There are multiple effective and well-tolerated systemic therapy treatments for the treatment of advanced melanoma, as well as new immunotherapy and targeted therapy agents in clinical trials. Traditional cytotoxic chemotherapy and targeted BRAF inhibitors can increase antigen presentation and can rebalance the intratumoral immune milieu. The combination of pulsed cytotoxic therapy and immunotherapy is a logical next step in designing treatment regimens. Combination radiotherapy and immunotherapy also has experimental and clinical support. The standard of care for patients with advanced melanoma remains participation in clinical trials in order to enhance understanding of the effectiveness and toxicities of combination regimens.
Key points
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In the unprecedented circumstance of multiple effective and well-tolerated treatments approved by the US Food and Drug Administration for patients with advanced melanoma, the next logical step is exploration of combination therapy.
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Cytotoxic therapies, including targeted therapies, increase antigen presentation and in many cases create a favorable environment for the action of immune therapy.
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Response to the combination of targeted therapy and immunotherapy may vary by tumor genotype (eg, concurrent PTEN loss).
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Exploration of combination therapy should be explored in a clinical trial setting because of possible unanticipated adverse effects, and to maximize scientific understanding through correlative studies.
Introduction
The past several years have seen a rapid increase in effective and tolerable treatment options for patients with advanced melanoma across the major modalities in systemic therapy: options have progressed from cytotoxic chemotherapy to targeted therapy to dramatic improvements in immunotherapy. Despite multiple clinical trials of various combination regimens, cytotoxic chemotherapy has not proved effective in increasing overall survival but can lead to an objective response in a fraction of patients. In the past, trials of biochemotherapy (cytokine therapy plus chemotherapy) regimens in advanced melanoma have not shown improved overall survival compared with chemotherapy. Targeted therapy has an excellent response rate in BRAF V600 E/K -mutant advanced melanoma: up to 76% when given as combination BRAF plus mitogen-activated extracellular kinase inhibition, but the duration of response is limited, with the longest median time to progression so far reported being 9.4 months. Immunotherapy with new anti-PD1 antibodies has shown a response rate greater than or equal to 30%, with even higher response rates when given in combination with anti-CTLA4 antibody ipilimumab (Yervoy), and responses have been durable in most patients. A next step in achieving both a higher overall response rate and a prolonged duration of response for patients with advanced melanoma is exploration of combination systemic therapy regimens across treatment types: chemotherapy, targeted therapy, and immunotherapy.
Introduction
The past several years have seen a rapid increase in effective and tolerable treatment options for patients with advanced melanoma across the major modalities in systemic therapy: options have progressed from cytotoxic chemotherapy to targeted therapy to dramatic improvements in immunotherapy. Despite multiple clinical trials of various combination regimens, cytotoxic chemotherapy has not proved effective in increasing overall survival but can lead to an objective response in a fraction of patients. In the past, trials of biochemotherapy (cytokine therapy plus chemotherapy) regimens in advanced melanoma have not shown improved overall survival compared with chemotherapy. Targeted therapy has an excellent response rate in BRAF V600 E/K -mutant advanced melanoma: up to 76% when given as combination BRAF plus mitogen-activated extracellular kinase inhibition, but the duration of response is limited, with the longest median time to progression so far reported being 9.4 months. Immunotherapy with new anti-PD1 antibodies has shown a response rate greater than or equal to 30%, with even higher response rates when given in combination with anti-CTLA4 antibody ipilimumab (Yervoy), and responses have been durable in most patients. A next step in achieving both a higher overall response rate and a prolonged duration of response for patients with advanced melanoma is exploration of combination systemic therapy regimens across treatment types: chemotherapy, targeted therapy, and immunotherapy.
Combination immunotherapy plus chemotherapy
Rationale
Cytotoxic chemotherapy can act in 2 complementary ways: direct damage and death of cancer cells, and the attraction and activation of cytotoxic immune cells. Cell death triggered by treatment with chemotherapy has been shown to be immunogenic and to lead to dendritic cell activation and subsequent activation of tumor antigen–specific T cells. After administration of dacarbazine (DTIC), activation of genes involved in cytokine production, leukocyte activation, immune response, and cell motility have been observed, changes thought to create a favorable environment for tumor antigen–specific CD8+ T-cell responses. In another study, a low dose of melphalan (Alkeran) was shown to induce tumor expression of chemokines that lead to enhanced recruitment of tumor-reactive T cells and improved response to anti-CTLA4 therapy. In addition, in examination of pretreatment biopsy specimens, a tumor microenvironment with infiltrate featuring CD8+ T cells has been associated with an improved response rate to chemotherapy.
Clinical Trials
Phase II to III trials have shown early evidence of tolerability and efficacy with the combination of ipilimumab with cytotoxic drugs such as alkylating agents dacarbazine and temozolomide, which is also active in the central nervous system, or fotemustine, a drug that is available in Europe ( Table 1 ).
| Regimen | Phase | N | ORR (%) | PFS | OS (%) |
|---|---|---|---|---|---|
| Ipilimumab plus dacarbazine vs ipilimumab | II | 35 vs 37 | 14.3 vs 5.4 | No difference | 14.3 mo vs 11.4 mo; 1-y OS, 62 vs 45; 2-y OS, 24 vs 21; 3-y OS, 20 vs 9 |
| Ipilimumab plus dacarbazine vs dacarbazine | III | 196 vs 218 | 38 vs 26; 4 CR, 34 PR, and 45 SD vs 2 CR, 24 PR, 50 SD | No difference | 1-y OS, 47.3 vs 36.3; 2-y OS, 28.5 vs 17.9; 3-y OS, 20.8 vs 12.2 |
| Ipilimumab plus temozolomide | II | 64 | 28.1; 10 CR, 8 PR | 5.1 mo | NR |
| Ipilimumab plus fotemustine | II | 86 | irORR 29.1; 5 CR, 20 PR | irPFS, 5.3 mo | 1-y OS, 51.8 |
Combination immunotherapy plus targeted therapy
Rationale
The combination of targeted therapy and immunotherapy seems to be symmetric: high response rate and rapid onset of action in targeted therapy, with hope of long-term response to slower-acting immunotherapy. There is no evidence that patients with BRAF V600E mutations are less likely to respond to immunotherapy. Vemurafenib (Zelboraf) and the biochemically similar compound PLX4720 have been shown to have a cytotoxic effect in melanoma, and as previously discussed with chemotherapy, drugs with cytotoxic effect can enhance immune activity. BRAF inhibition has been shown to enhance T-cell recognition of melanoma cells and not interfere with lymphocyte functioning. Review of tumor biopsies from patients treated with BRAF inhibitors vemurafenib or dabrafenib (Tafinlar) showed enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Response to ipilimumab is linked to an immune-active tumor microenvironment.
Preclinical testing of combination immunotherapy plus targeted therapy has been done in the context of an anti-CTLA4 monoclonal antibody plus PLX4720 (vemurafenib precursor) in an immune-competent mouse model of BRAF V600E /PTEN −/− mutant melanoma. In contrast with the observed cytotoxicity of BRAF inhibitors reported in human patients with melanoma, treatment in this mouse model does not cause cell death but leads to decreased tumor proliferation. Decreased tumor-resident lymphocyte frequencies were observed after treatment with PLX4720 (decreased CD45+ leukocytes, CD8+ T cells, CD4+ T cells, T regs ; no change in B-lymphocytes; slightly increased natural killer cells, myeloid-derived suppressor cells, macrophages), along with decrease in visible inflammation at tumor sites. These changes in T-lymphocyte frequencies were not found elsewhere in the mouse tissues (lymph nodes or spleen) or in similarly treated mice with BRAF-WT tumors, arguing against a direct effect of PLX4720 on the T cells. No synergy was observed in the combination of PLX4720 and anti-CTLA4 monoclonal antibody (mAb) in this study. Concurrent treatment with PLX4720 and the anti-CTLA4 mAb did not restore the intratumoral immune milieu. In a group of human patients with BRAF V600E mutations treated with dabrafenib, those with concurrent PTEN loss had decreased median progression-free survival. One interpretation of this may be that, in patients with PTEN loss, a tendency for BRAF inhibitors to have a more cytostatic than cytotoxic effect may lead to decreased efficacy, and there may also be a deleterious effect on the immune tumor microenvironment that decreases the likelihood of response to anti-CTLA therapy. It should also be noted that PLX4720 has a less dramatic effect in mouse models than vemurafenib does in human melanoma. This observation needs further examination in clinical trials of the combination of BRAF inhibitors and the anti-PD1 antibodies, with studies of the correlation between observed clinical responses, tumor genetics, and lymphocyte profiling.
Ipilimumab Plus Vemurafenib
A recent phase I study of concurrent vemurafenib plus ipilimumab showed dose-limiting toxicity of grade III to IV hepatotoxicity in 50% of patients and asymptomatic liver function tests increases that were reversible with dose interruption or administration of corticosteroids, and the study was closed to further accrual. Efficacy outcomes were not reported. The investigators recommend well-designed clinical trials to examine future combinations even of approved therapies with nonoverlapping toxicities and separate mechanisms of action.
Sequential therapy
Rationale
In clinical oncology, combination regimens are often developed to maximize response, but these can be limited by overlapping toxicities, and patients often proceed from one regimen sequentially to another at the time of progression of disease or end of tolerability. As targeted therapies, anti-CTLA4 antibodies, and anti-PD1/PDL1 antibody drugs, have all been under development during recent years, and patients have been treated sequentially, going from one clinical trial to another.
As monotherapy (eg, choosing between available open clinical trials) has often been the only option at a given point in a patient’s care, targeted therapy may be the first option chosen for its high response rate and rapid onset of action; for example, in a patient presenting with widely metastatic disease or bulky symptomatic disease causing pain or threatening organ function, whereas immune therapy may be chosen in advance for patients with a low burden of disease who are able to tolerate a delayed onset of action and trade a lower response rate for the opportunity for a long-term response.
Experience and Next Directions
An dichotomy of response has been revealed in patients at the time of discontinuation of BRAF inhibitor therapy. A retrospective review of 28 patients first treated with a BRAF inhibitor (vemurafenib or dabrafenib) followed by ipilimumab reported that 43% of the patients experienced rapid progression of disease when the BRAF inhibitor was discontinued, and this prevented successful completion of planned treatment with ipilimumab. However, in another series of patients, a proportion were observed to have tumor shrinkage at the time of discontinuation of BRAF inhibitor. The response to BRAF inhibitors can be rescued in some patients with reinitiation of treatment after an interruption. This finding has led to exploration of intermittent dosing of BRAF inhibitors in an effort to delay or overcome resistance. A strategy of continuous targeted therapy followed by abrupt discontinuation of treatment at time of progression and then initiation of immunotherapy is unlikely to be successful in many patients, and combination strategies (with or without intermittent dosing of BRAF inhibitor) are more likely to yield long-lasting benefits.
Sequential Therapy Versus Combination Therapy
As multiple agents are approved by the US Food and Drug Administration, and combination therapies are explored in ongoing clinical trials, there will be keen interest in the outcomes of efficacy and tolerability/toxicity. There will also be practical questions of cost, because each individual agent will be patent protected for the near future. Overall, a combination that provides a rapid, deep, and prolonged response will likely prove cost-effective because patients achieve many more high-quality years of life after a complete response to a well-tolerated therapy, and they avoid the many medical comorbidities caused by progression of disease. Discontinuation trials after complete responses to immunotherapy will also contribute important information for the design of optimal and cost-effective combination regimens.
Recent trials of other combinations across modalities or pathways
Rationale
Given the complexity of cell signaling and the multitude of genetic errors characteristic of advanced melanoma tumors, trials are ongoing with various combinations of agents designed to affect multiple targets of growth signaling, combine cytotoxicity with immunotherapy, or otherwise take advantage of synergy between agents with different mechanisms ( Table 2 ).
| Regimen | Phase | N | ORR | PFS | OS |
|---|---|---|---|---|---|
| Preclinical studies revealed that the proteasome inhibitor bortezomib plus cytokine IFN-α synergistically induce apoptosis in human melanoma cells, and combined treatment in a murine model led to improved survival. A phase I study showed : | |||||
| IFN α-2B plus bortezomib | I | 16 | 1 PR, 7 SD, 8 PD | 2.5 mo | 10.3 mo |
| Preclinical studies showed that bortezomib and sorafenib, a multikinase inhibitor that blocks tumor growth and angiogenesis, modulate expression of BCL-family members and augment cytotoxicity in cell lines. A phase I study showed : | |||||
| Bortezomib plus sorafenib | I | 11 | 2 SD, 9 PD | NR | NR |
| The MET receptor tyrosine kinase is activated in NRAS-mutant melanoma. Oral MET inhibitor tivantinib was studied in combination with sorafenib. Preclinical data indicated synergy between these two agents. A phase I study performed in patients with NRAS-mutant or NRAS-WT melanoma showed: | |||||
| Sorafenib plus tivantinib | I | 11 | 1 CR, 3 PR, 3 SD | 5.3 mo | NR |
| NRAS-mutant patients only: | 8 | 1 CR, 1 PR, 2 SD | 9.2 mo | NR | |
| A double-blind, randomized, placebo-controlled phase III study showed no improvement in OS with the addition of sorafenib to cytotoxic chemotherapy with carboplatin plus paclitaxel | |||||
| Sorafenib plus carboplatin plus paclitaxel vs carboplatin plus paclitaxel | III | 823 | 20 vs 18%, P = .427 | 4.9 vs 4.2 mo | 11.3 vs 11.1 mo |
| A phase II trial in patients with metastatic uveal melanoma was closed early for lack of response | |||||
| Sorafenib plus carboplatin plus paclitaxel | II | 24 | 0 | 4 mo; 6 mo PFS 29% | 11 mo |
| Multikinase inhibitor sorafenib was the foundation of 2 compared regimens: sorafenib plus mTOR inhibitor temsirolimus vs sorafenib plus tipifarnib, an oral farnesyl transferase inhibitor in a randomized phase II trial. Neither combination showed sufficient activity to merit further use | |||||
| Sorafenib plus temsirolimus vs sorafenib plus tipifarnib | II | 63 vs 39 | 3 PR vs 1 PR | 2.1 vs 1.8 mo | 7 vs 7 mo |
| In preclinical models, bevacizumab, an mAb to VEGF inhibiting angiogenesis and tissue growth, suppressed growth and hepatic establishment of micrometastases, and a potential clinical benefit of the combination of bevacizumab plus alkylating agent dacarbazine. A phase II trial (BEVATEM) showed : | |||||
| Bevacizumab plus temozolomide | II | 35 | 9/35 SD | 3 mo; 6-mo PFS 26% | 12 mo |
| Temsirolimus is a targeted inhibitor of mTOR kinase activity, blocking progression of the cell cycle past G1 phase. A phase II trial of the combination of temsirolimus and bevacizumab showed : | |||||
| Bevacizumab plus temsirolimus | II | 16 | 3 PR in BRAF-WT patients, 9 SD; 1 response duration >3 y | NR | NR |
| A phase II trial evaluated bevacizumab in combination with oral alkylating agent temozolomide | |||||
| Bevacizumab plus temozolomide | II | 62 | 1 CR, 9 PR (16.1%) | 4.2 mo | 9.6 mo; BRAF-WT 12 mo, BRAF V600E 9.2 mo, P = .014 |
| A phase II trial compared bevacizumab as the foundation of 2 regimens: BT vs ABC | |||||
| BT vs ABC | II | 42 vs 51 | 1 CR, 9 PR (23.8%) vs 0 CR, 17 PR (33.3%) | 3.8 vs 6.7 mo; 6 mo PFS 32.8 vs 56.1% | 12.3 mo vs 13.9 mo |
| Another randomized phase II study evaluated CBP vs CP alone | |||||
| CBP vs CP | II | 143 vs 71 | 25.5% vs 16.4%, P = .1577 | 5.6 vs 4.2 mo, P = .1414 | 12.3 vs 8.6 mo, P = .0366 |
| Hypomethylating agent decitabine was evaluated in combination with temozolomide, an oral alkylating agent, in a phase I/II trial | |||||
| Decitabine plus temozolomide | I/II | 35 | 2 CR, 4 PR, 14 SD | 3.4 mo; 6-mo PFS 32% | 12.4 mo; 1-y OS 56% |
| ALT-801 is recombinant human interleukin-2 fused to a single-chain T-cell receptor specific to human p53 peptide antigen presented in the setting of HLA-A2 positivity. This fusion protein showed activity as monotherapy and synergy with cisplatin in melanoma xenograft mouse models. This phase Ib study showed : | |||||
| Cisplatin plus ALT-801 | Ib | 22 | NR | NR | 6-mo PFS 87%; 12-mo PFS 58% |
| Angiogenesis inhibitor rh-endostatin in combination with dacarbazine was compared with dacarbazine monotherapy in this randomized, placebo-controlled phase II Chinese trial that showed: | |||||
| Dacarbazine plus rh-endostatin vs dacarbazine alone | II | 110 | NR | 5 vs 1.5 mo | 16 vs 7 mo; 1-y OS 51 vs 22% |
| Lenvatinib is an oral, receptor TKI targeting VEGFR1–VEGFR3, FGFR1–FGFR 4, RET, KIT, and PDGFRβ. DTIC upregulates VEGF and has been shown to confer resistance in cell lines. A phase II study was performed to investigate whether combinations of antiangiogenic drugs could potentiate DTIC | |||||
| Lenvatinib plus DTIC vs DTIC | II | 78 | NR | 19.1 wk vs 7 wk | NR |
| Lenvatinib was given at 24 mg PO daily plus temozolomide 150 mg/m 2 PO on days 1–5 of 28 in this phase Ib trial. | |||||
| Lenvatinib plus temozolomide | Ib | 32 | 6 PR | 5.4 mo; 6-mo PFS 37% | NR |
| Plitipepsin is a synthetic form of a peptide isolated from Aplidium albicans that triggers apoptosis and blocks VEGF secretion in tumor models. A phase I/II trial of dacarbazine plus plitidepsin vs plitidepsin alone showed : | |||||
| Dacarbazine plus plitidepsin vs plitidepsin | I/II | 28 vs 16 | 1 CR, 5 PR, 9 SD vs 0 CR, 0 PR, 2 SD | 3.3 vs 1.5 mo | NR |
| Histone deacetylase inhibitor panobinostat and demethylating agent decitabine were given in combination with temozolomide to overcome development of epigenetically mediated temozolomide resistance in this phase I/II trial. The MTD of this combination has not yet been reached | |||||
| Decitabine plus panobinostat plus temozolomide | I/II | 17 | NR | NR | NR |
| ERK1/2 is constitutively active in melanoma cells regardless of BRAF mutation status; selumetinib is a highly selective allosteric inhibitor of MEK1/2, suppressing pERK levels in melanoma independently of BRAF and NRAS mutation status. Selumetinib and docetaxel have shown synergy in xenograft models of melanoma. A randomized phase II trial (DOC-MEK) showed : | |||||
| Selumetinib plus docetaxel vs docetaxel | II | 83 | 32% vs 14% | 6-mo PFS 40% vs 26% | NR |
| Selumetinib was also tested in combination with cytotoxic alkylating agent dacarbazine vs dacarbazine alone in a phase II double-blind randomized study | |||||
| Selumetinib plus dacarbazine vs dacarbazine | II | 45 vs 46 | 1 CR, 17 PR, 13 SD vs 1 CR, 11 PR, 10 SD | 5.6 vs 3 mo, P = .021 | 13.9 mo vs 10.5 mo, P = .39 |
| YM155 is an inhibitor of survivin, a microtubule-associated protein overexpressed in melanoma and associated with cell viability and regulation of mitosis. An open-label phase II study of YM155 in combination with microtubule-stabilizing chemotherapy agent docetaxel showed: | |||||
| Docetaxel plus YM155 | II | 64 | 8 PR (12.5%), 33 SD (51.6%) | 6-mo PFS 34.8% | 1-y OS 50.5% |
| Everolimus is an oral inhibitor of mTOR, a component of the PI3k/AKT pathway, and has single-agent activity in advanced melanoma. A phase II trial tested everolimus in combination with chemotherapy with DNA cross-linking agent carboplatin and microtubule-stabilizing agent paclitaxel. Because this was not a marked improvement compared with previously published data with carboplatin plus paclitaxel alone, further development was not recommended | |||||
| Everolimus plus carboplatin plus paclitaxel | II | 70 | 12 PR, 42 SD | 4 mo | 10 mo |
| Pazopanib is an antiangiogenic inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFR-β, and c-KIT with activity in melanoma tumor xenografts. A phase II study of pazopanib given in combination with paclitaxel showed : | |||||
| Pazopanib plus paclitaxel | II | 31 | 32%: 1 CR, 9 PR, 13 SD, 8 PD | NR | NR |
| PARP inhibitor rucaparib was examined in combination with oral alkylating agent temozolomide in a phase II trial that showed : | |||||
| Rucaparib plus temozolomide | II | 46 | 8 PR 17.4%, 8 SD | 3.5 mo; 6-mo PFS 36% | 9.9 mo |
| Preclinical data indicated that Src inhibitors sensitize cells to the effects of cytotoxic chemotherapy. Src and c-Kit inhibitor dasatinib was combined with dacarbazine in a phase I trial | |||||
| Dasatinib (70 mg PO BID cohort) plus dacarbazine | I | 29 | 4 PR, 17 SD | 6-mo PFS 20.7% | 12-mo OS 34.5% |
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