Checkpoint Inhibition of PD-1: The Promise of Pembrolizumab (MK-3475) and Beyond

Zeynep Eroglu, MD

Immunotherapy

The idea of harnessing a patient’s own defenses and actively augmenting a deficient immune response to help fight disease has been implemented since the 18th century. Adoption of immunotherapy into clinical practice has been difficult until recently, when many late-stage clinical trials demonstrating an overall survival (OS) advantage in melanoma and prostate cancer have brought immunotherapy to the forefront. Immunotherapy is not a new concept for physicians treating malignant melanoma. The approval of interferons as adjuvant therapy, with relapse-free survival and OS advantage, and high-dose interleukin-2 (IL-2) in the metastatic setting has allowed patients to achieve durable responses. However, translation into clinical practice has been difficult due to toxicity and restricted access to therapy.

The advent of new immunotherapeutic strategies targeting immune checkpoint pathways, leading to enhanced immune response to tumors, has provided renewed promise in immunotherapy that extends beyond malignant melanoma. Success with the anti–CTLA-4 (cytotoxic T-lymphocyte antigen-4) antibody, ipilimumab, in metastatic melanoma led to approval by the FDA in 2011. This was based on 2 randomized phase 3 studies demonstrating improved survival in the ipilimumab treatment arms. In a phase 3 trial comparing ipilimumab to the gp100 vaccine in previously treated advanced melanoma, an overall response rate (ORR) of 10.9% and a median OS of 10.1 months was observed with the ipilimumab arm, with 45.6% of patients alive at 12 months.¹ This benefit has led to extended survival at 10 years.² As the field of immune checkpoint inhibitor therapy has grown, a number of other antibodies that block inhibitory pathways or stimulate agonist pathways have appeared on the horizon. Initial trials have shown promising results of the ability to overcome tumor defenses (Table 1).



Pembrolizumab is a humanized monoclonal antibody against the immune checkpoint receptor programmed death–1 (PD-1). PD-1 and its ligands, PD-L1 and PD-L2, inhibit T-cell response and consequently suppress antitumor immunity. Recognition of a tumor by the T cell through major histocompatibility complex/antigen interaction mediates PD-L1/2 upregulation on the tumor, which enables cancer cells to evade T-cell–mediated death through immune suppression. While PD-1 expression is induced when a T cell is activated, it is also induced on other non–T lymphocytes including B cells and natural killer cells.3 PD-L1 expression has been shown on a number of solid tumors, including melanoma, lung, colon, breast, and other malignancies.^4-7 PD-1 expression is also upregulated in tumor-infiltrating lymphocytes (TILs) in many tumor types, which may contribute to tumor immunosuppression.

PD-L1 expression correlates with unfavorable prognosis in several cancers.^4,8 In a study of melanoma patients, Breslow tumor thickness in the high-expression PD-L1 group was significantly higher than in the low-expression group, and the OS rate of the high-expression group was significantly lower than that of the low-expression group. In all patients with stage IV disease examined as part of the study, tumor-infiltrating T cells expressed high levels of PD-1, and this expression was elevated further during the clinical course.⁹ PD-1 blockade enhances the activity of T cells in the tumor microenvironment, restoring antitumor T-cell activity, and may also increase natural killer cell activity in tumors and antibody production of PD-1–positive B cells.³ In addition, chronic antigen exposure seen in cancer can lead to persistent PD-1 expression, inducing anergy in antigen-specific T cells, which may also be reversible by PD-1 blockade.³ Preclinical studies of cancer in mouse models have demonstrated enhanced antitumor immunity through antibody blockade of PD-1 or its ligands.^6,10 Preclinically, pembrolizumab has shown antitumor activity in multiple tumor types and has high affinity for the PD-1 receptor, strongly inhibiting binding of both PD-L1 (IC50 ? 0.1-0.3 nM) and PD-L2 (IC50 ? 0.5-0.9 nM).¹¹

Clinical Experience

The first phase 1 trial of pembrolizumab was conducted to determine its safety, pharmacokinetics, and response rates in several advanced cancers refractory to prior therapies.¹² Doses of 1, 3, and 10 mg/kg were given on the first day of a 28-day cycle and then continued with every 2-week dosing. Enrolled patients included 3 with non–small cell lung cancer (NSCLC), 2 each with melanoma and rectal cancer, and 1 each with sarcoma and carcinoid. No dose-limiting toxicities were observed in the 3 dose levels. One drug-related grade 2 adverse event (AE) of pruritus was reported. No drug-related grade ?3 AEs were observed. Using RECIST 1.1 response criteria with every 8-week imaging, 1 patient with melanoma had a partial response, and tumor size reduction was seen in 3 other patients.¹²

A phase 1 expansion study was performed in 135 advanced melanoma patients with an ECOG score of 0 or 1 who had received ?2 prior systemic therapies if they were ipilimumab naive, with no restriction on lines of therapy if they were ipilimumab pretreated.^11,13 Patients with active and untreated central nervous system metastases were excluded. Pembrolizumab was administered in a 10-mg/kg dose every 2 or 3 weeks, or 2 mg/kg every 3 weeks, with response assessments performed every 12 weeks via RECIST criteria. Most frequent treatment-related AEs included fatigue (37%), pruritus (26%), rash (22%), and diarrhea (21%). Two patients each had grade 3/4 treatment-related AEs (aspartate transaminase increase, fatigue, rash, and renal failure). Most treatment-related AEs were successfully managed with treatment discontinuation, supportive care, and occasionally, glucocorticoids. Potentially immune-related AEs are discussed further below.

In an update of the results presented, an ORR of 41% was observed across all doses, with a 51% rate seen in the 10-mg/kg-every-2-week cohort along with a 14% complete response (CR) rate in this group.¹¹ Overall, a reduction in tumor size was seen in 74% of evaluable patients. Patients with a confirmed CR who had been on therapy for at least 6 months were able to discontinue therapy after receiving at least 2 doses beyond initial determination of CR, with the ability to resume therapy in the case of progression. Overall, a 9% CR rate and a 41% response rate were seen among all patients treated. In contrast to earlier checkpoint inhibitor therapies, evidence of early tumor size reduction was seen that continued throughout therapy. Late responses were seen as far as 48 weeks from initial therapy, with response rates for all cohorts improving over time.

Similar to previous trials with immune checkpoint inhibitor therapy, patients had significant disease burden, with 77% of patients having M1c disease (visceral, brain, high lactate dehydrogenase), and 36% having received prior ipilimumab. Median time to CR was 32 weeks. Subgroup evaluation of the ipilimumab-naive and ipilimumab-pretreated cohorts showed equal benefit and response. This mimics the benefits seen in the initial ipilimumab trials, as patients pretreated with IL-2 have shown no detriment in chance of clinical response. Additionally, an 18% response rate was seen in patients with previously treated, stable brain metastases. While an 81% OS rate was observed at 12 months, median OS was not yet reached for any dosing cohort. The 81% 1-year survival, although preliminary, compares favorably with the historical 25% and 46% 1-year survivals quoted for ipilimumab. It is hoped that this high percentage of response and its durability will ultimately translate into survival benefit.

Anti–PD-1 therapy holds the promise of improved benefits for more patients in the field of immune checkpoint blockade. Initial reported response rates are nearly triple those previously observed in ipilimumab clinical trials prior to its approval in metastatic melanoma. An international phase 3 study of pembrolizumab compared with ipilimumab as first- or second-line therapy in advanced melanoma is ongoing (NCT01866319). In this study, 645 patients are randomized 1:1:1 into 1 of 2 dosing cohorts of pembrolizumab 10 mg/kg every 2 or 3 weeks or ipilimumab 3 mg/kg. Coprimary end points include progression-free survival (PFS) or OS, with ORR as a secondary end point.

Other anti–PD-1 antibodies are also currently in clinical trials in advanced melanoma, with response rates similar to or slightly lower than those observed with pembrolizumab. One such anti–PD-1 antibody is nivolumab, which also has high affinity for PD-1 and blocks binding to both PD-L1 and PD-L2. In a phase 1 study, nivolumab was administered every 2 weeks and showed an acceptable safety profile.¹⁴ In a cohort expansion for 107 heavily pretreated patients with advanced melanoma, ORR was 31%, with a median PFS of 3.7 months.¹⁵ Median duration of response was 24 months, and median OS was 16.8 months. The 1-year survival rate was 62%.

Nivolumab was combined with a multipeptide vaccine in another phase 1 trial in patients with advanced melanoma.¹⁶ In both ipilimumab-refractory and -naive patients, a RECIST response rate of 25% was seen, while the median duration of response was not yet reached at a median follow-up of 8.2 months. Using immunohistochemistry (IHC) staining for PD-L1, the ORR was 67% (8 of 12 patients) in the 5% membranous staining positive group, while ORR was 19% (6 of 32 patients) for those with negative staining.

MPDL3280A is an antibody that targets PD-L1 and prevents binding to PD-1 receptors. In an expansion of a phase 1 study, metastatic melanoma patients received MPDL3280A every 3 weeks for up to 1 year.¹⁷ In 43 evaluable patients, an ORR of 28% by RECIST was observed, with a 24-week PFS of 41%. Patients with tumor samples that were IHC 2 and IHC 3 had ?5% tumor-infiltrating immune cells positive for PD-L1, whereas IHC 0 and IHC 1 had <5% positive cells for PD-L1. Although ORRs were similar, tumor sample analysis showed that PD-L1–positive patients had a higher rate of disease control (CR + progressive disease + stable disease; 16 of 20 patients, 80%) versus PD-L1–negative patients (5 of 19, 60%). Serial biopsy examinations revealed enhanced immune cell infiltrates, PD-L1 induction, and increased markers of T helper cell type 1 activation (including granzymes, interferon gamma [IFN-?], and TNF-?) in the tumors of responding patients relative to baseline. Grade 3/4 treatment-related AEs included elevated AST/alanine amminotrans ferase, increased amylase, fatigue, increased gamma-glutamyl transferase, increased bilirubin, increased lipase, and decreased lymphocytes. There was no grade 3-5 pneumonitis or colitis observed.



Pembrolizumab in NSCLC

The expression rate of PD-L1 in NSCLC has also been associated with OS. Patients with either an adenocarcinoma subtype or less than a 3-year survival after surgery showed a higher expression rate of PD-L1.¹⁸ In a phase 1b trial, pembrolizumab was administered at 10 mg/kg every 3 weeks to patients with NSCLC previously treated with 2 systemic regimens.¹⁹ Imaging was done every 9 weeks to check for response. PD-L1 expression on the pretreatment tumor sample was determined by IHC. Thirty-eight patients were enrolled, 16% with squamous histology. Ten percent had previously treated, stable brain metastases. The median OS was 51 weeks. Using RECIST criteria, the ORR was 21%.

Higher levels of PD-L1 expression appeared to be associated with increased clinical activity. An ORR of 57% (4 of 7) by RECIST was seen in patients whose tumors had high levels of PD-L1 expression, compared with an ORR of 9% (2 of 22) in patients with low expression. Preliminary results of an additional cohort of 44 NSCLC patients with nonsquamous histology and PD-L1 expression >0 demonstrated similar response rates, with an ORR of 27%. The most common AEs were rash (21%), pruritus (18%), fatigue (16%), and diarrhea (13%). Only 1 patient had a drug-related grade 3/4 AE, grade 3 pulmonary edema. A phase 2/3 trial is now ongoing comparing pembrolizumab at 2 dose levels versus docetaxel in NSCLC patients who have received at least 1 prior treatment regimen (NCT01905657). There is also a phase 1 trial in patients with NSCLC of pembrolizumab in combination with cisplatin/pemetrexed or carboplatin/paclitaxel (NCT01840579), and a phase 1b trial in PD-L1–positive NSCLC (NCT02007070) with a primary end point of ORR.

Ipilimumab and anti–PD-1/PD-L1 antibodies have also been studied in NSCLC. A randomized phase 2 trial of paclitaxel plus carboplatin alone versus with ipilimumab on 2 different schedules (phased or concurrent) was conducted in stage IIIB/IV NSCLC. The trial included 204 chemotherapy-naive patients with advanced NSCLC. The median OS was 12.2 months for the phased schedule, 9.7 months for the concurrent schedule, and 8.3 months for the chemotherapy only group, with ORR by World Health Organization criteria of 32%, 21%, and 14%, respectively.²⁰

An expansion of a phase 1 trial with nivolumab included heavily pretreated NSCLC patients.¹⁴ In an update of the trial results of the 129 patients with NSCLC evaluable for response, objective responses were seen in 17% of patients by RECIST, including both squamous and nonsquamous histology. Median duration of response was 17 months, with a median OS of 9.6 months and a 1-year survival rate of 42%. Patients without tumor expression of PD-L1 had no documented tumor responses, but 36% of patients with PD-L1 expression were objective responders.

A phase 1 trial of an anti PD-L1 monoclonal antibody (BMS-936559) also included a dose expansion cohort of patients with advanced NSCLC.²¹ Objective response was seen in 5 of 49 NSCLC patients evaluable for response. Tumor response was seen in both squamous (1 of 13 patients, 8%) and nonsquamous (4 of 36 patients, 11%) histologies. Another PD-L1 antibody, MPDL3280A, was tested in NSCLC patients in a phase 1 expansion study.²² Grade 3/4 AEs regardless of attribution were 34%, with no grade 3-5 pneumonitis seen. In 53 NSCLC patients, an ORR of 23% (12 of 53) was demonstrated. The objective response rate was 46% in patients with intermediate PD-L1 expression (IHC 2 and IHC 3) and 83% (5 of 6) in patients with the highest level of PD-L1 expression (IHC 3).

Toxicity

The toxicity spectrum of lambrolizumab and other PD-1/PD-L1 antibodies differs significantly from other immunotherapies. Similar to other checkpoint inhibitors, treatment with pembrolizumab is associated with immune-related AEs (irAEs). Surprisingly, the spectrum and severity of these irAEs differ from toxicity seen with anti–CTLA-4 therapy. Multiple irAEs, particularly pneumonitis, have been associated with PD-1 blockade. In the phase 1 expansion trial of pembrolizumab in advanced melanoma, 7 patients (5%) had grade 1/2 pneumonitis, and 1 patient had grade 2 interstitial lung disease. The incidence of drug-related AEs appears to be lower compared with ipilimumab, with 10% to 15% of patients experiencing grade 3/4 AEs,¹ including 1 patient with grade 3 hyperthyroidism, 2 patients with grade 3/4 transaminase elevations, 2 patients with grade 3 renal insufficiency, and 1 patient with grade 3/4 colitis.¹¹ In an updated analysis of the nivolumab phase 1 trial, 12 of 306 patients (4%) had pneumonitis, including 4 patients (1%) with grade 3/4 disease,²³ and 3 patients died of pneumonitis. In the nivolumab and ipilimumab phase 1 trial, there was a 5% (4 of 86 patients) incidence of pneumonitis, including 1 patient (1%) with grade 3/4 severity.²⁴ Nivolumab in combination with a multipeptide vaccine showed a 3% (3 of 90) incidence of pneumonitis, with 2 patients having grade 3/4 severity.¹⁶ This has led to increased precaution for early detection and management of pneumonitis in clinical trial patients, with dose delays and discontinuation if needed. The severity of pneumonitis appears to be less with anti–PD-L1 antibodies; with BMS-936559, only 3 of 284 patients (1%) experienced this AE, and none were grade 3/4. All AEs can be successfully managed with early identification and intervention.

Biomarkers

Given the role of PD-L1 in immune inhibition within the tumor microenvironment, PD-L1 expression patterns were reviewed in an attempt to identify its role as a predictive marker. Preclinical data suggest that expression patterns of PD-1 ligands may be crucial for determining the suitability of therapeutic blockade of this pathway.³ Several clinical trials with anti–PD-1 and anti–PD-L1 antibodies have attempted to determine whether tumor PD-L1 expression is correlated with improved prognosis and likelihood of benefit from PD-1–targeted therapy. Initial data presented indicated no benefit in patients (0 of 17 patients) with solid tumors without PD-L1 expression.^14,19 Recent trials show that patients with negative staining for PD-L1 have response to treatment,¹⁶ with a proportion of patients achieving responses despite negative PD-L1 expression by IHC. This response rate in PD-L1–negative tumors is higher than that seen with previous melanoma therapies. This finding points out the need to improve our understanding of PD-L1 expression as a marker of response. Different trials have used different methods for PD-L1 staining or cutoff points for PD-L1 expression positivity. Tumor expression of PD-L1 may also be dynamic, depending upon changes in the tumor microenvironment. In an evaluation of 150 melanoma tumor samples, tumor PD-L1 expression was highly concordant with immune infiltrates and the presence of IFN-? in the tumor microenvironment.²⁵ Also, as soluble cytokines such as IFN-? upregulate PD-L1 expression, fresh tumor samples may have better predictive value than the archived tumor biopsy tissues that are frequently used in clinical trials.²⁶ The utility of PD-L1 staining as a predictive biomarker will need to be further explored in large randomized studies. Current phase 3 trials with pembrolizumab are evaluating PD-L1 expression in tumor tissue from metastatic sites with prospective randomization based on expression.

In combination therapies with anti–PD-1 and anti–CTLA-4 antibodies, TILs were evaluated to elucidate the role of other coinhibitory ligand receptors that could suppress the tumor microenvironment.²⁷ Interestingly, TIL and peripheral blood lymphocyte CTLA-4 expression increased in response to nivolumab treatment,²⁸ and PD-1 expression was induced in T cells after CTLA-4 blockade. This finding indicates a probable benefit of combination therapy or sequential therapy with immune checkpoint inhibition. When nivolumab was administered with ipilimumab in a concurrent or sequenced regimen, a 53% ORR was seen.²⁴ IHC testing was used to measure PD-L1 expression of tumor samples, with a sample defined as positive if at least 5% of tumor cells expressed PD-L1 staining. With the concurrent regimen, objective responses were observed in patients with either PD-L1–positive tumor samples (6 of 13 patients) or PD-L1–negative tumor samples (9 of 22 patients). In the sequenced regimen cohorts, a higher number of overall responses were seen among patients with PD-L1–positive tumor samples (4 of 8 patients) than among patients with PD-L1–negative tumor samples (1 of 13 patients).

Upcoming Studies

While most of the current clinical trials have been focused on advanced melanoma and NSCLC patients, pembrolizumab is also undergoing further testing in other solid tumors (Table 2). In high-risk renal cell carcinoma (RCC) patients, higher levels of immune cells expressing PD-1 have been observed.²⁹ An expansion cohort of 34 patients investigated nivolumab in RCC and demonstrated an ORR of 29%, with a median PFS of 7.3 months. A median OS of more than 22 months was observed along with a 1-year survival rate of 70%.²³ A phase 1 trial of pembrolizumab in combination with pazopanib in RCC patients has recently opened (NCT02014636).



An evaluation of tissue samples from colorectal cancer (CRC) patients revealed that PD-L1 and PD-L2 status may be a predictor of prognosis for these patients.³⁰ In the nivolumab phase 1 trial, no responses were seen in CRC or castrate-resistant prostate cancer patients. Pembrolizumab is also undergoing evaluation in a phase 2 trial with 3 arms including microsatellite instability (MSI)-positive colon cancer, MSI-negative colon cancer, and patients with other MSI-positive cancers (NCT01876511). PD-L1 immunodetection was shown to correlate to tumor size, invasion, lymph node metastasis, and survival time of patients with gastric cancer, as enhanced PD-L1 immunolabeling was seen when the tumor infiltrated into the deep muscular layers.³¹ Patients with esophageal PD-L1–positive cancer were also found to have a significantly poorer prognosis than PD-L1–negative patients.³² An ongoing phase 1b trial is examining pembrolizumab in 4 cohorts of advanced gastric, head and neck, urothelial, and triple-negative breast cancer patients (NCT01848834).

PD-1 and PD-L1 are also expressed in multiple myeloma cells, some primary T-cell leukemias and lymphomas, and Hodgkin lymphoma.^33-35 There is an ongoing phase 1b trial of pembrolizumab in several hematologic malignancies (NCT01953692). Other anti–PD-1 and PD-L1 drugs are also under investigation in hematologic malignancies. In a phase 2 study, the anti–PD-1 antibody pidilizumab in combination with rituximab was tested in patients with relapsed follicular lymphoma. No autoimmune or treatment-related grade 3/4 AEs were seen. Of the 29 evaluable patients, 19 (66%) had objective responses, including a CR in 15 (52%), and measurable tumor regression occurred in 86% of patients.³⁶

These ongoing trials with pembrolizumab will further help define its role in advanced melanoma, including whether it is appropriate for use in the first-line setting or in ipilimumab-refractory patients; there will also be trials of pembrolizumab in combination with other immunotherapeutics, including ipilimumab and other immune checkpoint inhibitors, to determine if improved response rates can be achieved while maintaining acceptable toxicity. The recent approval of dual targeted therapy (BRAF + MEK inhibition) in melanoma has led to a proposed triple combination trial with pembrolizumab. Results of ongoing studies of pembro­lizumab in NSCLC may also help to determine not only where it fits into the current armamentarium of therapeutics available for these patients but also further delineate the role of PD-L1 expression as a biomarker. Improved understanding of predictive and prognostic markers will increase the efficacy of PD-1 antibody therapy with pembrolizumab.

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