapy) does not appear to impact response rates to TKIs; however, one study did demonstrate a longer OS when ipilimumab was given prior to a BRAF inhibitor compared with a sequential BRAF inhibitor followed by ipilimumab, or with either agent alone. The safety profile of MAPK inhibitors after immunotherapy is manageable, although data do demonstrate increased rates of TKI-related adverse events and dose interruptions in patients who receive TKIs after immune checkpoint inhibitors.
There are little published data on the role of combination therapy (MAPK inhibition plus immunotherapy) as a way to overcome resistance; however, preclinical data support this combination.[54,55] The early combination of ipilimumab with dabrafenib/trametinib resulted in unacceptable rates of serious GI toxicity (colonic perforation); however, preliminary safety and efficacy results from KEYNOTE-022 are encouraging. In this phase I/II study examining the use of combination dabrafenib, trametinib, and pembrolizumab in treatment-naive patients (N = 14), the safety profile was acceptable and efficacy data were promising: 5 patients achieved a confirmed response, 9 patients achieved an unconfirmed response, and 13 of the 14 patients experienced a reduction in tumor size. The randomized portion of the study is ongoing (ClinicalTrials.gov identifier: NCT02130466).
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