November 2015, Vol. 2, No. 6

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Targeting Programmed Death-1 (PD-1) and Its Ligand (PD-L1)

Immune Checkpoint Blockade

Immunologic checkpoint blockade with antibodies targeting PD-1 or one of its ligands, PD-L1, is showing promise as a method for reversing cancer immunosuppression and thereby promoting immune responses against several cancer types.1 While the first checkpoint inhibitor approved by the FDA in 2011 was ipilimumab, an antibody that targets cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) instead of either PD-1 or PD-L1, 2 anti–PD-1 agents (pembrolizumab and nivolumab) are currently approved by the FDA for the treatment of cancer (Table 1). At this time, ipilimumab is the only checkpoint inhibitor approved for the first-line treatment of melanoma.



Both pembrolizumab and nivolumab are currently indicated for the second-line treatment of patients with unresectable or metastatic melanoma and disease progression following therapy with ipilimumab or after treatment with ipilimumab and a BRAF inhibitor in patients who carry a BRAF V600 mutation.2,3 In March 2015, the FDA expanded the approved use of nivolumab to include metastatic squamous non–small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.3 Both pembrolizumab and nivolumab are currently being investigated in additional clinical studies, which will be discussed below. Other anti–PD-1 inhibitors in current clinical studies include pidilizumab (CT-011) and MEDI0680 (formerly known as AMP-514); anti–PD-L1 inhibitors include atezolizumab (formerly MPDL3280A), durvalumab (formerly MEDI4736), and avelumab (also known as MSB0010718C) (Table 2).



Pembrolizumab

First-Line Pembrolizumab in Melanoma
At the 2015 Annual Meeting of the American Association for Cancer Research (AACR), results were presented from a randomized phase 3 study (KEYNOTE-006; NCT01866319) comparing pembrolizu­mab versus ipilimumab in the first-line treatment of patients with advanced (unresectable stage III or IV) melanoma who had received ≤1 prior systemic therapy.4 A total of 834 patients were randomized to receive either 4 cycles of ipilimumab 3 mg/kg every 3 weeks (q3w; the approved dosage), 10 mg/kg of pembrolizu­mab q3w, or 10 mg/kg of pembrolizumab every 2 weeks (q2w). Both dosing regimens of pembrolizumab are higher than the FDA-approved regimen of 2 mg/kg q3w. Response was assessed at week 12 and every 6 weeks thereafter by RECIST 1.1. Median follow-up was 8 months. Progression-free survival (PFS) rates after 6 months of treatment were 47.3% for pembrolizumab q3w, 46.4% for pembrolizumab q2w, and 26.5% for ipilimumab, according to the second interim analysis. Six-month overall survival (OS) rates were 84.8%, 87.6%, and 74.6%, respectively. Both PFS and OS benefits were seen across all subgroups. Furthermore, the objective response rate (ORR) was also improved among patients treated with pembrolizumab. ORR was 33.7% for pembrolizumab q2w (P = .00013), 32.9% for pembrolizumab q3w (P = .00002), and 11.9% for ipilimumab. The toxicity profiles of the agents were consistent with what has previously been observed, the study authors noted. Although pembrolizumab was administered for a longer duration, rates of grades 3 to 5 adverse events (AEs) were numerically lower than in the ipilim­umab arm (11.7% vs 19.9%).

Other Actively Recruiting Studies of Pembrolizumab in Melanoma (Table 3)
Pembrolizumab is being studied in pediatric patients with advanced melanoma in a phase 1/2 study (KEYNOTE-051; NCT02332668), as well as in combination with trametinib and dabrafenib in another phase 1/2 study (KEYNOTE-022; NCT02130466). A phase 3 randomized, double-blind study (KEYNOTE-054; NCT02362594) will determine whether pembrolizumab is better than placebo in the adjuvant melanoma setting. Patients at high risk for recurrence will be randomized to receive either pembrolizumab or placebo after complete resection of stage IIIA/B/C or stage IV melanoma.



Pembrolizumab in High PD-L1–Expressing NSCLC

An ongoing multicenter, single-arm, open-label phase 1 study (KEYNOTE-001; NCT01295827) is evaluating pembrolizumab in more than 1000 patients with diverse late-stage cancers (predominantly lung and melanoma). Results from a cohort of patients with high PD-L1–expressing NSCLC in the study were presented at the 2015 AACR annual meeting5 and published in The New England Journal of Medicine.6 The KEYNOTE-001 study included 495 previously treated and treatment-naive patients with advanced or metastatic NSCLC. The total population comprised a training set of 182 patients and a validation set of 313 patients. Pembrolizumab was administered at 3 dosages: 2 mg/kg q3w, 10 mg/kg q3w, or 10 mg/kg q2w. The researchers assessed patient responses every 9 weeks. In the entire study population, the ORR was 19.4%, and median OS and PFS were 12.0 and 3.7 months, respectively. The median duration of response was 12.4 months.

In the validation group, researchers were able to evaluate PD-L1 expression in 204 patients using an immunohistochemical assay. Patients were divided into 3 groups based on whether they had membranous PD-L1 expression in their tumor cells of ≥50% (n = 73), 1% to 49% (n = 103), or <1% (n = 28). The ORR was 45.2% (95% CI, 33.5-57.3) in patients with ≥50% of tumor cells positive for PD-L1 expression. In the other PD-L1 subgroups, ORR was 16.5% (95% CI, 9.9-25.1) in patients with 1% to 49% of tumor cells positive for PD-L1 expression and 10.7% (95% CI, 2.3-28.2) in patients with <1% of tumor cells positive for PD-L1 expression. The results were comparable but slightly better among patients who had not received prior therapy versus those who were previously treated.

Survival data were also presented for 356 patients in the total population whose PD-L1 levels were evaluable. After a median follow-up of 10.9 months, OS was not yet reached in the high PD-L1 group (n = 119) and was 8.8 months in both the intermediate (n = 161) and low (n = 76) PD-L1 groups. PFS was 6.3, 3.3, and 2.3 months in the 3 groups, respectively. The duration of response was similar in the 3 cohorts at 12.5 months, 7.2 months, and not yet reached.

The most common treatment-related AEs were fatigue, pruritus, and decreased appetite. Grades 3 to 5 treatment-related AEs occurred in 9.5% of patients (n = 47). Treatment-related AEs of an inflammatory or immune-mediated nature that occurred in >2% of patients were infusion-related reactions (n = 15; 3.0%), hypothyroidism (n = 34; 6.9%), and pneumonitis (n = 18; 3.6%). One infusion reaction led to treatment discontinuation, and all hypothyroidism cases were successfully managed with medical therapy. There was 1 treatment-related death (pneumonitis), and grades 3 to 5 pneumonitis were observed in 1.8% of patients (n = 9).

Other Studies of Pembrolizumab in NSCLC

A number of other studies of pembrolizumab are under way in NSCLC (Table 4). For example, 2 phase 3 studies (KEYNOTE-024 [NCT02142738] and KEYNOTE-042 [NCT02220894]) are evaluating the efficacy and safety of pembrolizumab compared with platinum-based chemotherapies in the first-line treatment of patients with PD-L1–positive advanced or metastatic NSCLC. Another phase 3 study (KEYNOTE-091; NCT02504372) is investigating the use of pembrolizu­mab as adjuvant therapy. Pembrolizumab is also being evaluated in combination with other agents. Studies include a phase 1/2 study (KEYNOTE-021; NCT02039674) that aims to determine the safety, tolerability, and efficacy of pembrolizumab in combination with chemotherapy or immunotherapy in participants with unresectable or metastatic NSCLC.



Pembrolizumab in Advanced PD-L1–Positive Solid Tumors

At the 2015 American Society of Clinical Oncology (ASCO) annual meeting, preliminary results were presented from an ongoing multicohort, nonrandomized phase 1b study (KEYNOTE-028; NCT02054806) of pembrolizumab monotherapy in more than 450 patients across 20 different types of cancer, including advanced small cell lung cancer (SCLC), esophageal cancer, and ovarian cancer.7 The study evaluated patients with PD-L1–positive advanced solid tumors that had not responded to current therapy or for which current therapy is not appropriate.

Preliminary results from a cohort of 20 heavily pretreated patients with advanced SCLC showed an ORR (confirmed and unconfirmed) of 35% (7 of 20 patients) (95% CI, 15-59) as measured by RECIST v1.1.8 At the time of the analysis, 6 of 7 responses were ongoing. The median follow-up duration for evaluable patients was 21 weeks (range, 2-48 weeks). AEs were consistent with previously reported safety data for pembrolizumab. Treatment-related AEs (occurring in ≥2 patients) were observed in 14 patients. Grade 3/4 investigator-assessed, treatment-related AEs were asthenia (1 patient) and increased blood bilirubin (1 patient). Some patients experienced AEs of special interest, including autoimmune thyroiditis (n = 1, grade 2) and colitis (n = 1, grade 5).

Preliminary results from a cohort of 23 heavily pretreated patients with advanced esophageal cancer showed an ORR (confirmed and unconfirmed) of 30.4% (7 of 23 patients) (95% CI, 13.2-52.9) per RECIST v1.1.9 In patients with squamous cell carcinoma, the ORR was 29.4% (5 of 17 patients), and in patients with adenocarcinoma, the ORR was 40% (2 of 5 patients). The median duration of response was 40 weeks (range, 0.1+ to 40 weeks), with 6 of 7 responses ongoing. Tumor shrinkage was achieved in 52.2% of evaluable patients. AEs were consistent with previously reported safety data for pembrolizumab. No treatment-related deaths occurred.

Preliminary results from a cohort of 26 heavily pretreated patients with advanced ovarian cancer showed an ORR (confirmed and unconfirmed) of 11.5% (3 of 26 patients) (95% CI, 2.4-30.2) per RECIST v1.1.10 Additionally, a disease control rate (DCR) of 34.6% (9 of 26 patients) (95% CI, 17.2-55.7) was seen. At the time of the analysis, the median duration of response had not been reached. No treatment-related deaths occurred.

Pembrolizumab in Colorectal Cancer and Other Solid Tumors With/Without DNA Mismatch Repair

DNA mismatch repair (MMR) is a process the body uses to recognize and repair genetic mismatches generated during DNA replication; a defective MMR system allows mismatch mutations to persist.11 In a phase 2 study, 48 evaluable, heavily pretreated patients with advanced colorectal cancer and other solid tumors (with and without MMR deficiency) were treated with pembrolizumab.11,12 In the colorectal cancer group with MMR-deficient tumors, an ORR of 62% (8 of 13 patients) was observed. In contrast, no responses (0 of 25 patients) were observed in the colorectal cancer group with MMR-proficient tumors. At the time of analysis, the median PFS and OS were not reached in the MMR-deficient colorectal cancer group. In contrast, PFS was 2.3 months, and OS was 7.6 months in the MMR-proficient colorectal cancer group. The median duration of follow-up for all patients was 5.9 months (0.9-16.6 months); 8.3 months (2.2-16.6 months) in the MMR-deficient colorectal group, 4.9 months (0.9-15.6 months) in the MMR-proficient colorectal group, and 7.1 months (2.4-16.4 months) in the MMR-deficient other cancers group. Of the responders, no patients in the MMR-deficient colorectal cancer group and 1 patient in the MMR-deficient other cancers group had progressed at the time of the analysis. Treatment-related AEs in the study were generally consistent with previously reported safety data for pembrolizumab. The most common treatment-related AEs (occurring in ≥10% of patients) included: rash/pruritus (17%), pancreatitis (15%), and thyroiditis/hypothyroidism (10%). A grade 3/4 treatment-related AE occurred in 1 patient (2%). Based on the encouraging results from this early study, a registrational phase 2 study (KEYNOTE-164) is being initiated to evaluate the efficacy and safety of pembro­lizumab based on MMR status in locally advanced unresectable or metastatic (stage IV) colorectal cancers.

Additional Pembrolizumab Studies in Other Tumor Types
A recent search of ClinicalTrials.gov revealed that pembrolizumab is being investigated—both as monotherapy and in combination with other therapies—in 126 open studies in various tumor types, including 26 studies in NSCLC, 25 in melanoma, 10 in breast cancer, 9 in ovarian cancer, 8 in bladder cancer, 5 in Hodgkin lymphoma, and 4 in head and neck cancer. Examples of some of the actively recruiting studies in other tumor types are listed in Table 5.



Additional studies continue to be added to the pembrolizumab development program, including studies in new types of cancer (eg, nasopharyngeal carcinoma, anal cancer, Merkel cell carcinoma, and biliary tract cancer).13

Nivolumab

Nivolumab plus Ipilimumab in Advanced Melanoma
Studies have shown that combining checkpoint inhibitors with different mechanisms of action has promise in advanced melanoma. At the 2015 AACR annual meeting, results from a phase 2 study (CheckMate 069; NCT01927419) showed that the combination of nivolumab plus ipilimumab improved responses over ipi­l­imumab alone.14 The results, which were simultaneously published online in The New England Journal of Medicine, showed that the checkpoint inhibitor combination had an ORR of 61% in a subgroup of patients with BRAF V600 wild-type tumors, including 22% complete responses (CRs) and 39% partial responses (PRs), versus 11% in the group that received ipilimumab monotherapy, including no CRs and 4 PRs.15 Among BRAF-positive patients, the ORR was 52% with the 2-drug regimen versus 10% with ipilimumab monotherapy. Responses in the combination arm included 5 CRs and 7 PRs. Safety data were available for 140 patients. Rates of all-grade AEs were similar between the combination and monotherapy arms at 91% and 93%, respectively. Grade 3/4 AEs were 54% versus 24% in the combination arm versus the control arm, leading to 36 and 6 discontinuations, respectively. The most common grade 3/4 AEs in patients receiving nivolumab/ipilimumab were colitis (17%), diarrhea (11%), elevated alanine transaminase (11%), increased lipase (9%), and elevated aspartate transaminase (7%). There were 3 treatment-related deaths in the combination arm versus none with ipi­limumab alone.

At the 2015 ASCO annual meeting, results were presented from a phase 3 study (CheckMate 067) of the frontline treatment of advanced melanoma with nivolumab alone versus the combination of nivolumab with ipilimumab versus ipilimumab alone.16 At a minimum follow-up of 9 months, the group that received the combination of nivolumab with ipilimumab and the group that received nivolumab alone experienced significantly improved PFS and ORR compared with the group that received ipilimumab alone. In the group that received the combination therapy (n = 314), median PFS was 11.5 months (8.9-16.7 months); in those who received nivolu­mab alone (n = 316), it was 6.9 months (4.3-9.5 months); and in those who received ipilimumab alone (n = 315), it was 2.9 months (2.8-3.4 months). In the group that received the combination therapy, the ORR was 57.6% (52.0%-63.2%); in those who received nivolumab alone, it was 43.7% (38.1%-49.3%); and in those who received ipilimumab alone, it was 19.0% (14.9%-23.8%) (Figure 1). The CR rates were 11.5% in the combination therapy group, 8.9% in the nivolumab group, and 2.2% in the ipilimumab group. Grade 3/4 treatment-related AEs (Figure 2) occurred in 55.0%, 16.3%, and 27.3% of patients in the combination therapy, nivolumab monotherapy, and ipilimumab monotherapy groups, respectively—most commonly diarrhea (9.3%, 2.2%, 6.1%), increased lipase (8.6%, 3.5%, 3.9%), increased alanine aminotransferase (8.3%, 1.3%, 1.6%), and colitis (7.7%, 0.6%, 8.7%). Treatment-related AEs led to discontinuation in 36.4%, 7.7%, and 14.8% of patients in the combination-therapy, nivolumab monotherapy, and ipilimumab monotherapy groups, with 0, 1, and 1 drug-related deaths, respectively.





Nivolumab plus Ipilimumab in Other Types of Tumors (Table 6)
Two phase 3 studies are investigating the combination of nivolumab plus ipilimumab in patients with recurrent glioblastoma (NCT02017717) and in patients with previously untreated advanced or metastatic renal cell carcinoma (NCT02231749). A phase 1/2, open-label study (NCT01928394) of nivolumab monotherapy versus nivolumab combined with ipilimumab is actively recruiting patients with advanced or metastatic solid tumors, including triple-negative breast cancer, gastric cancer, pancreatic cancer, SCLC, bladder, and ovarian cancer. Early-stage studies are evaluating the combination in patients with advanced colon cancer (NCT02060188) and hematologic cancers (NCT01592370).



Nivolumab Plus Other Checkpoint Inhibitors

The combination of nivolumab with other checkpoint inhibitors, lirilumab and BMS-986016, is also being evaluated in phase 1 studies in patients with advanced solid tumors (Table 7).



Nivolumab in Advanced NSCLC

Nivolumab is currently being investigated in patients with advanced-stage NSCLC both as monotherapy and in combination with other agents (Table 8). An open-label, randomized, phase 3 study (CheckMate 026; NCT02041533) is investigating whether nivolumab will improve PFS in treatment-naive patients with stage IV or recurrent PD-L1–positive NSCLC compared with the investigator’s choice of chemotherapy.17 A phase 3 safety study (CheckMate 153; NCT02066636) will evaluate the incidence and characterize the outcome of select high-grade AEs. Patients include those who have advanced or metastatic NSCLC and who have progressed during or after receiving at least 1 prior systemic regimen. A phase 1 study (CheckMate 012; NCT01454102) will compare nivolumab monotherapy versus various combinations of nivolumab plus chemotherapy or targeted therapy in chemotherapy-naive patients with stage IIIB/IV NSCLC.



Nivolumab in Head and Neck Cancer
A phase 3 study (CheckMate 141; NCT02105636) is investigating whether nivolumab will significantly improve OS compared with another therapy of the investigator’s choice in patients with recurrent or metastatic head and neck carcinoma.

Nivolumab in Hematologic Malignancies
Three phase 2 studies are evaluating nivolumab as treatment for blood cancers (Table 9). In CheckMate 140 (NCT02038946), the effect of nivolumab therapy is being assessed in patients with relapsed or refractory follicular lymphoma in whom therapy with both a CD20 antibody and an alkylating agent have failed. CheckMate 139 (NCT02038933) is no longer recruiting but is ongoing in determining whether nivolumab is effective in the treatment of diffuse large B-cell lymphoma (DLBCL) in patients who have failed or are ineligible for autologous stem cell transplant (ASCT). CheckMate 205 (NCT02181738) is assessing the response to nivolumab in patients with classical Hodgkin lymphoma after failure of ASCT.



Pidilizumab

Pidilizumab (CT-011) is being investigated in hematologic malignancies (Table 10).



MEDI0680 (Formerly AMP-514)

MEDI0680 is being investigated in 3 early-stage studies (Table 11). MEDI0680 is a humanized IgG4κ monoclonal antibody specific for human PD-1 that not only blocks PD-L1 but also blocks PD-1 ligand 2 (PD-L2).18 Blocking both PD-L1 and PD-L2 may achieve a more efficient blockade and may be more specific for different tumor groups in comparison with blocking either one alone. Durvalumab is a human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80 with high affinity and selectivity. Anti–PD-1 and anti–PD-L1 agents block distinct interactions contributing to immunosuppression, suggesting potential additive or synergistic effects. Preclinical data, including data from mouse models, support a potential benefit for anti–PD-L1 and anti–PD-1 in combination. In a phase 1, multicenter, open-label study (NCT02118337), the safety of MEDI0680 in combination with durvalumab is being evaluated in patients with advanced malignancies.18 Eligible patients (≥18 years) will have an ECOG performance status of 0-1. The primary objectives are to assess safety and tolerability and to determine the maximum tolerated dose of MEDI0680 in combination with durvalumab. Secondary objectives include assessment of antitumor activity (including ORR, DCR, duration of response, PFS, and OS), pharmacokinetics, and immunogenicity of the combination. Exploratory objectives include an evaluation of biomarkers within the tumor microenvironment and their relationship to tumor response, identification of genetic predictors of response or resistance, and an assessment of patient-reported outcomes. Recruitment is ongoing, with a target enrollment of approximately 150 patients across 3 centers in the United States.



A phase 1, multicenter, open-label, first-in-human, dose-escalation study (NCT02013804) is under way evaluating MEDI0680 in patients with advanced malignancies.19 Eligible patients (≥18 years) will have an ECOG performance status of 0-1, histologically or cytologically confirmed melanoma or clear cell renal cell carcinoma that is refractory to standard treatment or for which no standard treatment exists, ≥1 measurable lesion per RECIST v1.1, with prior treatment toxicities of grade ≤1. The primary objectives of the study are to assess the safety and tolerability and to define the maximum tolerated dose of MEDI0680. Secondary objectives include an evaluation of the pharmacokinetic and antitumor effects of MEDI0680. Recruitment is ongoing, with a target enrollment of approximately 48 patients across 5 centers in the United States.

PD-L1 INHIBITORS

Atezolizumab

Atezolizumab in NSCLC
Based on early-stage studies, the FDA granted atezol­izumab a breakthrough therapy designation in February 2015 for the treatment of patients whose NSCLC expresses PD-L1 and whose disease progressed during or after standard treatments, eg, platinum-based chemotherapy and appropriate targeted therapy for epidermal growth factor receptor (EGFR) mutation–positive or anaplastic lymphoma kinase (ALK)-positive disease.

Interim results were presented at the 2015 ASCO annual meeting from a multicenter, open-label, randomized phase 2 study (POPLAR; NCT01903993) of atezolizumab versus docetaxel in 287 patients with locally advanced or metastatic squamous or nonsquamous NSCLC in whom platinum therapy had failed.20 Patients were stratified based on PD-L1 expression using a highly sensitive and specific investigational immunohistochemistry assay that uses the antibody SP142 to measure PD-L1 expression on both tumor-infiltrating immune cells (ICs) and tumor cells (TCs). Results showed that in patients with the highest level of PD-L1 expression (TC3 or IC3), the median OS with atezolizumab was not yet reached compared with 11.1 months for docetaxel (hazard ratio [HR], 0.47; 95% CI, 0.20-1.11). In this same group (TC3 or IC3), the median PFS was 9.7 versus 3.9 months for the anti–PD-L1 antibody and docetaxel, respectively (HR, 0.56; 95% CI, 0.28-1.11), and the ORR was 38% with atezolizumab and 13% with chemotherapy. In patients without PD-L1 expression (TC0 and IC0), a difference was not observed between the groups (Figure 3). Across all patients in the study (n = 287), the median OS was 11.4 months with atezo­liz­umab versus 9.5 months with docetaxel (HR, 0.78); the median PFS in the atezolizumab arm was 2.8 versus 3.4 months with docetaxel (HR, 0.96).



A number of studies are under way with atezolizumab in lung cancer (Table 12). Results from a phase 1b study in which atezolizumab was combined with a range of platinum-based chemotherapy combinations (carboplatin plus either paclitaxel, pemetrexed, or nab-paclitaxel) commonly used in the treatment of advanced (stage IIIB or IV) or recurrent NSCLC showed that patients treated with the combination therapy achieved an ORR of 67%, including 2 CRs, and the combinations were well tolerated with no unexpected toxicities.21 Based on these encouraging data, 3 phase 3 studies (IMpower 130 [NCT02367781]; IMpower 131 [NCT02367794]; and IMpower 150 [NCT02366143]) of the combination of atezolizumab with chemotherapy as first-line treatment for advanced NSCLC have been initiated.



Atezolizumab in Triple-Negative Breast Cancer

Preliminary results from a cohort of 54 heavily pretreated patients with metastatic triple-negative breast cancer in a multicenter phase 1a study (NCT01375842) were presented at the 2015 AACR annual meeting.22 In this study, among 21 PD-L1–positive evaluable patients, the investigator-assessed ORR by RECIST was 19%, including 9.5% CRs and 9.5% PRs. At the time of analysis, 75% of responses were ongoing, with a median not yet reached (range, 18-56+ weeks). The 24-week PFS rate in the PD-L1–positive population was 27%. Three patients (14%) with PD-L1–positive triple-negative breast cancer experienced a phenomenon known as pseudoprogression with atezolizumab and were indicated as having progressive disease by RECIST. However, these patients continued to receive treatment and later demonstrated responses in the target and newly formed lesions. The safety analysis for the trial included data from all 54 patients. All-grade AEs were evident in 63% of patients. Overall, 11% of patients experienced a grade 3 AE, including low potassium level, low white blood cell count, dysp­nea, and adrenal insufficiency. There was 1 grade 4 event of pneumonitis.

Currently, a phase 3 study (IMpassion 130; NCT02425891) of atezolizumab in combination with nab-paclitaxel compared with placebo with nab-paclitaxel is under way in patients with previously untreated metastatic triple-negative breast cancer.

Atezolizumab in Advanced Urothelial Bladder Cancer
Based on phase 1 findings in heavily pretreated patients with metastatic urothelial bladder cancer, atezo­lizumab received a breakthrough therapy designation from the FDA in late May 2014.

Updated findings were presented at the 2015 ASCO annual meeting from a cohort of patients with metastatic urothelial bladder cancer in a phase 1a study.23 Results showed that in patients with the higher levels of PD-L1 expression (IC3 or IC2), the ORR was 50%, including 9 CRs and 14 PRs. Among the 32 patients with visceral metastases at baseline, the ORR was 38%. In the IC3 group alone (n = 12), the ORR was 67% (95% CI, 35%-90%), with a CR rate of 33%. In the IC2 group (n = 34), the ORR was 44% (95% CI, 27%-62%), and the CR rate was 15%. In patients with lower levels of PD-L1 expression (IC0/1), the ORR was 17% (95% CI, 7%-32%). The median PFS in the IC2/3 group (n = 48) was 6 months, with a 1-year rate of 39%. At a 14-month follow-up, the median OS in the IC2/3 group had not been reached, with a 1-year rate of 57%. In the IC0/1 group, the median PFS was 1 month, the median OS was 7.6 months, and the 1-year PFS and OS rates were 10% and 38%, respectively.

It was recently announced that an open-label, multicenter, single-arm phase 2 study (IMvigor 210) that evaluated the safety and efficacy of atezolizumab in patients with locally advanced or metastatic urothelial bladder cancer that had progressed on initial treatment (second-line or later), regardless of PD-L1 expression, met its primary ORR end point.24 High levels of PD-L1 expression correlated with increased response. AEs were consistent with what has previously been observed for atezolizumab.

Two phase 3 studies are also assessing atezolizumab for patients with bladder cancer (Table 13). In the phase 3 IMvigor 211 study, atezolizumab is being compared with chemotherapy in patients with relapsed urothelial bladder cancer. The phase 3 IMvigor 010 study will assess adjuvant atezolizumab versus observation in patients with early-stage muscle-invasive bladder cancer based on PD-L1 status.



In addition to lung, breast, and bladder cancer, atezolizumab is being studied in other solid tumors and in hematologic malignancies (Table 14).



Durvalumab

Durvalumab is a human IgG1 molecular antibody that blocks PD-L1 binding to PD-1 and CD80 with high affinity and selectivity.

Durvalumab in Advanced NSCLC
The durvalumab development program includes a number of studies in patients with advanced NSCLC (Table 15). In an open-label, international, multicenter, noncomparative, phase 2 study (ATLANTIC; NCT02087423), the efficacy and safety of durvalumab is being assessed in patients with PD-L1–positive, locally advanced or metastatic (stage IIIB-IV) NSCLC.25 Patients will be divided into 3 cohorts: cohort 1: patients with EGFR mutations or ALK alterations; cohort 2: patients with wild-type EGFR and ALK; and cohort 3: patients with wild-type EGFR/ALK and ≥90% of tumor cells PD-L1–positive. Cohorts 1 and 2 include patients whose tumor tissue samples have ≥25% of tumor cells with membrane staining for PD-L1. Eligible patients must have an ECOG performance status of 0-1 and have received ≥2 prior systemic treatment regimens, including 1 platinum-based chemotherapy and a tyrosine kinase inhibitor if EGFR or ALK positive. The primary outcome measure is ORR; secondary outcome measures will further assess efficacy (including DCR, duration of response, PFS, and OS), safety, tolerability, pharmacokinetics, and immunogenicity of durvalumab. Patients will be recruited at 100 to 150 sites across North America, Asia, and Europe.



Chemotherapy and radiotherapy upregulate the expression of tumor PD-L1, which could increase sensitivity to PD-L1–directed therapy. Based on this rationale, a randomized, double-blind, multicenter, international phase 3 study (PACIFIC; NCT02125461) will evaluate the efficacy and safety of durvalumab in patients with locally advanced, unresectable, stage III NSCLC whose disease has not progressed following platinum-based concurrent chemoradiation therapy.26 In this study, approximately 700 patients will be randomized 2:1 to receive durvalumab or placebo every 2 weeks for up to 12 months. Eligible patients must previously have received ≥2 cycles of platinum-based concurrent chemoradiation with no subsequent disease progression, have received a total dose of radiation of ≥60 Gy, and have archival tissue available. Patients treated with sequential chemoradiation therapy for locally advanced disease and those with metastatic disease are excluded. Randomization must occur within 42 days of radiation. Coprimary end points are OS and PFS; secondary end points include OS at 24 months, proportion of patients alive and progression-free at 12 and 18 months, time to second progression, ORR, duration of response, health-related quality of life, safety/tolerability, pharmacokinetics, and immunogenicity of durvalumab. Patients who achieve and maintain disease control up to 12 months will enter follow-up. Patients will be recruited at approximately 300 sites across Australia, Asia, Europe, North and South America, and South Africa. Recruitment is ongoing.

As we have seen, patients with high PD-L1–expressing tumors tend to respond better to anti–PD-1/PD-L1 agents. The subset of patients with PD-L1–negative tumors represents a cohort with limited therapeutic options who may benefit from the combination of an anti–PD-L1 agent and another checkpoint inhibitor. Therefore, durvalumab is being studied in combination with tremelimumab, a selective human IgG2 molecular antibody inhibitor of CTLA-4.

A randomized, open label, multicenter, phase 3 study (ARCTIC; NCT02352948) is under way to evaluate the efficacy and safety of durvalumab versus standard of care (the investigator’s choice of gemcitabine, vinorelbine, or erlotinib) in NSCLC patients with PD-L1–positive tumors (substudy A), and the combination of durvalumab and tremelimumab versus durvalumab or tremelimumab versus standard of care in patients with NSCLC with PD-L1–negative tumors (substudy B).27 Approximately 300 patients will be randomized 1:1 in substudy A and approximately 600 patients in a 3:2:2:1 ratio (durvalu­mab plus tremelimumab:standard of care:durvalumab: tremelimumab) in substudy B. Eligible patients include those with locally advanced or metastatic NSCLC who have received at least 2 prior treatment regimens, including 1 platinum-based chemotherapy. Patients with brain metastases or spinal cord compression are excluded unless asymptomatic, treated, and stable off steroids. Patients with known EGFR-activating mutations or ALK rearrangements are not eligible, nor are patients previously exposed to any anti–PD-1 or anti–PD-L1 antibody. The primary objective is to assess PFS and OS of durvalumab (among PD-L1–positive patients) and durvalumab plus tremelimumab (among PD-L1–negative patients), compared with standard of care. Secondary objectives include the proportion of patients alive at 12 months, ORR, duration of response, PFS at 6 and 12 months, safety, tolerability, pharmacokinetics, immunogenicity, and health-related quality of life. Recruitment to the study is ongoing since January 2015.

Durvalumab in Other Types of Cancer
A comprehensive development program for durvalu­mab as monotherapy and in combination with other agents is under way across multiple tumor types, including head and neck, gastric, pancreatic, breast, brain, esophageal, bladder, liver, and hematologic cancers. Examples of late-stage studies are listed in Table 16.



Avelumab

Avelumab (formerly known as MSB0010718C) is an investigational fully human anti–PD-L1 IgG1 monoclonal antibody currently being evaluated in an extensive clinical trial program (JAVELIN) as a potential treatment for multiple types of cancer as both a single agent and in combination with other agents.

An open-label, multicenter, randomized phase 3 study (JAVELIN Lung 200; NCT02395172) is assessing the efficacy and safety of avelumab compared with docetaxel in patients with stage IIIB-IV or recurrent NSCLC who have experienced disease progression after receiving a prior platinum-containing doublet therapy.

An open-label, multicenter, single-arm, phase 2 study (JAVELIN Merkel 200; NCT02155647) is investigating the clinical activity and safety of avelumab in patients with metastatic Merkel cell carcinoma (MCC) who have received 1 line of chemotherapy for the treatment of metastatic MCC.

Phase 1 studies of avelumab are under way in bladder, gastric, head and neck, ovarian, renal, and lung cancers.

Concluding Remarks

PD-1/PD-L1 checkpoint inhibitors are demonstrating great promise in the treatment of a wide range of tumor types, both as monotherapies and in combination with other agents. Combinations of an anti–PD-1/PD-L1 agent with an anti–CTLA-4 agent appear to increase clinical benefit but also increase toxicities. Much additional research is needed to determine the best way to use these powerful immunotherapeutic weapons in the battle against cancer.

References

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16th International Lung Cancer Congress - November 9, 2015

The Next Generation of Agents for Lung Cancer

At the 16th Annual International Lung Cancer Congress, Tony Mok, MD, Professor of Clinical Oncology, The Chinese University of Hong Kong, provided an overview of the next generation of agents, taking stock of the recent past for insights into the future of drug discovery. Drug discovery is rarely, if ever, [ Read More ]

European Cancer Congress - November 9, 2015

Another Immunotherapy for NSCLC?

Immunotherapy is poised to become a game changer for patients with non–small cell lung cancer (NSCLC). Nivolumab is now approved by the FDA for the treatment of NSCLC, and atezolizumab is the second checkpoint inhibitor to show promise as second- line or later therapy in NSCLC. Results of the POPLAR [ Read More ]