Targeting PD-1/PD-L1 in Non-small Cell Lung Cancer: An Update from ESMO 2016

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Vinod Chandran, DM, PhD

Associate Professor of Medicine,
Division of Rheumatology
University of Toronto
Staff Physician,
Division of Rheumatology
Toronto Western Hospital
Toronto, Ontario

Cathy Flanagan, MD, FRCPC

Clinical Assistant Professor,
Division of Rheumatology
University of British Columbia,
New Westminster, British Columbia

Introduction

The spondyloarthritides are common in Canada. It is estimated that there are approximately 300,000 Canadians living with ankylosing spondylitis (AS) and an additional 300,000 living with psoriatic arthritis (PsA). 1,2

Management of both conditions has evolved substantially during the biologic era. Anti-TNF therapies have been proven to be efficacious and safe in both AS and PsA, with five different agents indicated for the treatment of AS and PsA in Canada (Table 1).

Table1

In addition, biologics with other mechanisms of action have enriched the therapeutic armamentarium. Ustekinumab, an inhibitor of the p40 subunit of IL-12/23, is indicated for PsA, as is abatacept, a selective co-stimulation modulator. IL-17 inhibitors are the latest biologics to receive indications for SpA, with secukinumab now indicated for both AS and PsA and ixekizumab indicated for PsA (Table 1). Continuing research with these and other agents is likely to provide clinicians and their patients with further effective options to treat these common but disabling diseases.

The Scientific Meeting of the European League Against Rheumatism (EULAR) is one of the most important annual events in the field of rheumatology. This year’s event, held in Amsterdam from June 13 to 16, included a wealth of new research across rheumatologic disease states. This report provides a summary of the key highlights of new research in spondyloarthritis (SpA) presented at EULAR 2018, with a focus on AS and PsA. This includes a number of analyses looking at newer biologic therapies (e.g., anti-IL-17, anti-IL-23p19), as well as several that add to our understanding of the optimal use of existing therapies (e.g., anti-TNF agents). Beyond the traditional efficacy measures, researchers are also investigating and reporting other important outcomes, including radiographic progression, impact on extra- articular manifestations (EAMs) and quality of life (QoL).

In addition to the summaries of the key studies presented at EULAR, this document also includes expert commentary from Drs. Vinod Chandran and Cathy Flanagan, who give their interpretations of the studies and their potential implications in Canadian clinical practice.

Update on Ankylosing Spondylitis (AS)

Treat-to-target Approach in AS

The concept of treat-to-target, which is widely accepted in rheumatoid arthritis (RA),18 is also gaining acceptance in SpA.19 Further support for this approach was presented at EULAR 2018. Canadian rheumatologist Dr. Walter Maksymowych presented an analysis of data from two AS cohorts, showing that sustained disease remission of inflammation is associated with less radiographic progression over time.20 The study included 237 patients with early axial spondyloarthritis (axSpA) —161 from the EMBARK clinical study with etanercept and 76 from the DESIR cohort with no history of biologic treatment. In each group, those patients with sustained inactive disease (Ankylosing Spondylitis Disease Activity Score [ASDAS] < 1.3) had a significantly lower risk of radiographic disease progression than those without sustained remission.

New Research with Anti-IL-17 Agents

Secukinumab (anti-IL-17A)

Secukinumab’s efficacy and safety in AS has been previously demonstrated in the MEASURE-1, -2 and -3 studies, 21,22 in which secukinumab 150 mg showed significant improvements in signs and symptoms of AS in both anti-TNF-naïve and anti-TNF-inadequate response (IR) subjects vs. placebo.6,7 This was shown with or without an intravenous (IV) loading dose (10 mg/kg).21,22 In MEASURE-3, the 300 mg maintenance dose was also found to be efficacious, with no additional safety effects reported. In Canada, the current recommended dose is 150 mg by subcutaneous injection with initial dosing at Weeks 0, 1, 2, 3, and 4 followed by monthly maintenance dosing. 17

Using the MEASURE-2 cohort, investigators reported sustained efficacy of secukinumab out to four years, with no new safety signals and good retention rates.23,24

At EULAR 2018, several analyses of data from the MEASURE studies were presented. With respect to efficacy and safety outcomes from long-term follow-up, researchers from both the MEASURE-1 and -2 studies presented data over up to four years of follow-up. 23 Using the MEASURE-2 cohort, investigators reported sustained efficacy of secukinumab out to four years, with no new safety signals and good retention rates. 23,24 With respect to clinical signs and symptoms, the 4-year analysis of MEASURE-2 data showed similar proportions of patients maintaining ASAS20 and ASAS40 responses over the four years, for both those who were previously anti-TNF-naïve and those with prior inadequate anti-TNF response or intolerance (Figure 1). 24 The MEASURE-1 analyses included an assessment of radiographic progression. 23 As shown in Figure 2, secukinumab-treated patients had low rates of radiographic progression and sustained clinical efficacy over four years in that study.23 The only significant baseline predictors of future radiographic progression were male sex, presence of syndesmophytes and elevated C-reactive protein (CRP).23

Figure1

Figure2

Another set of researchers compared radiographic findings in the MEASURE-1 study with secukinumab to a historical cohort of AS patients not treated with biologic medication (the ENRADAS cohort). 25 They found that overall, the rates of radiographic progression were low in each cohort, and that secukinumab was associated with numerically less radiographic progression, although none of the comparisons were statistically significant.25

Also notably, with respect to subgroup analysis, using pooled data from both the MEASURE-1 and -2 studies, researchers showed a consistently significant treatment effect with secukinumab vs. placebo regardless of baseline CRP, although the treatment effect was larger among those with higher baseline CRP. 26

Incidence of concomitant conditions is another important area of study with anti-IL-17 agents. One of the particular conditions that has been a focus of attention is uveitis. At EULAR 2017, researchers presented an analysis of the secukinumab clinical study database, in which they showed that the overall incidence of uveitis was low, occurring in 3.3% (26/794) of patients treated with secukinumab across the trials. 27 This included 12 new-onset cases and 14 flares, and was equated to an incidence of 1.4 per 100 patient-years. This was reassuring in that background research showed an overall prevalence of uveitis of approximately 33% in patients with AS,28 and an incidence rate between 2.6 and 3.5 per 100 patient-years among patients treated with anti-TNF agents. 29-32 In the same report, the investigators showed the incidence in post-marketing use: 0.03 per 100 patient-years over more than 96,000 patient treatment years.27

Also importantly, analysis of phase 3 studies with secuk­inumab in both PsA and AS has shown that this agent is associated with very little immunogenicity.33

Investigational Anti-IL-17 Agents for AS

In addition to the research presented with secukinumab, the EULAR 2018 program also included presentation of some phase 2 data with other anti-IL-17 agents. Both bimekizumab, a novel inhibitor of IL-17A and F, and BCD-085, an IL-17A inhibitor, demonstrated promising clinical efficacy at Weeks 12 and 16, respectively, in dose-finding phase 2 studies. 34,35

Neither ixekizumab nor brodalumab, other anti-IL-17 agents, had any AS data presented at EULAR 2018.

New Research with Anti-TNF Agents

While anti-TNF agents have been in use for many years for the treatment of AS, research with these agents continues to refine and inform their optimal use in AS.

Other anti-TNF-related findings included observations that most of the radiographic progression appears to happen early for patients on long-term anti-TNF therapy;38 and that among patients with sustained remission/low disease activity on anti-TNF therapy, continuing therapy is associated with significantly better outcomes compared to treatment withdrawal.38

At EULAR 2018, one of the more interesting findings related to these agents was from a Canadian post-marketing study comparing adalimumab to conventional synthetic disease-modifying antirheumatic drugs (DMARDs).36 As shown in Figure 3, the investigators observed a greater improvement in key extra-articular manifestations (psoriasis, inflammatory bowel disease [IBD], uveitis or enthesitis) with adalimumab compared to non-biologic DMARDs.36 There was also a significant difference in Bath Ankylosing Spondylitis Functional Index (BASFI) scores from baseline to 12 months in favor of adalimumab, but no significant difference in changes in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) of the Short Form Health Survey (SF-12) physical or mental component scores.36

Figure3

Another study of interest was an analysis of 236 patients from the DESIR cohort, which showed that prior response to nonsteroidal anti-inflammatory drugs (NSAIDs) was not a predictor of subsequent response to anti-TNF therapy.37 Primary responders to NSAIDs had a 32.5% BASDAI50 response to their first anti-TNF therapy in this cohort, while those who were not primary NSAID responders had a 23.5% BASDAI50 response (between-group p = 0.316).37

Other anti-TNF-related findings included observations that most of the radiographic progression appears to happen early for patients on long-term anti-TNF therapy;38 and that among patients with sustained remission/low disease activity on anti-TNF therapy, continuing therapy is associated with significantly better outcomes compared to treatment withdrawal.39

Other AS Research

The diagnostic and prognostic utility of imaging in AS was an area of focus at EULAR 2018. One of the studies in this topic area showed that among 802 healthy volunteers aged younger than 45 years, there was a high incidence of MRI bone marrow edema and fatty lesions in the sacroiliac (SI) joint and the spine. 40 Another study supported the poor reliability of MRI evaluation alone, showing the presence of bone marrow edema, erosions and fatty lesions in non-AS groups with and without pain, particularly postpartum women.41 However, other investigators did report that baseline MRI-observed inflammation in the SI joint is associated with structural damage over five years in early axSpA.42

Finally, investigators of a nurse-led program in axSpA showed that nurse-guided self-management and self-assessment training was associated with improvements in patient coping, BASDAI score and frequency and duration of exercise.43


EXPERT COMMENTARY - Dr. Cathy Flanagan

Interpretation of New Information on AS from EULAR 2018

Some of the key topics in SpA presented at EULAR related to the concept of treat to target (T2T), tapering of biologics, misdiagnosis based on MRI results and new biologics. T2T is well accepted in RA and the TICOPA study in PsA showed better clinical outcomes if a T2T approach was used. The TICOSPA study is underway and will help to address whether using T2T will lead to better results in SpA. The clinical outcome measure used is most often ASDAS and Dr. Maksymowych looked at this in two cohorts; EMBARK, a 12-week RCT of etanercept in early axSpA followed by a 96-week open-label extension, and DESIR, an observational cohort of early SpA patients with no history of biologic use for over two years. The patients in both groups who had sustained ASDAS inactive disease < 1.3 had decreases in erosions and increase in backfill on MRI, suggesting less structural damage.

Further data from the DESIR cohort showed that the presence of local bone marrow inflammation was strongly associated with the development of structural damage over five years in the SI joints and spine in early SpA and was independent of systemic inflammation. These presentations suggest that early T2T may help to improve not only clinical but also radiographic outcomes. The topic of tapering is always relevant. Data from the ABILITY-3 study showed that patients with non-radiographic axSpA who achieved sustained remission by ASDAS on adalimumab who then withdrew drug had a risk ratio (RR) of flare with withdrawal of 1.77 and when patients restarted adalimumab, by 12 weeks, only 57% achieved ASDAS inactive disease again. Future studies with tapering in early disease need to be done.

The issue of misdiagnosis of SpA by MRI has been a topic for several years but at this EULAR, there were a number of presentations on the subject. These showed that healthy controls, as well as people with chronic back pain, runners and postpartum women with back pain had false positive MRIs, with the highest number being in postpartum women with back pain. The presence of deep bone marrow edema lesions on Spondyloarthritis Research Consortium of Canada (SPARCC) scoring was almost diagnostic of SpA, so MRIs should be read by experts in MSK radiology. In terms of new biologics in SpA, there were two phase 2 trials of new IL-17s: (1) bimekizumab, an inhibitor of IL-17A and F, and (2) BCD-085, an inhibitor of IL-17A.They were both effective and had a safety profile consistent with other IL-17 inhibitor biologics, so phase 3 studies are ongoing. As for secukinumab, results from MEASURE-1 showed low rates of radiographic progression and sustained clinical efficacy over four years. In MEASURE-3, 300 mg of secukinumab was used as a maintenance dose without any additional safety concerns and, despite the fact that the secukinumab dose indicated in Canada is 150 mg, 300 mg a month appears to be efficacious and safe.

Update on Psoriatic Arthritis (PsA)

New Research with Anti-IL-17 Agents

Secukinumab

The efficacy and safety of secukinumab 75, 150, or 300 mg every four weeks in PsA was established in the FUTURE-1 and -2 studies.44,45 The FUTURE-3 study provided corroboration of these findings, this time with the secukinumab 150 or 300 mg vs. placebo administered by the patients themselves using a subcutaneous autoinjector.46 The FUTURE-5 study showed that both the 150 and 300 mg doses were superior to placebo when administered with or without an initial IV loading dose.47 FUTURE-4, which has yet to be published, is evaluating the 150 and 300 mg doses administered by subcutaneous autoinjector, with or without an IV loading dose.48

In Canada, the currently recommended regimen for secukinumab in PsA is 150 mg by subcutaneous injection with initial dosing at Weeks 0, 1, 2, 3, and 4 followed by monthly maintenance dosing. For those patients who are anti-TNF inadequate responders, the product monograph recommends consideration of the 300 mg secukinumab dose.

At EULAR 2018, several analyses of data from the FUTURE studies were presented. Among these were three-year efficacy and safety data from the FUTURE-2 study.49 In that report, the investigators showed sustained levels of ACR20 and ACR50 responses over the duration of follow-up (Figure 4). Results were consistent among patients who were anti-TNF-naïve or anti-TNF-IR and among those who were or were not taking methotrexate.49 Figure4

Other subgroup analyses yielded similarly consistent findings. In an analysis of the FUTURE-5 study, researchers showed that inhibition of radiographic progression occurred with secukinumab regardless of whether the patients were anti-TNF-naïve or anti-TNF-IR (Figure 5) or whether they were taking methotrexate or not. 50 Figure5

In an analysis of the FUTURE-5 study, researchers showed that inhibition of radiographic progression occurred with secukinumab regardless of whether the patients were anti-TNF-naïve or anti-TNF-IR (Figure 5) or whether they were taking methotrexate or not.50

With respect to important manifestations of PsA, pooled data from FUTURE-2 and -3 showed that secukinumab treatment led to resolution of enthesitis in the majority of patients, even those with more severe baseline enthesitis. 51 A separate analysis, again using pooled data from FUTURE-2 and -3 showed that secukinumab treatment was associated with significantly better efficacy vs. placebo regardless of presence or absence of baseline enthesitis. 52

In addition to the efficacy findings, other researchers presented important safety data with secukinumab in PsA. This included an analysis of all phase 2 and 3 clinical trials in PsA or psoriasis, in which secukinumab demonstrated a consistent safety profile with low rates of IBD, cardiovascular complications and other serious adverse events. 53

Also, as mentioned in the AS section above, analysis of phase 3 studies with secukinumab in both PsA and AS has shown that this agent is associated with very little immunogenicity. 33

Finally, initial observations among women accidentally exposed to secukinumab during pregnancy were also presented at EULAR 2018. 54 Among the six case reports, there was no clear indication of harm. However, due to the lack of data, the authors cautioned that secukinumab should still be avoided in pregnancy unless a clear benefit overwhelms potential risk. 54

Ixekizumab

The efficacy and safety of this anti-IL-17 agent were established in the SPIRIT studies among patients who were anti-TNF-naïve (SPIRIT-P1) or anti-TNF-IR (SPIRIT-P2). 55,56 These trials evaluated ixekizumab 80 mg every two weeks or every four weeks versus placebo. The recommended dose for the treatment of PsA in Canada is 160 mg subcutaneously (two 80 mg injections) at Week 0, followed by 80 mg every four weeks. 16

At EULAR 2018, some important additional data were presented from the pivotal trials. In long-term follow-up of the SPIRIT-P1 study in anti-TNF-naïve patients, ixekizumab treatment was associated with sustained clinical response over three years (Figure 6). 57 Figure6

The SPIRIT-P2 data are somewhat less mature, but investigators of that study did present one-year data showing sustained efficacy over one year. 58

Data from both SPIRIT-P1 and -P2 were analyzed to determine how frequently patients treated with this agent were able to achieve low disease activity over one year. 59 A number of different metrics were used. Using the Disease Activity in Psoriatic Arthritis (DAPSA) scoring system, the rates of low disease activity over one year were 31% and 29% for the q4w regimen and q2w regimens, respectively, among anti-TNF-naïve patients and 34% and 26% for the q4w regimen and q2w regimens, respectively, among anti-TNF-IR patients. 59

With respect to particular manifestations, investigators analyzed the nail and skin findings from the SPIRIT-P2 study, and found that ixekizumab was associated with complete resolution of skin lesions (PASI100) in 40% and 35% of patients treated with the q4w regimen and q2w regimens, respectively, and complete resolution of nail lesions (NAPSI0) in 46% of q4w patients and 32% of q2w patients. 60

Separate assessments showed significant improvements in both enthesitis and dactylitis in pooled, 52-week analyses of the SPIRIT- P1 and -P2 trials. 61

With respect to safety, a pooled analysis of the SPIRIT trials was presented, showing that there have been no new safety signals reported with this agent among 1,118 patients over 1,373.4 patient-years of follow-up. 62

New research with Anti-IL-23p19 Agents

This class of biologic agents has shown promise for the treatment of both psoriasis and psoriatic arthritis. Guselkumab, which is indicated for the treatment of plaque psoriasis in Canada, 63 is also being evaluated for PsA in phase 2 clinical trials. At EULAR 2018, the results of one such phase 2 study were presented. Among 149 patients with active PsA (≥ 3 tender and ≥ 3 swollen joints, CRP ≥ 3 mg/L) and active psoriasis (≥ 3% body surface area), guselkumab was efficacious, showing ACR20, 50 and 70 response rates of 73.5%, 53% and 32.5% at week 56. 64 Separate presentations showed that this treatment was efficacious for controlling both enthesitis and dactylitis among patients with these manifestations at baseline. 65,66

Risankizumab is another agent within this class. Although not approved for use in Canada to date, it too showed promising activity in a phase 2 PsA study presented at EULAR 2018. Overall ACR 20, 50 and 70 rates at week 24 were 48%, 22% and 13% for risankizumab and 31%, 7% and 2% for placebo. 67

New Research with Anti-TNF Agents and Small Molecules

There was limited new information presented at EULAR 2018 pertaining to the use of more established agents. However, there was one interesting study that compared drug survival rates with various individual anti-TNF agents (adalimumab, etanercept, golimumab and infliximab). 68 This study showed that overall drug survival rate was 50% over five years, and that infliximab was the agent associated with the lowest rate of persistence.

There were also some reassuring data presented with apremilast, an oral PDE-4 inhibitor. In a long-term analysis of the PALACE studies, the investigators reported that apremilast treatment is associated with sustained, clinically meaningful improvements in signs and symptoms of PsA over five years. 69

There was also some research presented at EULAR providing new insights into the use of tofacitinib, a JAK inhibitor, for the treatment of PsA. Researchers presented a network meta-analysis of 21 RCTs evaluating tofacitinib, biologics or apremilast to treat active PsA in anti-TNF-naïve patients. 70 Bayesian techniques were used to compare ACR20 rates, change in Health Assessement Questionnaire Disability Index (HAQ-DI), change in Dactylitis Severity Score (DSS) and change in Leeds Enthesitis Index (LEI) across the various treatments. Tofacitinib 5 mg BID and 10 mg BID were ranked 14th and ninth among 18 comparators for ACR20 and 11th and eighth for change in HAQ-DI. In the two studies that evaluated change in DSS and LEI, there were no substantial differences for tofacitinib 5 or 10 mg BID vs. adalimumab 40 mg Q2W or ixekizumab 80 mg Q2W and Q4W. 70

Other findings with tofacitinib in PsA presented at EULAR 2018 included an analysis of pain data from phase 3 studies in RA and PsA and a phase 2 study in AS. 71 Across all these datasets, both doses of tofacitinib were associated with rapid improvement and sustained reduction of pain.

Finally, some reassuring safety data were presented with tofacitinib in PsA. Over three years of follow-up in a long-term extension trial (OPAL Balance, which included patients from three separate phase 3 randomized, controlled trials), no new safety signals were identified.72 Also, in an evaluation of the cardiovascular safety of tofacitinib in long-term use for PsA, the investigators reported that the magnitude and dose dependency of increases in lipid levels were consistent with findings in tofacitinib studies in patients with psoriasis and RA. 73

Other Research in PsA

There were some other intriguing data in the field of PsA research presented at EULAR 2018. One group of researchers from Hong Kong sought to evaluate the impact of PsA disease activity on markers of subclinical atherosclerosis. 74 They found that among those patients who had achieved minimal disease activity within one year and then sustained it for an additional year, there were benefits observed in mean carotid intima-media thickness and arterial stiffness. 74

In another study that may be a foreshadowing of treatment decisions in the future, investigators evaluated 24 patients with PsA by peripheral lymphocyte analysis (flow cytometry). 75 The goal was to select the optimal biologic for treatment (strategic treatment group) based on the individual’s profile of T-helper cells. An additional 38 patients were treated empirically with a standard biologic using EULAR recommendations. Among those in the strategic group, low PsA disease activity was achieved in 92.3% of patients (24/26). This was significantly higher than the 21 of 38 patients (55.2%) who achieved low disease activity in the standard biologic therapy group. 75


EXPERT COMMENTARY - Dr. Vinod Chandran

Interpretation of New Information on PsA from EULAR 2018

There is continuing research with huge impact on clinical practice in PsA that was showcased at EULAR 2018. Anti-TNF therapy has revolutionized PsA care over the last decade, but many patients do not respond or have secondary failure or contraindications to TNF inhibitors. Better understanding of the role of the TH-17 axis has led to development of drugs targeting key cytokines in this axis, including IL-17 and IL-23. Secukinumab and now ixekizumab have proven short-term efficacy in treating psoriasis and PsA. At the meeting, long-term efficacy and safety data were presented further cementing their role in the management of both bio-naïve and experienced PsA patients. No new safety signals were observed. It was also shown in phase 2 studies that IL-23 inhibitors are also effective in the various domains of PsA. Results from phase 3 trials are eagerly awaited. Small molecules such as tofacitinib, a JAK inhibitor, provide ease of administration. Data presented at EULAR speak to the safety and efficacy of tofacitinib in both biologic-naïve and experienced patients and is a welcome addition to our treatment options.

With many treatment options soon to be available in the management of PsA, rational treatment selection based on biomarkers may become a reality. However, research into precision medicine is still in its infancy. The study based on peripheral blood cell phenotyping demonstrated proof-of-principle and will need further verification and validation.

Comorbidities have a significant impact on treatment response in PsA. Moreover, better control of disease is likely to lead to less comorbidities, especially cardiovascular disease (CVD). At the EULAR it was demonstrated that extreme diets can induce significant weight loss and improve disease activity. Also, achieving sustained minimal disease activity (MDA) was associated with better surrogate indicators of CVD.

Thus, the studies reported at the EULAR 2018 give rheumatology practitioners greater confidence in the drugs currently available in treating PsA, provide early data on novel therapies, reinforce the need for managing comorbidities, and provide a glimpse of the promise of precision medicine.



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