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Evaluation of Maintenance Pembrolizumab in Extensive Small Cell Lung Cancer Patients

Simoneaux, Richard

doi: 10.1097/01.COT.0000524497.56334.44
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Small cell lung cancer (SCLC), also referred to as oat cell carcinoma, which comprises approximately 10-15 percent of all lung cancers (non-small cell lung cancer (NSCLC) accounts for roughly 80-85% of the total). In the U.S. each year, there are more than 30,000 new diagnoses of SCLC. Initially this disease will often present in the main airways and infiltrate the submucosa lining those airways. One of the major risk factors for this cancer is tobacco smoke. The clear majority of patients with this cancer will have a history of smoking.

Despite being located in the lungs, SCLC is actually a neuroendocrine disorder, and as such behaves in a completely different manner than NSCLC. Because neuroendocrine cells are involved in this disease, the ectopic secretion of adrenocorticotropic hormone or antidiuretic hormone may occur. Compared to the more common NSCLC, SCLC is the more malignant disease, having more rapid cancer cell division and development of metastases. Approximately 66 percent of the patients receiving a SCLC diagnosis will already have advanced stage disease.

For more than 30 years in the U.S., the standard treatment for SCLC has been 4-6 cycles of platinum (e.g., cisplatin or carboplatin)/etoposide chemotherapy. Once patients have undergone their initial chemotherapy regimen, the median progression-free survival (PFS) is a mere 2 months. Additionally, the median overall survival (OS) for these patients is 7 months. To address this unmet need, Nathan Pennell, MD, PhD, of the Cleveland Clinic, and colleagues conducted a phase II clinical study that evaluated the use of the checkpoint inhibitor pembrolizumab as maintenance therapy in advanced SCLC patients who had undergone 4-6 platinum/etoposide chemotherapy cycles. Results were presented at the 2017 ASCO Annual Meeting (Abstract 8504).

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Pembrolizumab

Pembrolizumab is a humanized monoclonal antibody that targets the PD-1 receptor, an immune checkpoint molecule present on lymphocytes that plays an important role in immune system self-regulation. By binding to this receptor on T cells, pembrolizumab prevents the immunosuppressive interaction with PD-L1. Many tumor cells have an overexpression of PD-L1 on their surfaces, which gives rise to the well-documented immunosuppressive tumor microenvironment.

As of this year, the use of pembrolizumab has been approved for a number of different cancers, including platinum-treated advanced or metastatic urothelial carcinoma, previously untreated NSCLC with high PD-L1 expression, refractory classical Hodgkin lymphoma, and previously-treated unresectable or metastatic solid tumors that are laboratory-confirmed to have microsatellite instability-high or mismatch repair-deficient status.

Because patients with SCLC are often smokers and have higher rates of mutation, it was thought that anti-PD-1 therapy might have some benefit for this population, as it has proven to be effective in NSCLC patients who share similar characteristics. In this study, it was decided to evaluate pembrolizumab as a maintenance therapy.

“It was thought that the maintenance setting would be an ideal one to test this immunotherapy, as patients have better performance status than at initial diagnosis or relapse, debulking of the tumor may speed up immune system clearance, and since the PFS was so short after chemotherapy cessation, there could be rapid assessment of clinical endpoints,” Pennell explained.

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Study Design

Abstract 8504

This study was limited to extensive stage SCLC patients who had complete response (CR), partial response (PR), or stable disease (SD) after 4-6 cycles of cisplatin/etoposide or carboplatin/etoposide. Patients with treated brain metastases were allowed, as was prophylactic cranial irradiation. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Additionally, restaging scans were performed within 3 weeks of receiving the experimental pembrolizumab therapy.

Patients were dosed with 200 mg pembrolizumab IV once every 3-week cycle for 24 months or until toxicity/disease progression. Dosing with pembrolizumab was initiated within 8 weeks of the last chemotherapy regimen. Additionally, disease assessment for these patients was performed every 2 cycles.

To better assess the patients' outcomes with regards to their disease characteristics, correlative studies were performed. Tumor tissues from 30 patients were assessed for PD-L1 expression using 22C3 immunohistochemical (IHC) analyses. Separately, PD-L1 staining was assessed at the stromal interface for 20 patients. When asked about the reason for this testing, Pennell replied, “In some previous studies, it has been noted that patients with elevated tumor PD-L1 expression levels have had improved outcomes relative to those who had lower expression levels of this key biomarker. It is worth noting that the tumor PD-L1 IHC and stromal interface PD-L1 analyses were independently analyzed.” In addition to PD-L1 testing, blood was drawn for circulating tumor cell (CTC) DNA analysis before cycles 1, 2, and 3 of pembrolizumab dosing.

The primary endpoint for this study was PFS, as determined using RECIST v.1.1 methodology. An improvement of 50 percent for the median PFS was considered to be clinically meaningful. A quantity of 40 patients gave 80 percent power to reject the negative hypothesis that the median PFS with the experimental pembrolizumab maintenance therapy was 2 months or less. As a result, the target enrollment was set at 45 patients, as doing so would allow there to be 40 participants for evaluation, even in the event that 10 percent of the patients were deemed to be non-evaluable. Secondary endpoints included OS, response rate (RR)—defined as those patients showing PR and complete response, disease control rate (DCR)—defined as the RR + the number of patients showing SD, and adverse events (AEs). The data cutoff date was April 15, 2017.

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Results

The median PFS for the patients in this study was 1.4 months (90% confidence interval (CI) – 1.3-2.8 months), while the 6-month PFS was 21 percent (90% CI – 12-28%). The median OS for these 45 patients was 9.4 months (90% CI – 7.5-10.6 months). The 6-month OS was 72 percent (90% CI – 58-82%), while the 12-month OS was 30 percent (90% CI – 16-46%).

An interesting trend emerges when one considers the PFS data for patients who had stromal interface PD-L1 staining. For these 20 patients, eight tested positive for the presence of PD-L1, while 12 were negative. For the 12 non-staining patients, the median PFS was 1.3 months (90% CI – 1.1-1.5 months) and the median OS was 7.2 months (90% CI – 1.3-10.4 months). The figures for the eight patients having PD-L1 staining at the stromal interface were quite different: median PFS—5.5 months (90% CI – 5.3-7.8 months); median OS—10.1 months (90% CI – 7.2-17.2 months).

Of the 30 patients who underwent tumor tissue IHC analysis, only three patients (10%) tested positive (i.e., their tumor cells showed any sign of PD-L1 expression). For these three patients, the PFS values ranged from 4.8-9.8 months. Moreover, none of these patients, as of the cutoff date, had experienced progression.

Among patients having measurable tumors (N = 34), only one showed CR and three showed PR for an RR of 11.8 percent (90% CI – 5-24%). For this group, the DCR was 38.2 percent (90% CI – 26-52%).

The most frequently encountered AEs of any grade were fatigue (47%), pruritus (42%), and nausea (33%). The most frequently encountered grade 3-5 AEs were hyponatremia (13%), dyspnea (7%), nausea (4%), and elevated aspartate aminotransferase levels (4%).

When asked about the tolerability for this regimen, Pennell noted, “Generally speaking, most patients did very well with this regimen; there were few serious treatment-related AEs. A particular AE of interest was one patient who developed type 1 diabetes, which is an autoimmune disorder that could conceivably be linked to this immunological therapy.

“We were very pleased to find that no patients developed paraneoplastic syndromes, a potential complication from the immunological cancer therapy.”

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Study Discussion

“In our study, we were hoping to have a higher RR than 11.8 percent for patients with measurable tumors; however, this figure is in line with data from the CheckMate 032 trial (NCT01928394), where an objective response was noted in 11-12 percent of the SCLC patients receiving the experimental nivolumab (also a PD-1-targeting monoclonal antibody) monotherapy,” Pennell reported. “In all likelihood, we will have to utilize a combination therapy to increase the efficacy of the therapy, as was done in CheckMate 032, where the use of the nivolumab/ipilimumab combination essentially doubled the objective response of the nivolumab monotherapy (~20% vs. ~10%). However, in doing so, we likely increase the risk of treatment-related autoimmune disorders.”

When commenting on SCLC, Pennell had the following observation. “There is a huge unmet need with SCLC patients who have undergone progression after the current standard platinum/etoposide combination chemotherapy, as they have few treatment options available. After progression, these patients can receive the topoisomerase inhibitor topotecan, but even that therapy has not been tremendously effective. Unlike other cancers, which have known targetable drivers, SCLC has few documented drivers; the mutations that are known are tumor suppressors such as p53 and RB, which are thus far non-targetable.

“One potentially promising therapy for SCLC is rovalpituzumab tesirine, a drug-antibody conjugate consists of the anti-DLL3 antibody, rovalpituzumab, and the DNA-binding agent tesirine,” Pennell related. “In principle, rovalpituzumab targets the DLL3 expressed on the SCLC tumor cells, which then delivers the attached chemotherapeutic agent tesirine.” This antibody-drug conjugate is also being evaluated in combination with nivolumab and nivolumab/ipilimumab therapies as treatments for extensive stage SCLC (NCT03026166).

When asked about the CTC analyses done on the blood samples drawn from the study participants, Pennell noted, “While we did not present the data from those studies at ASCO, we will present the results from those analyses in an upcoming publication.

“At this time, we don't yet know the right patients for using this immunotherapy,” he concluded.

Richard Simoneaux is a contributing writer.

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
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