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Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 43-48

Immune checkpoint inhibitors in the driver’s seat: Evaluating the evolving evidence in the treatment of extensive-stage small-cell lung cancer


1 Regional Cancer Centre South East, University Hospital Waterford, Waterford, Ireland
2 Medical Oncology Department, Sligo Regional Hospital, Sligo, Ireland

Date of Web Publication30-Dec-2019

Correspondence Address:
Dr. Yasar Ahmed
Regional Cancer Centre South East, University Hospital Waterford, Waterford.
Ireland
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jco.jco_12_19

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  Abstract 

Until recently, improving treatment-related outcomes remained an unmet medical need for patients with extensive-stage small-cell lung cancer (ES-SCLC). Because of its rapid growth profile and tendency to metastasize early in the disease course, ES-SCLC accounts for approximately two-thirds of all SCLC diagnoses. Although treatment-naïve ES-SCLC is highly responsive to initial therapy with a platinum compound in combination with etoposide (EP), most patients experience disease recurrence within six months, and fewer than 5% survive to five years. In the platinum resistant/refractory settings, there are no standard guidelines for treatment, with various studies showing similar response rates (RRs) and survival outcomes for different single agent chemotherapies.Immune checkpoint inhibitors (ICIs) have been shown to improve outcomes in patients with a range of tumor types, especially in those characterized by high tumor mutational burden (TMB). The success of studies evaluating ICIs in multiple treatment settings and tumors, including SCLC, has led to trials assessing their role in ES-SCLC. Results from these trials suggest that this modality can improve outcomes, including in the first-line setting. Recent data show improved survival for patients with treatment-naïve ES-SCLC who received an ICI in combination with standard chemotherapy. Multiple trials evaluating a potential role for ICIs in the first-line setting are currently ongoing, with results expected within the next year.This paper incorporates clinical trial data and current guideline recommendations to show current evidence related to clinical decision making and patient management for those receiving ICI-containing regimens as first-line therapy for ES-SCLC.

Keywords: Extensive-stage small-cell lung cancer, immune-checkpoint inhibitors, immunotherapy


How to cite this article:
Ahmed Y, Calvert P, Dennehy C, Lee J. Immune checkpoint inhibitors in the driver’s seat: Evaluating the evolving evidence in the treatment of extensive-stage small-cell lung cancer. J Curr Oncol 2019;2:43-8

How to cite this URL:
Ahmed Y, Calvert P, Dennehy C, Lee J. Immune checkpoint inhibitors in the driver’s seat: Evaluating the evolving evidence in the treatment of extensive-stage small-cell lung cancer. J Curr Oncol [serial online] 2019 [cited 2020 Jul 7];2:43-8. Available from: http://www.journalofcurrentoncology.org/text.asp?2019/2/2/43/274297




  Clinical Trial Data: Immune Checkpoint Inhibitor-Containing Regimens as First-Line Therapy for Extensive-stage Small-cell Lung Cancer Top


Immune checkpoint inhibitor in induction therapy

Despite consistently poor outcomes, the treatment of extensive-stage small-cell lung cancer (ES-SCLC) has remained stagnant for decades.[1],[2],[3] Initial platinum-based chemotherapy achieves rapid and even complete responses, but these benefits are distressingly transient, with most patients progressing shortly after completing initial chemotherapy.[3],[4] With immunotherapy having fundamentally changed our approach to treating non-SCLC, we have eagerly awaited its development in SCLC, a tumor characterized by a high mutational burden and predicted to benefit from immunotherapy.[5],[6] Since 2016, several clinical trials have compared immune checkpoint inhibitor (ICIs) in combination with standard chemotherapy vs. chemotherapy alone in individuals with untreated ES-SCLC [Table 1]. Thus far, data from primary analyses for two trials have been published, with several expected to be released in 2019 and 2020.[7-9],[11],[12]
Table 1: Clinical trials of ICIs in adults with SCLC

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The placebo-controlled phase-3 IMpower133 trial evaluated patient outcomes and safety associated with the addition of atezolizumab, a PD-L1-blocking antibody, to standard first-line chemotherapy with carboplatin/etoposide (CE).[7] Participants were randomly assigned to treatment with CE/atezolizumab or CE/placebo and received four treatment cycles in the induction phase, which was followed by maintenance therapy that comprised continued atezolizumab or placebo until intolerable toxicity or disease progression. The researchers concluded that atezolizumab significantly improved survival as compared with standard CE therapy.

At a median follow-up of 22.9months, median overall survival (OS) remained 12.3months in patients randomized to atezolizumab and 10.3months in the placebo group (HR, 0.76; 95% CI, 0.60–0.95; P=.0154). IMpower133 is the first trial to show a significant improvement in survival as first-line treatment for patients with SCLC since the introduction of platinum-based chemotherapy in the 1990s.

Phase-1 safety evaluation of atezolizumab/CE did not identify any new safety concerns. Rates of grade 3/4 adverse events (AEs) were comparable between treatment arms (56.6% for CE/atezolizumab vs. 56.1% for CE/placebo); neutropenia, anemia, and decreased neutrophil count were most frequently reported. A greater portion of participants who received atezolizumab experienced irAEs (39.9% vs. 24.5%); rash and hypothyroidism were most commonly reported. Treatment-related deaths occurred with each regimen and were similar between study groups (3 for atezolizumab/CE: neutropenia, pneumonia, and unspecified; 3 for placebo/CE: pneumonia, septic shock, and cardiopulmonary failure).[7] On the basis of these data, the United States Food and Drug Administration (FDA) approved the use of atezolizumab in combination with CE as first-line therapy for ES-SCLC on March 18, 2019.[13]

CA184-156, a large phase-3 trial, evaluated the CTLA-4-blocking antibody ipilimumab in combination with EP or placebo.[11] Among ipilimumab-treated participants, no improvement was observed in OS, but a modest improvement in progression-free survival (PFS) was reported. Treatment with ipilimumab/EP and placebo/EP, respectively, led to comparable rates of any-grade (82% vs. 76%) and grade 3/4 AEs (48% vs. 44%). Ipilimumab treatment was associated with a higher rate of discontinuation because of AEs (18% vs. 2%); diarrhea and colitis were the most common treatment-related AEs leading to discontinuation. Ipilimumab was also associated with more treatment-related deaths (five deaths: two from colitis, two from sepsis, and one from liver toxicity) than placebo (two deaths: one from sepsis and one from bone-marrow suppression). Deaths because of sepsis were judged to be related to chemotherapy and not to ipilimumab, whereas gastrointestinal and skin-related irAEs occurred most frequently among participants who received ipilimumab.[11]

Several large clinical trials are investigating additional ICI-containing regimens as first-line treatment for ES-SCLC, including the CASPIAN and KEYNOTE-604 phase-3 trials. The estimated primary completion dates for these trials are late 2019 and 2020.[8],[9],[12]

Maintenance therapy

Several trials have evaluated the role of ICIs as maintenance therapy after response to induction therapy with EP, but findings do not support their use in this setting.[14],[15],[16] For example, the large phase-3 CheckMate-451 trial found that the PD-1-blocking antibody nivolumab with or without ipilimumab as maintenance after EP failed to improve OS, the trial’s primary end point.[16] Similarly, in a phase-2 study, maintenance therapy with single-agent pembrolizumab in participants who responded to first-line EP did not improve PFS as compared with historical controls.[15]


  Key Considerations for Including Immune Checkpoint Inhibitor in First-line Extensive-stage Small-cell Lung Cancer Treatment Strategies Top


Role of consolidative thoracic radiation therapy and prophylactic cranial irradiation in immune checkpoint inhibitor-treated extensive-stage small-cell lung cancer

Consolidative thoracic radiation therapy (CTRT) and prophylactic cranial irradiation (PCI) have played a role in improving outcomes in patients with ES-SCLC who respond favorably to induction chemotherapy with EP.[10],[17] For example, CTRT in patients with residual disease localized to the chest area has been shown to decrease the number of symptomatic recurrences and improve long-term survival in some patients.[10],[18] In addition, although studies of PCI after induction chemotherapy have not showed improved OS, they have shown a reduced risk of brain metastasis.[17] Meta-analyses have described a survival benefit for PCI in patients who experience a complete response to induction chemotherapy in the era of magnetic resonance imaging (MRI) brain imaging.[19]

The role and optimal administration of RT in the era of systemic therapy with ICIs for ES-SCLC remains unknown. Participants in IMpower133 did not receive CTRT during the maintenance phase of study treatment, although palliative radiation and PCI were permitted.[7] Response rates (RRs) for individuals in IMpower133 who did and did not receive PCI have yet to be reported. In general, combination therapy with RT and ICIs is thought to have synergistic immune effects with little increase in toxicity.[20] RT can lead to the immunologic activation of tumors whereby localized immunosuppression in tumors is overcome and recruitment of immune effector cells is increased. However, a recent retrospective analysis of the safety of central nervous system (CNS) RT in patients with non-SCLC and melanoma suggested a higher likelihood of CNS-AEs when administered within three months of ICI therapy, which was recently confirmed when an updated analysis from IMpower133 found that participants with ES-SCLC who received atezolizumab and PCI experienced higher rates of headache (8/23 vs. 3/21), asthenia (5/23 vs. 2/21), and dizziness (2/23 vs. 0/21).[21],[22]

Two ongoing clinical trials are investigating potential sequences of RT and immunotherapy. MCC-18914 is a phase 1/2 study of an ipilimumab–nivolumab combination with thoracic RT following a complete response, partial response, or stable disease after receiving four to six cycles of first-line platinum-based chemotherapy.[23] The estimated primary completion date is April 2021. In addition, a phase-1 study is evaluating the safety and maximum tolerated dose of pembrolizumab administered concurrently with EP chemotherapy and RT or concurrently with RT after completion of EP induction.[24]

Patient subpopulations and immune checkpoint inhibitor treatment

Treatment with ICIs alone in many tumor types, including SCLC, is associated with low RRs, and benefit is typically limited to a subset of patients.[25],[26] In addition, particular subsets of patients with ES-SCLC, such as those with brain metastases or paraneoplastic syndromes (PNS)/autoimmune disease, are largely excluded from clinical trials of ICIs as first-line treatment of ES-SCLC.[7-9],[11],[12] Current trials seek to identify patient-, disease-, or tumor-related factors that can predict response to ICIs, as well as understand the use of this drug class in specific subpopulations of patients with ES-SCLC.

Predicting response to immune checkpoint inhibitors in extensive-stage small-cell lung cancer

Subgroup analyses from numerous clinical trials of ICIs in ES-SCLC have yet to show a consistent association between patient-, disease-, or tumor-related factors—such as age, sex, race, Eastern Cooperative Oncology Group (ECOG) performance status, smoking status, baseline lactate dehydrogenase, and the presence of brain metastases—and improved outcomes.[5],[7],[11],[15],[27] The IMpower133 subgroup analyses indicated a benefit to all evaluated participant subpopulations, and, based on these results, the current National Comprehensive Cancer Network (NCCN) guidelines recommend atezolizumab/CE for all patients with ES-SCLC who are receiving systemic therapy, including those with brain metastases.[7],[10]

No validated biomarkers are currently available to help identify patients with ES-SCLC who can most benefit from treatment with PD-1-, PD-L1-, or CTLA-4-blocking agents. Efforts to validate biomarkers in ES-SCLC are confounded by the difficulty in obtaining tissue for analysis and the absence of identified driver mutations.[1],[7],[28] The value of TMB and PD-L1 in predicting benefit from ICI therapy when used in tandem has been reported in several tumor types, including melanoma, bladder, head and neck, and non-SCLC.[29]

Clinical trial evidence regarding the use of TMB in ES-SCLC as a biomarker has been mixed.[7],[30] For instance, an exploratory analysis of IMpower133 on efficacy according to blood-based TMB found OS and PFS benefits associated with atezolizumab therapy irrespective of the prespecified cutoffs of 10 and 16 mutations per megabase.[7] However, a subgroup analysis of CheckMate 032 found that, compared with low- or medium-tissue TMB, a high TMB signature was associated with longer survival and higher RRs to treatment with nivolumab monotherapy or nivolumab–ipilimumab combination therapy.[30] Thresholds for TMB expression must continue to be validated prospectively in SCLC.

Similarly, evidence has been mixed regarding the link between PD-L1 expression, which is characteristically low in SCLC, and treatment benefit in patients with SCLC.[5],[6] Moreover, defined thresholds of positivity can differ among clinical trials.[5],[6] In CheckMate 032, in which the threshold for PD-L1 positivity was set at a tumor proportion score of at least 1%, no differences in objective tumor responses to nivolumab with or without ipilimumab were found between the two groups.[5] In contrast, a subset analysis of KEYNOTE-158 evaluating pembrolizumab in the second-line setting found higher RRs in participants with PD-L1-positive vs. PD-L1-negative tumors (36% vs. 6%) and a similar median PFS.[6] This trial established a PD-L1 threshold of a combined positive score of at least 1.[6] It is unclear whether the differences in scoring tumor expression of PD-L1 played a role in these conflicting results.

Patients with paraneoplastic syndromes

The incidence rate of PNS is approximately eight times higher in patients with SCLC than in the general population; the most commonly found PNS in patients with SCLC are neurologic or related to endocrine function.[10],[31] Of note, the prevalence of the syndrome of inappropriate antidiuretic hormone in SCLC patients is approximately 7%–16%.[32] Clinical trials of ICIs as first-line therapy for ES-SCLC have excluded individuals with autoimmune disease and/or those receiving immunosuppressive therapy from enrolment, leading to a dearth of data available to inform decision-making regarding treatment for this patient population.[7],[11]


  Clinical Management of Patients Receiving Immune Checkpoint Inhibitors for Extensive-stage Small-cell Lung Cancer Top


Monitoring patients undergoing Immune checkpoint inhibitor-containing therapy

A thorough baseline assessment for ES-SCLC patients who are undergoing treatment with ICI-containing regimens should include clinical assessment (e.g., physical and neurologic examinations, medical history), imaging, bloodwork, and testing for dermatologic, pancreatic, thyroid, adrenal/pituitary, pulmonary, cardiovascular, and musculoskeletal function.[33] In particular, initial evaluation should include chest/abdominal computed tomography (CT) with contrast, brain MRI rather than brain CT with contrast for appropriate patients, a complete blood count, an electrolyte test, liver function tests, and a creatinine blood test.[10]

Patients must be monitored during therapy with ICI-containing regimens for the emergence of endocrine irAEs, such as hypophysitis, thyroid dysfunction, and insulin-dependent diabetes mellitus.[34] Baseline values for thyroid-stimulating hormone and free T4 should be established for patients taking PD-1/PD-L1 ICIs; if treatment contains a CTLA-4 ICI, adrenocorticotropin hormone and cortisol values (ideally at or before 8:00 am) can also be measured. Current recommended monitoring intervals for these values include monthly testing for the first six months, every three months for at least the next six months, and then every 6–12 months thereafter.[34]

Importantly, patients who are being treated with ICIs can experience pseudoprogression, in which treatment response occurs after the appearance of progression.[35] Fewer than 10% of patients who are treated with ICIs experience pseudoprogression, and reported rates in patients who are treated with atezolizumab are low (1.6%–3.6%). Clinical trials of ICIs for the first-line treatment of ES-SCLC have relied on RECIST 1.1 criteria to assess response, but efforts are ongoing to standardize criteria that better accommodate evaluation of patients receiving ICI-containing treatment. The iRECIST criteria are consistent with RECIST 1.1 regarding the definition of measurable and non measurable disease as well as target and nontarget lesions, although their use requires further validation.[35]

Response assessment for patients receiving ICIs should occur every two or three cycles during treatment (or every two cycles for patients with asymptomatic brain metastases or those who are not yet receiving whole-brain RT) and at the completion of therapy.[10] In addition, follow-up monitoring after initial therapy should occur every two months for the first year, every three or four months during years 2 and 3, every six months during years 4 and 5, and then annually thereafter.[10]

Appropriately identifying and managing irAEs

The management of irAEs has been informed primarily by case series, case reports, and observational data because no prospective clinical trials are available to help define best practices.[3],[36] Several working groups and advisory panels have developed comprehensive recommendations based on expert consensus for clinicians who are introducing ICIs into their oncology practices.[33],[36] As a first step for the identification and management of irAEs, the American Society of Clinical Oncology (ASCO) practice guideline recommends educating patients and caregivers on the mechanisms of immunotherapy and potential symptoms associated with irAEs.[36] By encouraging surveillance and conducting follow-up visits with patients, appropriate management can be implemented promptly to resolve irAEs. In general, clinicians should consider:[33],[36]

  • withholding ICI therapy for grade 2 irAEs and


  • permanently suspending ICI therapy for grade 3 or 4 irAEs (with the exception of endocrine-related toxicities, when a replacement therapy can be given).


  • If grade 2 irAEs or laboratory values improve and return to grade 1, the immunotherapeutic regimen may be restarted with caution.[33],[36] Dose adjustments to improve tolerability are not recommended.[36]


      Conclusion Top


    The investigation of ICIs in combination with standard first-line chemotherapy has led to improved outcomes for patients with ES-SCLC. Atezolizumab/CE represents the first modification to standard first-line therapy that has improved survival for patients with ES-SCLC in three decades, leading to FDA approval for this indication. Reports from ongoing studies in 2019 and 2020 are expected to clarify whether other ICIs in combination with chemotherapy can also be used in this treatment setting. As ICIs enter the first-line treatment space, the focus must remain on the use of clinical management practices for assessing disease response and appropriate monitoring for the potential onset of irAEs.

    Financial support and sponsorship

    Nil.

    Conflicts of interest

    There are no conflicts of interest.



     
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