Performance Status and Age as Predictors of Immunotherapy Outcomes in Advanced Non–Small-Cell Lung Cancer

doi:10.1016/j.cllc.2020.01.001

Clinical Lung Cancer

Volume 21, Issue 4, July 2020, Pages e286-e293

https://doi.org/10.1016/j.cllc.2020.01.001 Get rights and content

Abstract

Introduction

Immunotherapy has become a key treatment for patients with advanced non–small-cell lung cancer (NSCLC). While a survival advantage has been proven for patients who are medically fit, it is unknown whether a benefit exists for patients with poor performance status (PS).

Patients and Methods

We performed a retrospective analysis of NSCLC patients who received immunotherapy in our health system. Age and PS at the time of initial immunotherapy administration were assigned based on physician documentation. Radiographic response and date of progression were assigned according to the treating physician’s assessment and confirmed by the study team. Immune-related adverse events were extracted from records.

Results

We identified 285 NSCLC patients who received immunotherapy between January 2014 and April 2018. In this group, 153 patients (53.7%) had PS 0-1, 114 (40.0%) had PS 2, and 18 (6.3%) had PS 3. Response rates were similar across PS groups with 26.6% for PS 1, 25.2% for PS 2, and 23.1% for PS 3 (P = .95). Survival outcomes varied with pretreatment PS. For PS 0-1, PS 2, and PS 3, median overall survival was 14.7, 8.3, and 1.5 months (P < .001), and progression-free survival was 7.4, 5.1, and 1.3 months (P < .001). Patients aged < 70 had a lower rate (7.6%) of immune-related adverse events requiring steroids compared to patients ≥ 70 (15%) (P = .04).

Conclusion

Patients with poor baseline PS demonstrate similar response rate but inferior progression-free survival and overall survival compared to medically fit patients. Prospective trials are needed to optimize treatment for this large population.

Introduction

Drugs targeting the programmed death 1 (PD-1) receptor and programmed death ligand 1 (PD-L1) have demonstrated survival benefits for patients with non–small-cell lung cancer (NSCLC). Pembrolizumab is now considered a standard of care in the front-line setting either in combination with chemotherapy or as monotherapy for patients with PD-L1 tumor proportion score (TPS) above 50%. While immunotherapy and chemoimmunotherapy have changed the current treatment paradigm, most published studies restricted participation to medically fit patients.1, 2, 3, 4, 5, 6, 7 The Eastern Cooperative Oncology Group (ECOG) performance status (PS) is known to predict outcomes for patients receiving chemotherapy.⁸ Given the toxicity profile of immunotherapy it is unclear if the ECOG scale will continue to have predictive value when using this newer class of drugs.

PS has been established as one of the most powerful independent prognostic factors in advanced NSCLC since it is a strong predictor of survival and adverse events.⁸ When treated with conventional chemotherapy, patients with PS 2 and 3 have worse outcomes and higher rates of toxicity which is why they have been excluded from many clinical trials.⁹^,¹⁰ Standard treatment is generally recommended in patients with PS 0-1, while best supportive care is offered to patients with PS 4. Clinical trials are needed to define the best practices for patients with PS 2 and PS 3. Prior studies indicate that patients with PS 2 and PS 3 account for approximately 30% and 15% of lung cancer patients representing a substantial population without sufficient representation in randomized trials.¹¹

Lung cancer is predominantly a disease of older adults¹² with approximately 50% of lung cancers diagnosed in patients at least 70 years of age with 15% older than 80 years of age.¹³ Advanced age alone does not predict for a lack of clinical benefit in most studies with cytotoxic chemotherapy.14, 15, 16 However, increasing age does predict a higher risk of chemotherapy toxicities.¹⁷ For immunotherapy, subgroup analyses (≥ 65 vs. < 65 years old) from 3 registration trials have shown no difference³ or decreased survival benefit for elderly patients (≥ 65 years old).⁵ There are a limited number of immunotherapy clinical trials dedicated to the elderly, potentially putting such patients at risk for undertreatment and overtreatment biases.¹⁸

Given a more favorable toxicity profile, it is possible that immunotherapy with PD-1/PD-L1 inhibitors would be an acceptable treatment regimen in patients with poor PS and in adults of advanced age. In this retrospective study, we analyzed patients with advanced NSCLC who were treated with immunotherapy at our institution and investigated survival outcomes and adverse events based on PS and age.

Section snippets

Patients

This retrospective study was approved by the Institutional Review Board of Wake Forest University. We reviewed the medical records for all patients with a diagnosis of lung cancer and who were treated with immunotherapy between January 01, 2014 and April 1, 2018. Data were collected by chart review. Inclusion criteria were: age at start of immunotherapy > 18 years, diagnosis of Stage IV NSCLC, and administration of immunotherapy (pembrolizumab, nivolumab, atezolizumab or ipilimumab) within our

Patient Characteristics

A total of 285 patients with NSCLC were treated with immunotherapy between January 2014 and April 2018. Patient characteristics stratified by PS level are summarized in Table 1. One hundred fifty-three patients (53.7%) had an ECOG PS of 0-1, 114 (40.0 %) had a PS of 2, and 18 patients (6.3%) had a PS of 3. The median age at start of immunotherapy was related to PS, with those with less favorable PS levels having a higher median age (P = .007). There were no significant differences in the

Discussion

Patients with advanced NSCLC who have PS 2 or 3 have been excluded from many clinical trials and determining the best course of treatment remains clinically challenging. Several studies have demonstrated that patients with poor PS experience increased toxicities and have poor survival outcomes when treated with conventional chemotherapy.²⁰ Since the toxicity profile of immunotherapy differs from cytotoxic chemotherapy, it is possible that baseline PS will have less of an impact on predicting

Disclosure

The authors have stated that they have no conflict of interest.

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Immune checkpoint inhibitor-based combination therapy (ICI-based combination) is a new standard of care for metastatic clear cell renal cell carcinoma (mRCC) in the frontline setting. Patients with poor performance status (PS) (≥2) were excluded from pivotal trials. Hence, the activity and safety of ICI-based combination therapy in this group of patients is still unknown.
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We report the first cohort of PS ≥2 mRCC patients treated with frontline ICI-based combination therapy. The survival outcomes in our cohort were inferior to that reported in pivotal trials. No significant differences in ORR, PFS, OS or toxicity were seen between NI and AP. Prospective real-world studies are needed to confirm these results.
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Thus, it is critical that methods for improving treatment tolerance are developed. One strategy that aims to improve treatment tolerance is the Eastern Cooperative Oncology Group (ECOG) Performance Status Scale, which is a widely accepted and guideline-based measure that predicts survival among cancer patients receiving treatment [8–10]. Another scale used specifically to assess fitness among older patients is the Clinical Frailty Scale (CFS).
Age-related disparities in non-small cell lung cancer (NSCLC) treatment are well known, but few studies have assessed the impact of sex on treatment disparities. Disparities in guideline-adherence may explain the superior survival in women with NSCLC. Therefore, we aimed to define patient- and tumor-related factors associated with non-adherence to guidelines in NSCLC management with a special focus on sex and age.
Patients with NSCLC who received first-line treatment at the Vaasa Central Hospital between 2016 and 2020 were included in the study. The primary outcome was guideline adherence, defined as adherent, undertreatment, or overtreatment considering performance status. A binary logistic regression model was used to calculate the adjusted odds ratio (aOR) for non-adherence to treatment guidelines depending on patient- and tumor-related factors.
321 patients were included in the study. Non-adherence was highest in ≥75-year-old women (41.3%), followed by ≥75-year-old men (32.6%), <75-year-old men (27.6%) and lowest in women <75-year-old (19.7%) (p = 0.035). Non-adherent care consisted more often of undertreatment in <75-year-old men than women (26.0% versus 12.1%) and overtreatment in <75-year-old women than men (7.6% versus 1.6%). Non-adherence was associated with stage III disease (aOR 2.21; 95% CI 1.07–4.59), poor pulmonary function (aOR 3.69, 95% CI 1.56–8.71), and Charlson Comorbidity Index 1–2 (aOR 2.09; 95% CI 1.09–4.01).
Sex- and age-related disparities in guideline adherence were observed in <75-year-old men and in ≥75-year-olds. Stage III NSCLC was associated with non-adherence.
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The latter is important because our study may suggest that the association between concomitant use of GAS and poor survival in NSCLC patients receiving PD-1/PD-L1 inhibitors may be independent of some possible clinical factors that may influence the survival. As indicated by previous studies, factors such as age group [43], functional status [44], smoking history [45], and clinical stages of NSCLC [46] may affect the efficacy of PD-1/PD-L1 inhibitors. Taken together, our results support the previous hypothesis that concomitant use of GAS may compromise the therapeutic efficacy of PD-1/PD-L1 inhibitors in NSCLC patients.
Influence of concomitant use of gastric acid suppressants (GAS) on survival of non-small cell lung cancer (NSCLC) patients receiving programmed death-1/ligand-1 (PD-1/PD-L1) inhibitors has rarely been comprehensively evaluated. A meta-analysis was performed to systematically evaluate the effect of concomitant GAS in NSCLC patients receiving PD-1/PD-L1inhibitors.
Relevant observational studies were identified by search of Medline, Embase, and Web of Science databases from inception to May 26, 2022. A random-effect model which incorporates the possible between-study heterogeneity was used to combine the results.
Ten retrospective and one prospective cohort studies including 5892 patients were patients were included. Influence of concomitant proton pump inhibitors (PPIs) was evaluated in ten studies, and influence of GAS, including PPIs or histamine type-2 receptor antagonists were evaluated in one study. Pooled results showed that concomitant use of GAS was associated with worse progression-free survival (PFS, adjusted hazard ratio [HR]: 1.32, 95% confidence interval [CI]: 1.20 to 1.45, P < 0.001; I² = 0%) and overall survival (OS, adjusted HR: 1.36, 95% CI: 1.26 to 1.48, P < 0.001; I² = 0%) in NSCLC patients taking PD-1/PD-L1inhibitors. Subgroup analyses indicated that the association between concomitant use of GAS and poor survival in NSCLC patients taking PD-L1inhibitors was consistent in univariate and multivariate studies (P values for subgroup difference both > 0.05 for PFS and OS).
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All authors had full access to all the data in the study and the corresponding author had final responsibility for the decision to submit for publication. A total of 4504 publications were retrieved through the literature search, and 67 studies with a total of 26,442 patients (individual study median: 217, range: 44−2,302) were included in the final analyses (Fig. 1, Table D.01) [6,7,26–90]. Among these, there were 3890 PS ≥ 2 patients (median: 39, range: 11–241) and 22,552 PS ≤ 1 patients (median: 170, range: 32−2,129).
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Original StudyPerformance Status and Age as Predictors of Immunotherapy Outcomes in Advanced Non–Small-Cell Lung Cancer

Abstract

Introduction

Patients and Methods

Results

Conclusion

Introduction

Section snippets

Patients

Patient Characteristics

Discussion

Disclosure

Lancet

J Thorac Oncol

J Thorac Oncol

Eur J Cancer

Lancet

J Thorac Oncol

J Thorac Oncol

Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer

N Engl J Med

Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer

N Engl J Med

Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer

N Engl J Med

Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC

N Engl J Med

Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer

N Engl J Med

Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer

N Engl J Med

Chemotherapy for advanced non–small-cell lung cancer: who, what, when, why?

J Clin Oncol

Treatment of performance status 2 patients with advanced non–small-cell lung cancer: what we know and what we don’t know

Future Oncol

Original Study
Performance Status and Age as Predictors of Immunotherapy Outcomes in Advanced Non–Small-Cell Lung Cancer