Combination Therapy Paves the Way Forward for CTLA-4 Antibodies

Five years after its debut, ipilimumab (Yervoy) has revolutionized the treatment of patients with metastatic melanoma and ushered in the era of immune checkpoint inhibitors into anticancer therapies.

Now, however, the CTLA-4 inhibitor has been eclipsed by anti-PD-1 antibodies, which are approved not only in melanoma but also in non—small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Although ipilimumab continues to demonstrate strikingly durable responses in melanoma, some lasting up to a decade, these occur in the minority of patients and a frustrating dearth of predictive biomarkers makes it hard to pick those patients out from the crowd.

Nevertheless, new research is carving out a role for ipilimumab and a second CTLA-4-targeting drug, tremelimumab, as combination therapy with potential in a variety of solid tumors. In addition to combinations with other immune checkpoint inhibitors, the agents are being evaluated across a breadth of other strategies, including in combination with conventional cytotoxic therapies, targeted therapies, and other types of immunotherapy (Table).

A Breakthrough for Immunotherapy

The identification of signaling pathways that control the activity of T cells, a central component of the immune response, has paved the way for checkpoint blockade agents.

Activation of T cells requires a dual signal. First, specific antigens are presented to the T cell and engage the T-cell receptor (TCR) on its surface. This is amplified by a second antigen-nonspecific costimulatory signal, resulting from the interaction between costimulatory molecules expressed on the T cell and antigen-presenting cell (APC). The best characterized costimulatory signal is generated by CD28 on the T cell, binding to B7-1 (CD80) or B7-2 (CD86) on the APC. Alternatively, T-cell activation can be inhibited at this second step, via the action of coinhibitory signals.

Stimulatory and Inhibitory Responses Mediated by Immune Checkpoints

CTLA-4 is among many immune system regulators with cellular effects. Stimulatory effects are depicted with green arrows, and inhibitory effects are depicted with red symbols. PD-1, KIR, LAG-3, GITR, and TIM-3 are immune checkpoints.

DC indicates dendritic cell; MHC, major histocompatibility complex; NK, natural killer; TCR, T-cell receptor; T REG, regulatory T cell.

Patel MA, Kim JE, Ruzevick J, Lim M. Present and future of immune checkpoint blockade: monotherapy to adjuvant approaches. World J Immunol. 2015;5(1):1-15. Reprinted with permission.

Ipilimumab and Tremelimumab Emerge

One of the best known coinhibitory signals is cytotoxic T-lymphocyte antigen (CTLA-4). This receptor is usually found in the cytoplasm but, upon activation of the TCR, is transported to and expressed on the cell surface. CTLA-4 has a higher binding affinity than CD28 for CD80 and CD86 and it outcompetes the costimulatory signal.Once it became clear that CTLA-4 functioned as a T cell off-switch, it was thought that blocking its activity might help to reinstate antitumor immunity. In 2011, research into the strategy culminated in the FDA's approval of ipilimumab for the treatment of metastatic melanoma. It was the first treatment in more than 30 years to provide a significant survival benefit for patients with this cancer type. The pivotal clinical trials included a phase III, randomized trial in previously treated patients with unresectable or metastatic melanoma in which a combination of ipilimumab and the glycoprotein 100 (gp100) peptide vaccine was compared with ipilimumab monotherapy or gp100 monotherapy. Both ipilimumab-containing arms demonstrated an overall survival (OS) benefit compared with the vaccine alone (median OS was 10 months, 10.1 months, and 6.4 months, respectively).

A second phase III trial of ipilimumab also demonstrated significant survival gains in combination with dacarbazine in treatment-naïve patients, though toxicity was greatly increased with the addition of the chemotherapy agent. Another CTLA-4-targeting monoclonal antibody, tremelimumab, was developed at the same time but has not proved as successful. Despite promise in early clinical testing, a phase III trial versus standard chemotherapy in metastatic melanoma did not meet statistical significance for improved OS and the trial was stopped for futility. There has been much speculation over the reasons for tremelimumab’s failure, especially given the fact that it demonstrated an impressive median OS of 12.6 months. The outcome in the control arm (10.7 months) was unexpectedly positive, and patients in this arm were switched to ipilimumab in expanded access programs, which may have confounded the results. Others have postulated that it may be because tremelimumab is an IgG2 antibody, in contrast to ipilimumab, which is an IgG1 antibody; however, a recent study demonstrated that this should not impact its efficacy.

The precise mechanism of antitumor activity of ipilimumab is unclear and is an area of active investigation. It is now widely believed that there are multiple ways in which CTLA-4 blockade might boost antitumor immunity. In particular, recent research has suggested that CTLA-4 may critically alter the activity of regulatory T cells, which have an important immunosuppressive role. Other possible mechanisms of action might involve effects on interleukin-2 and on components of the TCR signaling pathway. Durable Responses, Long-Lasting Survival One of the hallmarks of ipilimumab therapy is the unprecedented durable responses achieved in about 20% of patients.

Recent studies have demonstrated that ipilimumab has the potential for even more durable benefit than originally thought. In a meta-analysis of 1861 patients across 12 clinical trials and an additional analysis of 2985 patients who were treated in expanded access programs, Kaplan-Meier survival curves began to plateau at 3 years at around 20%, but extended up to 10 years in some patients.

Lessons Learned and Challenges Faced

Interestingly, a separate report recently detailed the long-term survival of 143 patients with stage IIIC and IV melanoma enrolled in four clinical trials of tremelimumab. A similar pattern of long-term survival was observed with this agent.Delayed or unconventional responses are common with immunotherapy agents. This has prompted the development of immune-related response criteria that incorporate the total tumor burden (both pre-existing lesions and new lesions), and allow for greater maximum tumor growth within the definition of stable disease. It is also recommended that, notwithstanding any potential toxicity, treatment should not be discontinued because of disease progression unless there is marked symptomatic progression.

Another unique challenge is the adverse event profile. Most toxicity is related to organ-specific inflammation as a result of the agents’ immune effects, most commonly a skin rash. Gastrointestinal toxicities can be particularly serious, especially inflammatory colitis, which can lead to death from bowel perforation. An algorithm has been developed to guide physicians on how to treat diarrhea, a common manifestation of inflammatory colitis. For the most part, the toxicities observed are transient and reversible and can be treated with systemic corticosteroids and other immunosuppressive drugs. The biggest issue associated with toxicity is the high level of treatment discontinuation, leaving patients without a clear treatment path.

Another challenge of tremendous clinical importance is the identification of biomarkers of response to predict which patients are most likely to achieve the long-term survival afforded by these drugs. Some potentially promising biomarkers have been proposed, including absolute lymphocyte count (either using a cutoff of >1000/μL or measuring the rate of rise), lactate dehydrogenase below the upper limit of normal (ULN), C-reactive protein below ULN, upregulation of T-cell activation marker—inducible costimulator (ICOS), and the development of a polyfunctional T-cell response to the tumor antigen NY-ESO-1, but none have been prospectively validated in confirmatory trials.

New Approval for Adjuvant Therapy

Recent research has also suggested a strong association between treatment outcome and the presence of a specific mutation profile. Genome-wide profiling studies are being undertaken in an effort to characterize these mutations. Other studies are examining how CTLA-4 blockade changes the repertoire of T-cell clones circulating in a patient.The success of ipilimumab in the setting of metastatic melanoma prompted researchers to evaluate its potential utility following surgical resection, when patients are at a high risk of recurrence. Recent success in the phase III EORTC 18071 trial, in which a dose of 10 mg/kg ipilimumab reduced the risk of recurrence by 25% compared with placebo, led to the approval of adjuvant ipilimumab.

New Niche in Combination Therapy

CTLA-4 blockade has also been evaluated in other tumor types, including prostate cancer, NSCLC, small cell lung cancer, RCC, pancreatic cancer, and hematologic malignancies. In many cases, ipilimumab showed some durable responses in a small number of patients. Other key questions about CTLA-4 blockade center around understanding the potential benefits of retreatment with ipilimumab in patients who experience progression, as studies have shown some benefit to this strategy, and the possible advantages to higher doses of ipilimumab or additional maintenance doses beyond the initial 4-dose schedule.Despite its significant efficacy in the treatment of metastatic melanoma, ipilimumab has been largely surpassed by nivolumab (Opdivo) and pembrolizumab (Keytruda), which target the programmed cell death-1 (PD-1) receptor.

Although CTLA-4 and PD-1 both act as negative regulators of T-cell activation, their mechanisms of action differ in many ways. For example, while CTLA-4 functions during what is known as the priming phase of the immune response in which naïve T cells are activated, PD-1 acts to downregulate the activity of previously activated T cells at later stages of the immune response.

Table. CTLA-4 Combinations Under Study

^aIndoximod inhibits the IDO immune checkpoint.

^bMogamulizumab is a chemokine receptor 4 inhibitor (CCR4).

^cBBI608 is a cancer stemness inhibitor.

DLBCL indicates diffuse large B-cell lymphoma; GBM, glioblastoma; HCC, hepatocellular carcinoma; NSCLC, non—small cell lung cancer; RCC, renal cell carcinoma; SBRT, stereotactic body radiation therapy; SCCHN, squamous cell carcinoma of the head and neck; SCLC, small cell lung cancer.

Source: NIH Clinical Trials Registry. www.ClinicalTrials.gov.

These differences suggested that combining CTLA-4 and PD-1 blockade could potentially have synergistic effects and prompted a flurry of research activity in testing combination therapy. Ultimately, in 2015 a combination of ipilimumab and nivolumab was approved for the treatment of patients with BRAF V600E wild-type, unresectable or metastatic melanoma. In the phase II CheckMate-069 study, combination therapy reduced the risk of progression or death by 60% compared with ipilimumab alone.

The FDA subsequently expanded the indication to include all patients, regardless of BRAF mutation status, on the basis of the phase III CheckMate-067 trial, in which 945 previously untreated patients with unresectable stage III or IV melanoma were randomized to receive either nivolumab monotherapy, ipilimumab monotherapy, or combination therapy. Nivolumab monotherapy and combination therapy both improved PFS compared with ipilimumab alone, regardless of BRAF status, but in PD-L1-negative tumors combination therapy was more effective than either agent alone.

The substantial efficacy of combination checkpoint blockade comes with a trade-off, since this regimen is significantly more toxic. More than 30% of patients in the combination arm dropped out as a result, most commonly because of diarrhea or colitis. The combination of nivolumab and ipilimumab has also been investigated as a sequential approach. In the phase II CheckMate-064 trial, patients with unresectable, stage III or IV melanoma were treated with nivolumab followed by ipilumumab (n = 68) or vice versa (n = 70). In both arms, patients then received nivolumab maintenance therapy until disease progression or unacceptable toxicity. Sequential treatment did not appear to offer an advantage over combination therapy, but what the trial clearly showed was that nivolumab outshines ipilimumab in the frontline setting. Patients who were offered ipilimumab first had significantly lower response rates at week 25 (20% vs 41.2%) and higher progression rates (60% vs 38.2%).

Tremelimumab is also being evaluated as part of combination therapy in clinical trials, predominantly with the PD-L1 inhibitor durvalumab (MEDI4736). The results of a phase I dose-escalation study of this combination in 84 patients with advanced NSCLC were recently presented at the annual Society for Immunotherapy of Cancer meeting. It was well tolerated and showed antitumor efficacy, with an objective response rate of 25%, regardless of PD-L1 status.

Jane de Lartigue, PhD, is a freelance medical writer and editor based in New Haven, Connecticut.

Key Research

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• Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98-106.
• Buchbinder E, Hodi SF. Cytotoxic T lymphocyte antigen-4 and immune checkpoint blockade. J Clin Invest. 2015;125(9):3377-3383.
• Callahan MK, Wolchok JD. Clinical activity, toxicity, biomarkers, and future development of CTLA-4 checkpoint antagonists. Semin Oncol. 2015;42(4):573-586.
• Hodi FS, Gibney G, Sullivan R, et al. An open-label, randomized, phase 2 study of nivolumab (NIVO) given sequentially with ipilimumab (IPI) in patients with advanced melanoma (CheckMate 064). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 23LBA.
• Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23-34.
• Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006-2017.
• Rizvi N, Chaft J, Balmanoukian A, et al. . Tumor response from durvalumab (MEDI4736) + tremelimumab treatment in patients with advanced non-small cell lung cancer (NSCLC) is observed regardless of PD-L1 status. J Immunother Cancer 2015;3(suppl 2):P193.
• Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33(17):1889-1894.