Emerging Treatment Strategies in Nonsquamous NSCLC

Emerging Immunotherapies

An immune checkpoint blockade or inhibitor is designed to target inhibitory checkpoint molecules, such as programmed cell death protein 1 (PD-1); and its ligand, PD-L1; or cytotoxic T-lymphocyte—associated antigen 4 (CTLA-4).1 Promising therapeutic activity with these agents in both squamous and nonsquamous NSCLC led to the FDA approval of 2 anti–PD-1 agents, nivolumab and pembrolizumab, and 1 anti–PD-L1 antibody, atezolizumab.^2,3

Atezolizumab, a selective humanized monoclonal IgG1 antibody against PD-L1, was granted an FDA approval in October 2016 for treating patients with PD-L1—positive NSCLC who progressed during or after standard treatment.³This approval was based on results from the phase II FIR, POPLAR, and BIRCH trials, and the phase III OAK trial.

The phase II FIR trial reported that PD-L1 expression was associated with response to atezolizumab.⁴Patients with the highest levels of PD-L1 expression demonstrated overall response rates (ORRs) between 25% and 29%, with a median progression-free survival (PFS) ranging from 2.3 to 5.4 months. No unexpected immune-related adverse events (irAEs) were reported.

The POPLAR trial enrolled 287 patients with previously treated NSCLC who were randomized to receive atezolizumab monotherapy or docetaxel chemotherapy.⁵In the overall population and in patients with PD-L1—positive tumors, patients receiving atezolizumab exhibited significantly improved survival compared with docetaxel chemotherapy. In contrast, overall survival (OS) was not different between groups in patients with PD-L1–negative tumors. Additionally, fewer grade 3 to 5 AEs were reported in patients treated with atezolizumab compared with docetaxel chemotherapy.

The BIRCH trial included 667 patients with positive PD-L1 tumor expression who were chemotherapy-naïve or previously treated patients with advanced NSCLC without brain metastases.⁶Among patients with the highest PD-L1 expression levels, ORRs reached 32%, with 6-month survival rates of 75% to 80%. No new safety signals were reported.

In the phase III OAK trial, second-line atezolizumab was administered intravenously every 3 weeks at 1200 mg/kg to patients with positive or negative PD-L1 expression.⁷Patients receiving atezolizumab exhibited significantly increased OS compared with patients receiving docetaxel (13.8 vs 9.6 months). Importantly, patients with no PD-L1 staining exhibited a significantly prolonged median OS with atezolizumab compared with docetaxel (12.6 vs 8.9 months). Fewer AEs were reported with atezolizumab compared with docetaxel, and no new safety signals were reported.

Nivolumab, a fully human immunoglobulin G4 (IgG4) PD-1 immune checkpoint antibody, disrupts T-cell activation and proliferation, resulting in restored antitumor immunity.^8,9A recent meta-analysis of 9 trials with 817 patients was conducted to evaluate the safety and efficacy of nivolumab in previously treated patients with advanced NSCLC.¹⁰This study revealed a pooled ORR of 20%, disease control rate of 36%, 1-year OS rate of 47%, and 1-year PFS rate of 21%. Importantly, only 8% reported grade 3/4 AEs. No significant differences in ORR were reported between patients with squamous and nonsquamous NSCLC; however, patients with at least 5% PD-L1—positive expression exhibited significantly greater ORR compared with patients with less than 5% PD-L1–positive expression (31% vs 12%). Although PD-L1–negative patients exhibited a lower ORR, patients did respond and reported manageable AEs, suggesting the potential of nivolumab for use as a second-line agent in patients with previously treated advanced NSCLC.

Various trials evaluating PD-1/PD-L1 pathway inhibitors in several tumor types have reported conflicting results regarding the role of PD-L1 expression on tumor cells for predicting treatment response. A large meta-analysis (20 trials; 1475 patients) was conducted to further explore the role of PD-L1 as a predictive factor.¹¹In the overall population, which included patients with NSCLC, melanoma, and genitourinary cancer, patients treated with either a PD-1 or a PD-L1 inhibitor who were PD-L1—positive exhibited a significantly higher response rate compared with PD-L1–negative patients. This difference was also significant in the subgroup of patients treated with nivolumab and among patients with NSCLC. Importantly, this study also highlighted the fact that a non-negligible proportion of PD-L1–negative patients still respond to anti–PD-1 or anti–PD-L1 treatments.

For patients with NSCLC treated with nivolumab, published data remain controversial. Results from a nonrandomized subset of pre-treatment specimens from 42 patients suggested a predictive role for PD-L1 expression regarding response to nivolumab, with a 36% objective response rate in PD-L1—positive patients compared with a 0% objective response in PD-L1–negative patients.¹²Of the 10 patients with NSCLC evaluable for PD-L1 expression in this preliminary analysis, 5 were PD-L1—positive, with 1 patient—with 10% positive tumor cells—achieving a partial response with nivolumab at 10 mg/kg.

In a larger cohort of NSCLCs, no associations were reported between PD-L1 status and either OS or ORR.¹³Data from phase III trials suggest that PD-L1 expression may be predictive of improved nivolumab efficacy in terms of OS, PFS, and ORR for patients with nonsquamous NSCLC.¹⁴Across other trials, objective responses and longer durations of response have been reported in patients with both PD-L1—positive and PD-L1–negative NSCLC, even if these values have been numerically higher among positive tumors.^15,16Furthermore, no significant differences have been reported for various levels of PD-L1 expression (1%, 5%, or 10% positive tumor cells).^14,15,17,18

In general, nivolumab is well tolerated, with no effects of performance status on treatment tolerability.¹⁹Phase III trial data comparing nivolumab with docetaxel demonstrated that nivolumab induced fewer grade 3/4 AEs than chemotherapy (7%-10% vs 54%-55%, respectively).^14,17Treatment-related AEs (TRAEs) of any grade have been reported in 58% to 74% of patients across trials.^13-15,17Frequently reported TRAEs include fatigue, decreased appetite, and asthenia. Between 7% and 17% of patients reported grade 3/4 AEs, with fatigue being the most common event. No clear relationship was observed between the occurrence of AEs and treatment duration or dose level.^13,17

Immune-related adverse events (irAEs) were reported in approximately 50% of patients with NSCLC who received nivolumab treatment. The most frequently reported irAEs included skin toxicity (5%-16%, consisting mainly of rash and pruritus), gastrointestinal events (8%-12%), and pneumonitis (3%-6%).^13,15,17In most cases, irAEs were low grade. Other less common irAEs included endocrinopathies (4%-7%), nephrotoxicity (2%-3%, mainly consisting of blood creatinine elevation), rare infusion reactions (1%-3%), and elevation of blood liver function parameters (1%-3%). Other anti—PD-1 and anti–PD-L1 compounds, such as pembrolizumab, showed a comparable safety pattern.

As previously mentioned, the PD-1 inhibitor pembrolizumab (Keytruda) has demonstrated a PFS benefit in patients with nonsquamous NSCLC when in combination with carboplatin/pemetrexed, which was demonstrated in cohort G of the open-label, randomized, phase II KEYNOTE-021 trial.²⁰These findings were the basis for the regimen’s FDA accelerated approval in May 2017.¹⁷Pembrolizumab’s NCCN Category 1 recommendation as a subsequent therapy for patients with metastatic nonsquamous NSCLC and PD-L1 expression is based on findings from the KEYNOTE-010, KEYNOTE-001, and its FDA approval.^2,21,22

Moreover, while the TRAEs were similar between the combination arm and those who received chemotherapy alone, the patients in the combination arm reported that the most frequently reported grade 3 or worse TRAEs were comprised of anemia, decreased neutrophil count, acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, sepsis, and thrombocytopenia. Additionally the PD-1 inhibitor was discontinued in 10% of the patients due to AEs.¹⁶There were 3 treatment-related deaths were reported overall, with 1 due to sepsis in the combination group.

Heather Wakelee, MD, associate professor of medicine (oncology) at Stanford Medicine, commented at a recent medical meeting on the combination approval. "That was a pretty surprising approval for most of us because it was based on a randomized phase II study that was small, and while there was a PFS benefit in some of the subgroups, there was no OS benefit. In some of the subgroups, especially if you look at the PD-L1 expression between 1% and 49%, chemotherapy was actually better than the combination. So, we were really surprised by that indication."²³

As the FDA approval was based on a smaller-size phase II study, the phase III KEYNOTE-189—the follow-up to KEYNOTE-021—is designed to serve as the confirmatory trial for the accelerated approval. The ongoing trial, which has a primary completion date of September 2017, is investigating the efficacy and safety of pembrolizumab combined with platinum-based therapy with pemetrexed versus platinum-based chemotherapy alone in 570 patients with advanced or metastatic nonsquamous NSCLC who have not previously received systemic therapy for advanced disease in a 1:1 ratio.²⁴Pembrolizumab will be administered at 200 mg IV every 3 weeks. The primary endpoint is PFS, with secondary endpoints being overall response rate and OS.

There are also other emerging immunotherapies under investigation, including OX40, lymphocyte activation gene 3 (LAG-3), and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3). OX40 is a secondary immune checkpoint receptor expressed on activated T cells. After binding with OX40 on antigen-presenting cells, OX40 leads to the expansion of memory and effector T cells. GSK3174998, a humanized IgG1 anti-OX40 monoclonal antibody, suppresses the differentiation of CD4-positive T cells into immunosuppressive regulatory T cells.^25,26ENGAGE-1 is a first-in-human study evaluating the effects of GSK3174998 alone and in combination with pembrolizumab in patients with solid tumors, including NSCLC.²⁷Other OX40 antibodies, such as MEDI6383, are also being studied in patients with NSCLC and other solid tumors.²⁸

Urelumab, an anti—LAG-3 monoclonal antibody, targets another immune checkpoint on activated T cells that inhibits immune function following binding with major histocompatibility complex II.²⁹Ongoing clinical studies are investigating urelumab with anti—PD-1 agents in patients with NSCLC (NCT01968109, NCT02460224).

Emerging Combination Approaches

TIM-3 upregulation has been shown in the tumor microenvironment in a murine model of anti—PD-1 resistant NSCLC.³⁰Two TIM-3 monoclonal antibodies, MBG453 and TSR-022, are under investigation in ongoing clinical trials (NCT02817633, NCT02608268).

In the randomized, open-label phase III IMpower110 trial, the efficacy and safety of standard platinum-doublet therapy are compared with atezolizumab monotherapy in chemotherapy-naïve patients with PD-L1—positive advanced NSCLC.³¹Another phase III trial, IMpower132 (NCT02657434), evaluates atezolizumab with carboplatin or cisplatin and pemetrexed against carboplatin or cisplatin and pemetrexed in patients with stage IV nonsquamous NSCLC. IMpower150 (NCT02366143) is a randomized, open-label phase III study evaluating atezolizumab in combination with carboplatin plus paclitaxel with or without bevacizumab in comparison with carboplatin/paclitaxel/bevacizumab in chemotherapy-naïve patients with stage IV nonsquamous NSCLC.

Emerging Biosimilar Therapies

PPHM 1501, a randomized, open-label phase II trial, was evaluating the combination of durvalumab (Imfinzi) with or without bavituximab in patients with previously treated metastatic NSCLC.³²However, the trial was suspended. Durvalumab is a human monoclonal antibody that inhibits the binding of PD-L1 to PD-1. Bavituximab is a monoclonal antibody that leads to production of pro-inflammatory cytokines and induction of tumor- specific cytotoxic T-lymphocyte immunity. A previous phase II trial reported 60% improved median OS in patients treated with bavituximab compared with the control arm.

Biosimilars are biological products that receive approval based on data demonstrating that they are highly similar to an FDA-approved biological product (the reference product).³³Furthermore, the biosimilar can have no clinically meaningful difference in terms of safety and effectiveness from the reference product. In biosimilar products, only minor differences in clinically inactive components are allowed. Regarding biosimilar candidates for bevacizumab, however, it should be noted that bevacizumab has patent exclusivity until July 2019.

ABP-215, a biosimilar candidate for bevacizumab, was previously shown to be pharmacokinetically similar to bevacizumab in a previous phase I study. A double-blind, active-controlled phase III study included 642 patients with nonsquamous NSCLC who received first-line chemotherapy with carboplatin/paclitaxel and were randomized to receive ABP-215 or bevacizumab to evaluate clinical equivalence(TABLE 1).³⁴Similar numbers of responders were reported in both groups. The duration of response, OS, and PFS were similar between groups. Furthermore, no significant differences in treatment-emergent AEs were reported. Overall, this study met its primary and secondary objectives, demonstrating the clinical equivalence of ABP-215 and bevacizumab.

TABLE 1. APB-215 Equivalency to Bevacizumab³⁴

TABLE 1. APB-215 Equivalency to Bevacizumab

Source:Thatcher N, Thomas M, Ostoros G, et al. Randomized, double-blind, phase 3 study comparing biosimilar candidate ABP 215 with bevacizumab in patients with non-squamous NSCLC.J Thorac Oncol. 2017;12(1S):S902-S903. doi: 10.1016/j.jtho.2016.11.1234.

DOR, duration of response; PFS, progression-free survival; TEAS, treatment-emergent adverse events; OS, overall survival.

In July 2017, the FDA’s Oncologic Drugs Advisory Committee recommended the approval of ABP-215 for treating various solid tumors.³⁵This approval was based on the determination that ABP-215 is highly similar to bevacizumab, with no clinically meaningful differences between the drugs. Amgen and Allergan have filed a biologics license application for 6 indications, including for use with carboplatin and paclitaxel for first-line treatment of unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC. This approval was based on a study in patients with advanced NSCLC that demonstrated similar ORRs, duration of response, and PFS. Furthermore, safety signals were similar to those previously shown in studies of bevacizumab.

Another bevacizumab biosimilar, BCD-021, demonstrated equivalence in a study of 138 patients with advanced nonsquamous NSCLC (NCT01763645).³⁶No significant differences were reported in terms of ORR, stable disease rate, or progression rate between groups(TABLE 2). Furthermore, no significant differences in AEs were reported between groups.

TABLE 2. BCD-021 Equivalency to Bevacizumab³⁶

TABLE 2. BCD-021 Equivalency to Bevacizumab

Source:Filon O, Orlov S, Burdaeva O, et al. Efficacy and safety of BCD-021, bevacizumab biosimilar candidate, compared to Avastin: results of international multicenter randomized double-blind phase III study in patients with advanced nonsquamous NSCLC.J Clin Oncol. 2015;33(suppl 15; abstr 8057). doi: 10.1200/jco.2015.33.15_suppl.8057.

ORR, overall response rate; CR, complete response; PR, partial response; SD, stable disease.

A randomized, double-blind phase III study (NCT02754882) was designed to establish biosimilarity of SB8, a proposed bevacizumab biosimilar, to bevacizumab in patients with metastatic or recurrent nonsquamous NSCLC.³⁷This study is currently recruiting patients(FIGURE 1).

FIGURE. SB837 in Patients With Advanced Nonsquamous Non—Small Cell Lung Cancer

Source:ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT02754882. Updated July 10, 2017. Accessed August 11, 2017.

NSCLC, non—small cell lung cancer; IV, intravenously; AUC, area under the curve; PFS, progression-free survival; OS, overall survival; DOR, duration of response.

Together, these studies illustrate the emerging treatment options for NSCLC, including immunotherapies, combination therapies, and biosimilars. “Until recently, chemotherapy has been the only available option for patients diagnosed with NSCLC not amenable to radical-intent local treatment,” explained Giulia Zago, MD, of the Netherlands Cancer Institute, Amsterdam, and colleagues in a recent issue ofBiologics: Targets and Therapy.³⁸“Immunotherapy is opening new perspectives for the treatment of lung cancer, giving new effective options for this highly fatal disease, and new results from the ongoing trials are awaited in the next years,” they continued. Ongoing investigations in these areas will provide more effective treatment options for patients, especially those with nonbiomarker nonsquamous NSCLC who have not experienced benefit from recently developed targeted therapies.

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