Clinical Trial Eligibility and Outcomes in Patients With Metastatic NSCLC Treated Outside of Clinical Trials

Abstract

Introduction: There are limited data available regarding patient outcomes in those who would have been ineligible to receive therapy based on the original clinical trial eligibility criteria. We decided to conduct a retrospective study to evaluate outcomes based on clinical trial eligibility in patients with metastatic non–small cell lung cancer (NSCLC).

Methods: A retrospective chart review of all patients with metastatic NSCLC who received first-line systemic therapy at a single academic institution was performed. Each patient’s chart was reviewed to determine if they would have qualified for the phase 3 clinical trial that led to the approval of the specific treatment regimen which they received. Data were analyzed to determine if there was a difference in survival time between those who would have been eligible compared with those who were ineligible for the clinical trial of the treatment regimen administered.

Results: There were 170 patients with a diagnosis of metastatic NSCLC who received first-line systemic therapy. Of these, 109 received combined chemotherapy, 25 received immunotherapy, and 36 received targeted therapy. There is a statistically significant difference in the restricted mean survival time between the eligible and ineligible groups in those who received combined chemotherapy (19.9 months vs 13.2 months; P = .03), but not in either the immunotherapy group (22.4 months vs 12.9 months; P = .06) or the targeted therapy group (57.7 months vs 39.0 months; P = .14).

Conclusion: These data support less restrictive clinical trial eligibility criteria for those with metastatic NSCLC. This is especially true regarding both targeted therapy and immunotherapy treatment regimens.

Introduction

Over the past few years, there has been a significant increase in the eligibility criteria for medical therapy clinical trials enrolling patients with lung cancer, especially for clinical trials focused on patients with more advanced-stage lung cancer.¹ The number of stringent eligibility criteria involving different organ systems, patients’ concurrent drugs, and previous cancer diagnoses has been increasing.^1,2 Many of these eligibility criteria are often reflexively incorporated into clinical trial protocols without definite scientific justification.^1,3 Although some of these criteria are important to ensure patient safety, the increase in eligibility criteria complicates the assessment of potential participants and decreases the applicability of the results of these trials to the general population of patients with cancer.¹

As investigators in multiple studies have noted, less than 5% of adults with cancer in the United States are enrolled in clinical trials.^2,4-7 One possible cause is the more restrictive eligibility criteria. Eligibility criteria are designed to limit the enrollment to a more homogenous population for easier detection of efficacy while optimizing safety.^1,3 Study populations often do not reflect the general population for whom the treatment might be prescribed.3 Hence, the majority of patients are treated based on information obtained from a relatively small number of patients.

There are limited data available regarding patient outcomes in those who would have been ineligible to receive therapy based on the original clinical trial eligibility criteria. Therefore, we decided to conduct a retrospective real-world study to evaluate outcomes from an academic medical center based on clinical trial eligibility in patients with metastatic non–small cell lung cancer (NSCLC). We hypothesized that real-world survival outcome data would support less restrictive clinical trial eligibility criteria for patients with metastatic NSCLC.

Methods

Data Source and Study Population

Local institutional review board approval was obtained prior to the initiation of this study. A retrospective chart review of all patients with metastatic NSCLC who received first-line systemic therapy at a single academic institution from August 2015 to August 2018 was performed. International Statistical Classification of Diseases, Tenth Revision (ICD-10) code C34.0 (malignant neoplasm of main bronchus) was used to search the electronic medical records for patients with metastatic NSCLC. The search criteria also included that the patient needed to receive any of the following drugs: carboplatin, pemetrexed, erlotinib, gefitinib, alectinib, crizotinib, osimertinib, or pembrolizumab. These drugs were selected because they are the mainstay of first-line treatment regimens for metastatic NSCLC. A list of patients who had an ICD-10 code of C34.0 and had received any of the above-listed drugs was generated.

Data Collection

The data that were collected on each patient included: date of birth, sex, initial ECOG performance status, date of cancer diagnosis, stage of cancer at diagnosis, histology, molecular mutations, presence or absence of brain metastases (and if present, whether treated with radiation or surgery), first-line treatment regimen, date of the first treatment, second-line treatment regimen (if applicable), date of death or last contact, and cause of death (if applicable). Patients who did not have a histologic diagnosis of NSCLC were excluded. For each first-line treatment regimen, the phase 3 clinical trial that led to the approval of that specific treatment regimen was identified. We selected phase 3 clinical trials instead of phase 2 clinical trials because phase 3 clinical trials typically have less restrictive eligibility criteria. Each patient’s chart was reviewed to determine whether they would have qualified for said clinical trial. If a patient would have been ineligible, the reason(s) for ineligibility was documented. Data collection was completed in January 2021, allowing time for the maturation of survival data.

Statistical Analysis

The number of inclusion and exclusion criteria that each patient did not satisfy were recorded. We further stratified those who would have been eligible and ineligible by sex, ECOG performance status, and survival status. We used the Pearson χ2 test to calculate the P value for each subgroup regarding eligibility and ineligibility. Survival time was calculated as the time between treatment initiation and the date of death or last contact.

The primary question in this analysis was to determine whether there was difference in survival time for patients with metastatic NSCLC between those who would have been eligible and those who would have been ineligible for the phase 3 clinical trial that led to the approval of the first-line treatment regimen the patient received. Restricted mean survival time was calculated to identify the variables associated with the difference in survival between those patients who would have been eligible and those who would have been ineligible.⁸ The Pearson χ2 test was used to evaluate the significance of the difference observed between restricted mean survival times for those who would have been eligible and those who would have been ineligible. Kaplan-Meier survival curves were generated for those who would have been eligible and those who would have been ineligible. A log-rank test was used to test the significance of the differences between outcomes. A P value of less than .05 was considered statistically significant.

Each patient received first-line treatment for metastatic NSCLC with 1 of 14 regimens. These regimens were classified into 3 different groups: combined chemotherapy, immunotherapy, and targeted therapy. The regimens included in the combined chemotherapy group were carboplatin/pemetrexed,⁹ cisplatin/pemetrexed,¹⁰ carboplatin/paclitaxel,¹¹ cisplatin/pemetrexed/bevacizumab,¹² carboplatin/pemetrexed/bevacizumab,¹³ and carboplatin/etoposide¹⁴ regimens. The immunotherapy group included pembrolizumab,¹⁵ carboplatin/pemetrexed/pembrolizumab,¹⁶ and carboplatin/paclitaxel/pembrolizumab.¹⁷ The targeted-therapy cohort included crizotinib,¹⁸ erlotinib,¹⁹ afatinib,²⁰ alectinib,²¹ and osimertinib²² regimens. Similar analyses as described above were conducted for these individual groups.

Since ECOG performance status was identified to be a common reason for patients being ineligible for clinical trials in our analysis, it was analyzed separately. The majority of phase 3 clinical trial eligibility criteria for the above regimens only included patients with an ECOG performance status of 0 or 1, but there were some clinical trials included in our analysis that allowed the enrollment of patients with an ECOG performance status of 2.9-22 Patients were classified based on ECOG performance status at treatment initiation into subgroups of ECOG performance status of 0 to 1 or ECOG performance status of 2 to 3. The analyses described above were performed in the ECOG subgroups as well.

Results

FIGURE 1. Patient Selection

A total of 170 patients with metastatic NSCLC received first-line systemic therapy. Of these, 109 received combined chemotherapy, 25 received immunotherapy, and 36 received targeted therapy (Figure 1). Table 1 details the number of patients in the study who received each first-line systemic therapy regimen (Table 1).

TABLE 1. Number of Patients Per Treatment Regimen

The initial ECOG scores were missing in 9 patients, and we were unable to determine eligibility in 7 patients due to missing data. There were 94 women and 76 men in the study, with a median age of 69.6 years. There were 131 individuals with an ECOG performance status of 0 or 1, and 30 individuals had an ECOG performance status of 2 or higher. Of the 170 individuals in this study, 136 had died by the time data collection was completed (Table 2).

TABLE 2. Descriptive Statistics

Of the 163 patients where we had enough data to determine eligibility, there were 105 patients (64.4%) who would have been eligible for the clinical trial of the first-line systemic therapy they received for their metastatic NSCLC and 58 patients (35.6%) would have been ineligible. Of the 58 patients who would have been ineligible for the clinical trials, 38 patients (65.5%) had 1 ineligibility criterion, whereas 20 patients did not fulfill 2 or more criteria for their given clinical trial (Table 2). Higher ECOG performance status and prior malignancy/chemotherapy accounted for approximately 40% of all the ineligibility criteria for ineligible patients. Other causes of ineligibility included prior radiation therapy, renal insufficiency, gastrointestinal disorder, infectious disease, bone marrow dysfunction, central nervous system metastasis, and immunocompromised status (Table 3). Sex was not associated with eligibility (P = .67). Patients with a lower ECOG performance status were significantly more likely to be eligible (P < .0001). When comparing all 3 groups of treatment categories, there was a significant difference in the frequency of eligibility between all groups (P = .008).

TABLE 3. Frequency of Each Ineligibility Criterion

The inclusion criteria were more stringent in the immunotherapy and targeted-therapy groups compared with the combined chemotherapy group. Of the patients who received chemotherapy, 72.1% would have been eligible, compared with only 40.0% and 58.8% of patients who would be eligible in the immunotherapy and targeted-therapy groups, respectively.

Concerning outcomes, patients with an ECOG performance status of 0 or 1 who were eligible had a restricted mean survival time of 32.2 months compared with 23.9 months for those who were ineligible. For patients with ECOG performance status of 2 or more, the restricted mean survival time was 24.5 months for those who were eligible and 13.3 months for those who were ineligible. These differences, however, were not statistically significant (P = .17 and P = .10, respectively) (Table 4). Not surprisingly, there was a significant difference, however, in the restricted mean survival time of those with low-performance status compared with those with high-performance status (23.5 months vs 16.3 months, respectively; P = .03).

TABLE 4. Multivariate Analysis of Factors Affecting Survival

At the time of data collection, 61.8% of those who would have been eligible had died compared with 75.0% in the ineligible group. Eligibility to the specific clinical trial was not associated with survival status (P = .163). There was a significant statistical difference in the restricted mean survival time in those who would have been eligible compared with those who would not have been eligible (31.5 vs 20.9 months; P = .03) (Table 3; Figure 2).

FIGURE 2. Survival Based on Clinical Trial Eligibility

There was also a statistically significant difference in survival probability between all 3 treatment groups (P = .0002) (Figure 3). When looking at each treatment group, there is a statistically significant difference in the restricted mean survival time between the eligible and ineligible groups in those who received combined chemotherapy (19.9 months vs 13.2 months; P = .03), but not in either the immunotherapy group (22.4 months vs 12.9 months;
P = .06) or the targeted-therapy group (57.7 months vs 39.0 months; P = .14) (Table 4; Figure 2)

FIGURE 3. Survival Comparisons Among All Treatment Groups

Discussion

The primary goal of this study was to gather and analyze data on patients with metastatic NSCLC who received first-line systemic therapy at a single academic institution to obtain real-world data regarding survival in those who would have been eligible and ineligible for the original phase 3 clinical trial that led to therapy approval. We did observe a significant difference in survival time between those who would have been eligible compared with those who would have been ineligible for their original clinical trial.

However, variations emerged when we divided patients by treatments received. Among patients who received a chemotherapy treatment regimen, those who would have been eligible had better survival time compared with those who would not have been eligible. Yet, there were no differences based on eligibility criteria in patients who received either immunotherapy or targeted therapy.

Interestingly, our data also showed a statistically significant difference between the 3 therapy groupings concerning the frequency of who would have been eligible for their original clinical trial. Of the patients in the combined chemotherapy group, 72.1% would have been eligible for their respective clinical trial, whereas this number was significantly lower (P = .008) in the immunotherapy group (40.0%) and the targeted-therapy group (58.8%), suggesting that the clinical trials for both immunotherapy and targeted-therapy regimens are likely more restrictive compared with clinical trials for combined chemotherapy regimens. Kim et al previously noted that molecularly driven clinical trials have more eligibility criteria compared with the already restrictive chemotherapy clinical trials for NSCLC.³ After reviewing the phase 3 clinical trials for all 14 treatment regimens for first-line treatment of NSCLC in our study, we noted that immunotherapy clinical trials and targeted-therapy clinical trials have higher numbers of eligibility criteria compared with chemotherapy clinical trials.^9-22

Our data suggest that there is no significant difference in clinical outcomes in terms of survival for individuals with metastatic NSCLC who are eligible to participate in both immunotherapy and targeted-therapy clinical trials compared with those individuals who are ineligible to participate. This indicates that reduction of both immunotherapy and targeted-therapy clinical trial eligibility criteria is possible while still having a study population where the investigators can optimize the scientific yield and maximize patient safety. That being said, we do understand that the small numbers of patients in the immunotherapy and targeted-therapy groups make our statistical analysis difficult to interpret.

Many factors may affect the low accrual of patients into cancer clinical trials, including the number of eligibility criteria.^1-7,23-25 Alleviation of eligibility criteria would increase accrual into cancer clinical trials by making the trials more generalizable and helping study completion.1-7 Less restrictive eligibility criteria could also help with the accrual of patients who are underrepresented in clinical trials.^4-7,23

Of the patients in our study who would have been ineligible for their respective clinical trials, 65.5% of them were only ineligible based on a single criterion. This suggests that minimal changes to metastatic NSCLC clinical trial eligibility criteria could lead to a marked increase in those who are eligible. Even a slight reduction in the number of eligibility criteria could potentially help with study accrual and generalizability. As previously stated, many of the eligibility criteria for clinical trials are reflexively incorporated into clinical trial protocols.^1,3 These are often carried over from previous trials without scientific justification.^1,3 Laccetti et al previously studied patients with stage IV lung cancer and gathered data on clinical outcomes depending on whether the patients previously had a prior cancer (regardless of stage).² They showed that patients with stage IV
lung cancer and a prior cancer diagnosis had better all-cause and lung cancer–specific survival compared with those without prior cancer,² suggesting that the inclusion of this specific criterion did not affect either the efficacy or safety of the agents studied.

Prior cancer diagnosis is a common exclusion criterion for metastatic lung cancer phase 3 clinical trials.^2,9-22,24 Laccetti et al showed that 14.7% of patients with advanced lung cancer have a prior cancer diagnosis.² They suggested that broadening the inclusion criteria to include those who had a prior cancer diagnosis could help with clinical trial accrual without impacting clinical trial outcomes.² Our study did further analysis on ECOG performance status and survival probability. We found that 76.7% of patients with higher ECOG performance status (2 or 3) were ineligible for their respective clinical trials for first-line treatment of metastatic NSCLC. Although studies have shown that patients with high-performance status tend to do worse, they form an important subgroup of patients, and these patients must be included in clinical trials in order to identify the best treatment approach for them.^26,27 It is possible that removing ECOG performance status as an eligibility criterion, at least for trials not involving cytotoxic chemotherapy, might have an impact on scientific yield and patient safety, therefore impacting clinical trial outcomes.

There has been recent work in the field of oncology to address low rates of patient participation in clinical trials. The LUNGevity Foundation convened a working group of experts to address the topic of outdated or unnecessary restrictions on lung cancer clinical trials.^28,29 Their work includes an evaluation of how certain criteria have played a role in excluding patients from clinical trials.28 They have provided scientific justification for reducing certain criteria that routinely exclude patients from lung cancer clinical trials. More recently, they have worked on standardizing eligibility criteria to simplify cancer clinical trials and harmonize trial populations.²⁹ We believe our study supports their work by providing real-world data on trial eligibility and outcomes in patients with metastatic NSCLC.

There are some limitations to our study. This was a retrospective single-institution analysis. Another limitation was the smaller number of patients who received either immunotherapy or targeted-therapy first-line treatment for their metastatic NSCLC. Both immunotherapy and targeted therapy were newer than combined chemotherapy for the treatment of metastatic NSCLC at the time of data collection. Also, both treatment groups require specific targets that can limit the number of patients who receive said treatment.^15-22 As immunotherapy and targeted-therapy treatment regimens become more broadly used for first-line treatment of metastatic NSCLC, repeat analysis can be done to help validate the findings of this study.

Conclusion

In summary, real-world survival outcome data supports less restrictive clinical trial eligibility criteria for patients with metastatic NSCLC. This is especially true regarding both targeted-therapy and immunotherapy treatment regimens, where survival probability and restricted mean survival time were not statistically different in those who would have been eligible compared with those ineligible for their respective phase 3 clinical trial for first-line systemic treatment of metastatic NSCLC. Our data show that both immunotherapy and targeted-therapy eligibility criteria are more restrictive compared with chemotherapy regimens. Less restrictive lung cancer clinical trials can have benefits for both individual patients and the health care system as a whole. Our data show that most patients are only ineligible based on 1 of the many eligibility criteria for a phase 3 cancer clinical trial for metastatic NSCLC. Even a slight relaxation of eligibility criteria could help address the major challenge of patient accrual to cancer clinical trials.

Corresponding Author

Alissa S. Marr, MD

Division of Oncology Hematology

Department of Internal Medicine

University of Nebraska Medical Center

Omaha, NE 68198

Phone: 402-559-8500

Fax: 402-559-6520

Email: amarr@unmc.edu

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