A Need for Improved Cancer Treatment

Surgery, chemotherapy, and radiation have been the mainstays of management for cancer prior to the approval of targeted therapies such as angiogenesis inhibitors (bevacizumab and ramucirumab) and tyrosine-kinase inhibitors (erlotinib, crizotinib, afatinib, gefitinib, ceritinib, and alectinib). For example, until recently, chemotherapy had been the standard of care for advanced marker-negative nonsquamous NSCLC and squamous NSCLC, accounting for the majority of lung cancer cases, creating the need for new therapeutic options with better efficacy and tolerability. Additionally, Cisplatin-containing combination chemotherapy with GC (gemcitabine and cisplatin) or standard MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) is the standard of care in patients with advanced surgically unresectable and metastatic bladder cancer who are fit enough to tolerate cisplatin.¹ Unfortunately, the number of patients eligible for cisplatin-based standard chemotherapy for perioperative as well as advanced and metastatic disease is decreasing, representing <50% of patients.² Carboplatin has been substituted for those patients with renal dysfunction, which rules out the use of cisplatin.³ The lack of eligibility due to the renal toxicity associated with cisplatin limits the systemic options, thereby increasing the urgency of new treatment options and expansion of targeted agents for this and other challenging types of cancer.

Immune Checkpoints as Targets for Therapy

The immune-checkpoint inhibitors that currently are the most advanced in clinical development inhibit cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed (cell) death protein 1 (PD-1), or programmed (cell) death ligand 1 (PD-L1).⁴ When these proteins are blocked, the “brakes” on the immune system are released, and T cells are able to kill cancer cells.⁵ CTLA-4 and PD-1 are receptors found mostly on the surface of effector T cells, and PD-L1 is a ligand for PD-1 that is broadly expressed. The main role of these immune-checkpoint proteins is inhibitory, dampening T-cell activation and effector function.^4,5 One of the differences between these two checkpoint inhibitors is that CTLA-4 regulates T-cell activity at an early stage, whereas PD-1/PD-L1 regulates later effector T-cell activity within tissue and tumors.⁵  In essence, immune checkpoints function as the physiological brakes to prevent over-activation of T cells, thereby preventing cell-mediated autoimmunity.⁶

PD-L1 can be expressed on tumor cells either endogenously or as the result of induction by association with T cells (adaptive immune resistance).^5,7,8 Binding of PD-L1 to PD-1 leads to the inhibition of intracellular signaling pathways controlling T-cell activation.⁵ In addition, PD-1 is highly expressed on T- regulatory cells infiltrating the tumor, and it is probable that their proliferation further suppresses effector immune responses. PD-1:PD-L1 interaction results in T-cell suppression, possibly via anergy, exhaustion, and death.⁵ It has been postulated that blocking the PD-1:PD-L1 interaction with monoclonal antibodies directed to either PD-1 or PD-L1 leads to inhibition of the PD-1/PD-L1 signaling pathway and the reactivation of T lymphocytes, thereby generating stronger antineoplastic responses.^5,9 Several other proteins that play a role in crucial steps of the cell immune cycle have been considered as potential targets for immunotherapies. These include CD137, OX40, and CD27 (priming and activation); vascular endothelial growth factor (infiltration of T-cell into tumors); Toll-like receptors; and CD40 (antigen presentation).^5,10

Many PD-1/PD-L1 pathway inhibitors are currently at different phases of clinical development for use in the management of advanced melanoma, advanced NSCLC, advanced renal cell carcinoma, as well as many other solid tumors.⁶ Both nivolumab and pembrolizumab, which are PD-1 monoclonal antibodies, have been FDA approved for use in chemotherapy-pretreated advanced NSCLC. Atezolizumab, a PD-L1 monoclonal antibody, is approved for second-line treatment of advanced or metastatic urothelial carcinoma and for selected patients with advanced NSCLC. Avelumab and durvalumab are also approved with varying indications. (See Table)

Efficacy of PD-1/PD-L1 Blockade

Non Squamous Cell Lung Cancer (NSCLC)

The approval of nivolumab was based on results from the CheckMate-017 landmark phase 3, open-label, randomized, multinational, multicenter clinical trial that evaluated nivolumab versus standard-of-care docetaxel in patients with metastatic squamous NSCLC who had progressed during or after a prior platinum doublet-based chemotherapy regimen.^11,12 This trial included patients regardless of their PD-L1 status. The study met its primary endpoint, demonstrating superior overall survival (OS) in patients receiving nivolumab compared with docetaxel (median OS was 9.2 months in the nivolumab arm versus 6 months in the docetaxel arm). The hazard ratio of 0.59 translates to a 41% reduction in the risk of death with nivolumab compared with docetaxel.^11,12

The accelerated FDA approval of pembrolizumab was based on the KEYNOTE-001 study, which assessed pembrolizumab in a cohort of 280 patients with metastatic NSCLC who had progressed following platinum-containing chemotherapy and, if appropriate, targeted therapy for epidermal growth-factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations.^13,14  This companion PD-L1 assay uses an antibody clone 22C3 (mouse anti-human PD-L1) and measures the percentage of membranous PD-L1 staining of neoplastic or intercalating immune cells (Dako PD-L1 IHC 22C3 pharmDx). A prospectively defined subgroup was retrospectively analyzed to evaluate PD-L1 as a biomarker among 61 patients with a PD-L1 TPS ≥50%. Patients received pembrolizumab monotherapy until unacceptable toxicity or disease progression. Primary endpoints were overall response rate (ORR) per RECIST 1.1 and duration of response. In the study, ORR for pembrolizumab was 41% (n = 25/61) in patients with a PD-L1 TPS ≥50%, and all responses were partial responses (95% CI, 29–54). Of the patients who responded, 84% (n = 21/25) continued to respond to treatment with pembrolizumab, including 11 patients with ongoing responses of six months or longer. The ORR and duration of response were similar regardless of dosing schedule (every 2 weeks or every 3 weeks). The most common adverse reactions (reported in at least 20% of study patients) were fatigue (44%), cough (29%), decreased appetite (25%), and dyspnea (23%).^13,14

Atezolizumab is another immune checkpoint inhibitor. It is a fully humanized, engineered monoclonal antibody of the IgG1 isotype against PD-L1. The POPLAR study was an open-label, phase 2, randomized, controlled trial comparing atezolizumab with docetaxel in patients with NSCLC who progressed on post-platinum chemotherapy. Patients were stratified by PD-L1 tumor-infiltrating immune cell status, histology, and previous lines of therapy. It is important to note that enrollment was stratified by PD-L1 expression using a novel IHC assay (Ventana SP142) that categorized PD-L1 positivity according to the expressing cell type (tumor cell [TC] or immune cell [IC]) and then scored along a gradient. Baseline PD-L1 expression was scored by IHC in tumor cells (as percentage of PD-L1-expressing tumor cells TC3≥50%, TC2≥5% and <50%, TC1≥1% and <5%, and TC0<1%) and tumor-infiltrating immune cells (as percentage of tumor area: IC3≥10%, IC2≥5% and <10%, IC1≥1% and <5%, and IC0<1%). Overall survival in the intention-to-treat population was significantly superior in the atezolizumab arm versus the docetaxel arm (12.6 months versus 9.7 months, respectively).¹⁵ Increasing improvement in overall survival was associated with increasing PD-L1 expression by IHC and preexisting immunity, defined by high T-effector interferon-γ-associated gene expression.¹⁵ The PD-L1 assay used was the PD-L1 IHC 22C3 pharmDx.

The phase III, global, multicenter, open-label, randomized, controlled OAK Study (NCT02008227) is evaluating the efficacy and safety of atezolizumab compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease progressed on or after treatment with platinum-containing chemotherapy. In a preliminary analysis of this study, atezolizumab showed a statistically significant and clinically meaningful improvement in OS versus docetaxel.¹⁶ Based on the results of the POPLAR and OAK studies, atezolizumab has been approved by the FDA for the treatment of patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy and who have progressed on an appropriate FDA-approved targeted therapy if their tumor has EGFR or ALK gene abnormalities.¹⁷ It is also indicated for certain patients with advanced urothelial carcinoma.

Another anti–PD-L1 antibody is durvalumab, which is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who: (1) have disease progression during or following platinum-containing chemotherapy, or (2) have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.  It is a high affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80.¹⁸ Durvalumab contains an engineered triple mutation in the Fc domain to remove antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. Durvalumab is being investigated alone or in combination with tremelimumab, a monoclonal antibody against CTLA-4, for its potential effects on NSCLC. Avelumab is a third PD-L1 antibody indicated for the treatment of metastatic Merkel cell carcinoma. This indication is approved under accelerated FDA approval.

Bladder/Urothelial Carcinoma (UC)

While many of the pivotal trials for cancer immunotherapy focused on NSCLC, these agents have also been studied in other types of cancer as well. Patients with metastatic urothelial cancer (UC), by far the most common type of bladder cancer, have a dismal prognosis and few treatment options after first-line chemotherapy. Additionally, responses to second-line treatment to this point have been uncommon. Four of the five PD-1/PD-L1 inhibitors are approved for UC including nivolumab, pembrolizumab, atezolizumab, and durvalumab. These indications are largely “accelerated,” based on successful early trials, and are contingent upon verification of results in future studies.

In the CHECKMATE 275 study, nivolumab monotherapy provided meaningful clinical benefit regardless of PD-L1 expression, and was associated with an acceptable safety profile in previously-treated patients with metastatic or surgically unresectable UC.¹⁹ Similarly, pembrolizumab showed antitumor activity in patients with advanced UC in the early phase KEYNOTE-012 and KEYNOTE-052 studies. The Phase III KEYNOTE-045 study showed that pembrolizumab was associated with significantly longer overall survival (by roughly 3 months) and with a lower rate of treatment-related adverse events than chemotherapy when used as second-line therapy for platinum-refractory advanced UC.²⁰

In the Phase II IMvigor 210 study, atezolizumab showed durable activity and good tolerability in patients with locally advanced and metastatic UC who progressed following treatment with platinum-based chemotherapy.²¹ The Phase III IMvigor 211 study did not meet the primary endpoint of overall survival compared to chemotherapy, though the safety profile was consistent with previous reports.²² These results are currently being analyzed. A Phase 1/2 open-label study of patients receiving durvalumab showed objective response rate and progression-free survival with durvalumab and an excellent safety profile in the UC population.²³Renal Cell Cancer (RCC)

Nivolumab was the first immunotherapy approved for RCC; the randomized, phase 3 CheckMate 025 study of nivolumab vs. everolimus in previously treated adults with advanced RCC demonstrated significantly improved overall survival and objective response rate.²⁴ The KEYNOTE 564, 426 and 427 studies of pembrolizumab are currently underway and are looking at both monotherapy and combination strategies.²⁵ In a 2016 Phase Ia study, atezolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with metastatic RCC.²⁶ A more recent Phase II study supports the role of atezolizumab plus bevacizumab for people with locally advanced or metastatic RCC, both in terms of safety and efficacy compared to sunitinib in those people whose disease expressed the PD-L1 protein.²⁷ The Phase Ib JAVELIN Renal 100 study of avelumab plus axitinib vs sunitinib also showed safety consistent with other immunotherapies as well as encouraging antitumor activity.²⁸ The Phase III JAVELIN 101 study is in progress. Other studies of immunotherapy for RCC are also underway, with impending indications likely forthcoming.

The above trials are only examples of trials that have been published for these agents in NSCLC, UC and RCC. The manufacturers of these agents all have extensive clinical trial development programs with hundreds of ongoing trials. These studies span several types of lung, kidney, breast, colorectal, skin, ovarian, prostate, bladder, and blood cancers, and address both monotherapy and combination methods.

Safety of Immune Checkpoint Blockade

The investigation of ipilimumab as treatment for melanoma revealed that the toxicity profile of this agent is autoimmune in nature, caused by immune cells infiltrating into non-cancerous tissues. ^29,30 These immune-related adverse events (irAEs) can affect any organ system throughout the body.⁴ With ipilimumab, irAEs occur in approximately 60% to 80% of patients with melanoma, with 10% to 40% being grade 3 or 4 in severity. ^31,32

In NSCLC, for example, irAEs associated with inhibitors of the PD-1/PD-L1 pathway appear to be both less frequent and less severe than those associated with ipilimumab.⁴ Looking at the overall safety profile, these inhibitors have manageable profiles with uncommon grade 3/4 AEs in patients with NSCLC.⁴ Across four large trials encompassing both squamous and nonsquamous lung cancer (ie, CheckMate 017, CheckMate 057, CheckMate 063, and KEYNOTE-001), treatment-related AEs of any grade ranged from 58% to 74%, and those of grade 3/4 severity ranged from 7% to 17%.^11,13,15,33 Similarly, examining safety in three of the larger phase I PD-L1 monotherapy trials, treatment-related AEs of any grade ranged from 48% to 76%, and grade 3/4 treatment-related AEs ranged from 6% to 12%.^34-36 The most common AEs in these trials included fatigue, nausea, rash, diarrhea, decreased appetite, and infusion-related reactions.

Although PD-1/PD-L1 inhibitors have limited toxicities when compared with conventional cytotoxic chemotherapy, and severe immune-related AEs are relatively rare, early recognition of these new and unique side effects and appropriate management by a multidisciplinary care team are essential steps.³⁷ Recommended monitoring for lung cancer patients on PD-1/PD-L1 inhibitors and guidance regarding steroid therapy and other treatments for endocrine toxicities (eg, hepatotoxicity and pneumonitis) and skin toxicities are required for better utilization of these immunotherapies in the clinic.³⁸

Exploring Combination Immunotherapy

While a subset of patients with advanced cancers can have a long-lasting response to single-agent immune-checkpoint blockade, combining immune-checkpoint inhibitors with other therapeutic modalities can extend the benefit of immunotherapy to a larger group of patients in the refractory setting. PD-1/PD-L1 inhibitors and CTLA-4 inhibitors enhance T-cell antitumor activity through distinct but complementary mechanisms.⁵ Preclinical data suggest synergy with dual CTLA-4 and PD-1/PD-L1 blockade versus either agent alone.^5,39 The PD-1/PD-L1 pathway has a subtler role in maintaining peripheral tolerance, and PD-1/PD-L1 blockade has become the backbone of combination therapies in development. Combinations with PD-1 and PD-L1 inhibitors have shown promising results in several phase I trials, including combinations with CTLA-4 blockers, cytotoxic chemotherapy, radiation therapy, or small-molecule inhibitors, such as vascular endothelial growth-factor receptor (VEGFR) tyrosine kinase inhibitors.³⁸ The combination of nivolumab and ipilimumab in melanoma and NSCLC have shown cumulative toxicities, mostly irAEs that are largely manageable with immunosuppressants.³⁸

Another strategy consists of combining immune-checkpoint blockade with chemotherapy in the first-line setting. The synergy between immune-checkpoint inhibitors and chemotherapy is likely related to the ability of chemotoxic agents to kill tumor cells, thereby increasing the amount of tumor antigen processed and presented to T cells and to deplete T-regulatory cells and myeloid-derived suppressor cells in the tumor microenvironment.³⁸ In a randomized, phase 2 cohort in the open-label KEYNOTE-021 study, the combination of pembrolizumab plus carboplatin and pemetrexed nearly doubled responses versus chemotherapy alone (ORR: 55% versus 29%, respectively) and significantly reduced the risk of disease progression or death compared with chemotherapy alone in advanced chemotherapy-naive NSCLC (hazard ratio 0.53, P=0.0102).³⁹ The most severe irAEs with this combination  (ie, hypothyroidism, hyperthyroidism, and pneumonitis) occurred at a rate similar to that with pembrolizumab monotherapy.³⁹

In addition to dual blockade of cell-to-cell signaling mediated by immunoreceptors (eg, natural killer-cell receptors or tumor necrosis-factor receptors), other promising combinations include PD-1 blockade with agents targeting immunosuppressors responsible for tumor escape; they include immunosuppressive cytokines (eg, TGF-β, IL-4, -6, -10) and indoleamine 2,3-dioxygenase (IDO) production.³⁸

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