ESMO 2014: Pembrolizumab Shows Promise in Several Solid Tumours

A promise from a monoclonal antibody designed to block PD-1 interaction with its ligands PD-L1 and PD-L2

Results from the studies of pembrolizumab in advanced non-small-cell lung cancer (NSCLC), melanoma, gastric cancer, urothelial cancer and head and neck carcinoma, presented during the ESMO 2014 Congress (Madrid, Spain), show promising activity and tolerability from this novel monoclonal antibody.

PD-1 is a negative co-stimulatory receptor expressed primarily on activated T cells. Binding of PD-1 to its ligands inhibits effector T-cell function. Expression of PD-L1 on tumour cells and macrophages can suppress immune surveillance and permit neoplastic growth.

Pembrolizumab is able to achieve a dual blockade (PD-L1 and PD-L2). It shows no cytotoxic (ADCC/CDC) activity. Pharmacokinetics support dosing every 2 weeks (Q2W) or every 3 weeks (Q3W). Pembrolizumab demonstrated a clinical activity in multiple tumour types.

Antitumour activity of pembrolizumab and correlation with PD-L1 expression in a pooled analysis of patients with advanced NSCLC

The anti-PD-1 antibody pembrolizumab has shown durable antitumour activity and acceptable toxicity in treatment-naïve and previously treated advanced NSCLC patients. Correlation between tumour PD-L1 expression and improved pembrolizumab antitumour activity has been observed. Prof. Edward Garon of the David Geffen School of Medicine at UCLA, Santa Monica, USA presented analysis in 282 patients with treatment-naïve or previously treated advanced NSCLC enrolled in randomised and non-randomised cohorts of the phase I KEYNOTE-001. The results were presented during the Proffered Paper session in metastatic NSCLC.

Tumour PD-L1 expression was determined prospectively by a prototype immunohistochemistry (IHC) assay in all patients. Samples were independently reanalysed using a clinical trial IHC assay.

Pembrolizumab was given at 2 mg/kg every 3 weeks (Q3W), 10 mg/kg Q3W, or 10 mg/kg Q2W until progression, death, or unacceptable toxicity.

Overall response rate (ORR) was assessed per RECIST v1.1 by central review and per immune-related response criteria (irRC) by investigator review.

Mature data are available for 262 patients with 5.4 months of median follow-up.

Grade 3-5 drug-related adverse events occurred in 24 (9%) patients, most commonly pneumonitis.

The ORR in patients with measurable disease at baseline was 21% RECIST v 1.1 and 23% (irRC) in overall study population (26%/47% treatment naïve, 20%/18% previously treated) and was 18% in patients with squamous and 23% in patients with nonsquamous histology. The ORR was 33%/67% at 2 mg/kg Q3W, 21%/22% at 10 mg/kg Q3W, and 21%/22% at 10 mg/kg Q2W. The ORR was 23%/25% in patients with ≥1% PD-L1 staining and 9%/13% in patients with negative PD-L1 staining.

In all treatment-naïve patients, the responses are still ongoing, while it is a case in 77% of previously treated patients.

In treatment-naïve patients progression-free survival (PFS) is 27 weeks with a 24-week PFS rate of 51%. In the same group, median overall survival (OS) is not reached yet and 6-month OS rate is 86%. In previously treated patients median PFS is 10 weeks, and 24-week PFS rate is 26%. The median OS is 8.2 months and 6-month OS rate is 59%.

In pooled population, median PFS is 13 weeks and 24-week PFS rate 30%. The median OS is 8.2 months with 6-month OS rate of 64%.

The data for PD-L1 staining using the clinical trial IHC assay are available for nearly half of the patients. In these patients, the overall response rate (ORR) was higher in patients with strong PD-L1 expression (≥50% staining) than in patients with weak/negative PD-L1 expression.

The PFS was longer in patients with PD-L1 strong-positive versus PD-L1 weak-positive/ negative tumours (hazard ratio, HR, 0.52). The OS was longer in patients with PD-L1 strong-positive versus PD-L1 weak-positive/negative tumours (HR, 0.59).

Prof. Garon concluded that pembrolizumab is tolerable and provides antitumour activity in treatment-naïve or previously treated advanced NSCLC, regardless of dose/schedule. Patients with strong PD-L1 tumour expression may derive particular benefit from pembrolizumab. Validation of the prospective PD-L1 cutpoint will be performed in an additional 300 patients enrolled in KEYNOTE-001. Ongoing studies with pembrolizumab in NSCLC are KEYNOTE-010, -024, and -042.

Pembrolizumab for advanced melanoma: Randomised comparison of two dosing schedules

Pembrolizumab has demonstrated strong antitumour activity in patients with advanced melanoma at doses of 10 mg/kg every 2 weeks (Q2W), 10 mg/kg Q3W, and 2 mg/kg Q3W. Previous randomised data from KEYNOTE-001 showed no difference in efficacy or safety between 10 mg/kg Q3W and 2 mg/kg Q3W.

To formally compare the efficacy and safety of pembrolizumab dosing schedules of 10 mg/kg Q3W and 10 mg/kg Q2W, an additional 244 patients were enrolled in KEYNOTE-001 and randomised 1:1 to treatment with pembrolizumab 10 mg/kg Q3W (121 patients) or 10 mg/kg Q2W (123 patients). Ipilimumab-naïve patients received ≤2 prior systemic therapies; ipilimumab-treated patients were not restricted by prior therapy. Response was assessed every 12 weeks. Primary endpoint was ORR per RECIST v1.1 by an independent central review.

The results were presented in the Poster Discussion session on Melanoma and other skin tumours by Dr Caroline Robert of the Institute Gustave Roussy, Villejuif, France.

As of February 2014, median follow-up was approximately 35 weeks, and all patients had ≥26 week follow-up. Arms were balanced for known prognostic factors. Median treatment duration was 21 weeks for the Q3W arm and 22 weeks for the Q2W arm. Among the 224 patients evaluable for ORR (108 at Q3W, 116 at Q2W), no significant difference was observed between schedules (28% at Q3W vs 33% at Q2W). Across schedules, confirmed ORR was 33% in ipilimumab-naïve and 28% in ipilimumab-treated patients.

Disease control rate was 44% at Q3W and 50% at Q2W. 24-week PFS rates were 43% at Q3W and 47% at Q2W, and there was no significant difference in PFS between schedules.

The safety profile was similar for both schedules, with grade 3-4 treatment-related adverse events observed in 12% of patients at Q3W and 15% at Q2W, discontinuations due to treatment-related adverse events in 1% at Q3W and 3% at Q2W, and no treatment-related deaths.

Overall, pembrolizumab showed similar efficacy and safety at 10 mg/kg Q2W and 10 mg/kg Q3W in patients with advanced melanoma. Considering previous randomised data showed no significant difference in efficacy and safety between pembrolizumab doses of 10 mg/kg Q3W and 2 mg/kg Q3W, the recommended pembrolizumab dose and schedule is 2 mg/kg Q3W.

Pembrolizumab has been recently approved in the United States for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.

A phase IB study of pembroluzumab in patients with advanced gastric cancer

In a phase Ib study the researchers assessed the safety, tolerability, and antitumour activity of pembrolizumab in gastric cancer patients. The results were presented by Dr Kei Muro of the Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.

Using a prototype IHC assay, PD-L1 expression was assessed in archival tumour samples from patients with recurrent/metastatic adenocarcinoma of the stomach or gastroesophageal junction. Eligible patients with PD-L1 staining in stroma or ≥1% of tumour cells were enrolled and treated with pembrolizumab 10 mg/kg every 2 weeks for up to 24 months or until complete response, disease progression, or unacceptable toxicity.

Enrolment was designed to include an equal number of patients from Asia Pacific and the rest of the world. Adverse events were monitored and graded per the NCI CTCAE v4.0. Radiographic imaging was performed every 8 weeks. Primary efficacy endpoint was ORR assessed by RECIST v1.1.

Of the 162 patients screened, 65 (40%) were PD-L1-positive of which 39 enrolled: 19 from Asia Pacific, 20 from rest of world. Median age was 63 years, and 72% of patients were men. Patients from Asia Pacific were more heavily pretreated than patients from rest of world (≥2 prior therapies in 79% vs 55%). Median follow-up duration was approximately 6 months.

The most common adverse events deemed treatment-related by investigators were hypothyroidism and fatigue. Grade ≥3 adverse events deemed treatment-related occurred in 3 patients (1 each for hypoxia, peripheral neuropathy, and pneumonitis).

The ORR (confirmed and unconfirmed) was 31.6% in Asia Pacific and 30% in the rest of world. Responses were ongoing for 6/6 Asia Pacific patients and 5/6 patients from the rest of world (median response duration not reached; range 8+ to 20+ weeks).

Evidence of an association between PD-L1 expression and PFS (p = 0.032) and ORR (p = 0.071) was observed.

Dr Muro concluded that pembrolizumab was generally well tolerated and provided antitumour activity in patients with advanced gastric cancer that expressed PD-L1. Preliminary data correlating PD-L1 expression with clinical outcomes will be further explored.

The robust antitumour activity observed supports the further development of pembrolizumab in advanced gastric cancer.

A phase IB study of pembrolizumab in patients with advanced urothelial tract cancer

Dr Elizabeth Plimack of the Oncology, Fox Chase Cancer Center, Philadelphia, USA and colleagues assessed the safety, tolerability, and antitumour activity of pembrolizumab in patients with recurrent or metastatic urothelial cancer in the KEYNOTE-012 study.

The KEYNOTE-012 study was a phase Ib multi-cohort study of pembrolizumab in patients with PD-L1-positive advanced solid tumours: triple-negative breast cancer, head and neck cancer, urothelial cancer, and gastric cancer.

Archival or newly obtained tumour samples from patients with advanced carcinoma of the renal pelvis, ureter, bladder, or urethra were screened for PD-L1 expression using a prototype IHC assay. PD-L1 expression in stroma or ≥1% of tumour cells was required for study entry. Patients received pembrolizumab 10 mg/kg every 2 weeks until complete response, progression, or unacceptable toxicity. Patients deriving benefit could remain on pembrolizumab beyond initial progression. Response was assessed every 8 weeks per RECIST v1.1 by an independent central review (primary efficacy endpoint).

The results were presented in the Proffered paper session on Genitourinary cancer.In total33 patients were enrolled, including 30 with transitional cell histology and 3 with non-transitional cell or mixed histology. Median age was 70 years (range 44-85), 70% had ECOG performance status (PS) 1, 52% received ≥2 prior therapies for advanced disease, 21% had liver metastases; and 22 patients (67%) received ≥3 pembrolizumab doses.

Median follow-up duration was 11 months (range 10-13), and 7 patients (21%) remain on therapy. Adverse events were reported in 61% of patients (≥1 drug-related), most commonly fatigue, peripheral oedema, and nausea; 4 patients (12%) reported grade 3-4 drug-related adverse events, with only rash seen in more than 1 patient. In total 29 patients received ≥1 dose of pembrolizumab, had a baseline scan with measurable disease, and were evaluable for response.

The ORR by central review was 24.1%, with 10.3% complete responses. Response duration is 16 to 40+ weeks (median not reached), with 6 of 7 responses ongoing. In the patients evaluable for response, median PFS is 8.6 weeks. In all patients, median OS is 9.3 months (6-months OS rate, 58%). Analysis of the relationship between PD-L1 expression and pembrolizumab efficacy is ongoing.

Pembrolizumab shows acceptable safety and tolerability and provides promising antitumour activity in patients with advanced urothelial cancer. These data support the continued development of pembrolizumab in advanced urothelial cancer.

A phase IB study of pembrolizumab in patients with human papillomavirus (HPV)-positive and -negative head and neck cancer

Dr Laura Chow of the Medical Oncology, University of Washington, Seattle, USA presented updated safety, tolerability, and antitumour activity of pembrolizumab for recurrent/metastatic head and neck cancer. Data from this cohort were previously reported at the 2014 ASCO Annual Meeting but the data presented at the Poster discussion session in Head and neck cancer at ESMO 2014 are updated and expanded.

During screening, PD-L1 expression in archival or newly obtained tumour samples was assessed using a prototype IHC assay; PD-L1 expression in stroma or ≥1% of tumour cells was required for study entry.

Pembrolizumab 10 mg/kg was given every 2 weeks until complete response, progression, unacceptable toxicity, physician decision, or consent withdrawal. Adverse events were recorded throughout the study. Response was assessed every 8 weeks. Primary endpoint was ORR per RECIST v1.1.

Out of 104 head and neck cancer patients screened, 81 (78%) were PD-L1-positive of which 61 enrolled, and 60 received ≥1 pembrolizumab dose: 23 HPV-positive, 37 HPV-negative. After a median follow-up of 10.2 months, 15 patients (25%) remain on pembrolizumab.

The ORR (confirmed and unconfirmed) per RECIST v1.1 by investigator review was 20%, and response duration ranged from 8+ to 41+ weeks (median not reached). Nine of 11 responders had a smaller target lesion burden at baseline. The ORR was similar in HPV-positive and HPV-negative patients, whereas PFS and OS were longer in HPV-positive patients. PD-L1 expression was positively correlated with ORR (p = 0.018) and PFS (p = 0.024). The ORR was 50% in the 12 patients with high PD-L1 expression.

Drug-related adverse events of any grade occurred in 58% of patients (grade ≥3 in 17%). The most common drug-related adverse events were fatigue (18%), pruritus (10%), and nausea (8%). There were no drug-related deaths.

The study researchers concluded that pembrolizumab is safe and tolerable and shows antitumour activity in both HPV-positive and HPV-negative advanced head and neck cancer. These findings support further development of pembrolizumab in advanced head and neck cancer.

References

All presented studies were supported by Merck Sharp & Dohme Corp.