
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12339-0
10.1016/j.heliyon.2024.e36308
e36308
Research Article
Half of oncologists fail to use ordered NGS results to guide their first-line treatment decision in advanced NSCLC: A retrospective study in a community-based integrated healthcare system
Megahed Ahmed I. ahmed.i.megahed@kp.org
a⁎
Zheng Dominick b
Chen Lie Hong a
Haque Reina ab
McGary Eric C. b
a Kaiser Permanente Southern California, Research & Evaluation, Pasadena, CA, USA
b Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA
⁎ Corresponding author. 100 South Los Robles, Pasadena, CA, 91101, USA. ahmed.i.megahed@kp.org
15 8 2024
30 8 2024
15 8 2024
10 16 e3630830 10 2023
6 8 2024
13 8 2024
© 2024 The Authors. Published by Elsevier Ltd.
2024

https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Purpose

Next generation sequencing (NGS) testing is used to identify driver mutation(s) in non-small cell lung cancer (NSCLC) that are amenable to targeted therapy, resulting in superior outcomes and improved tolerability. We characterized how clinicians in a large integrated healthcare system utilized NGS testing to inform first line treatment decisions in patients with stage IV NSCLC shortly after diagnosis.

Methods

We conducted a cross-sectional study of 964 patients within an integrated healthcare system, Kaiser Permanente Southern California (KPSC), who were diagnosed with stage IV NSCLC and completed NGS testing (Strata Oncology) between May 2019 to June 2021. Treatment start dates were used to divide patients into those who started treatment before or after NGS results, or those who did not receive treatment after NGS results. Patients harboring alterations in seven genes (EGFR, ALK, ROS-1, BRAF, KRAS, RET, and MET) were considered candidates for targeted first line therapy.

Results

First line treatment was initiated in half (52 %; n = 284) of all treated patients prior to NGS results. Just under half (48 %; n = 137) of these patients were found to have a targetable mutation by NGS, of whom 59 % received first line chemotherapy and/or immunotherapy, rather than targeted therapy. Nearly 27 % of the sample never received treatment, of which 31 % had a targetable mutation, and may have been candidates for targeted therapy. Not undergoing first line treatment was correlated with older age, higher comorbidity index, smoking history, and the lack of an identifiable driver mutation.

Conclusion

NGS tests results were not exclusively used to inform first line treatment decisions in most patients with stage IV NSCLC, and most patients with a targetable mutation were not treated with targeted therapy. Possible explanations include lengthy turnaround times for NGS testing and the availability of timelier but less accurate single gene testing.
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pmc1 Introduction

Lung cancer is the leading cause of cancer-related mortality in the United States, accounting for over 130,000 deaths annually [1]. The incidence of new lung cancer diagnoses has declined steadily since 2006, partly due to lower smoking rates [2]. Lung cancer-specific mortality rates are also declining, which may reflect advances in treatment and early detection [2]. However, the majority of patients are still diagnosed at an advanced stage when prognosis is poor, and treatment is considered palliative [3].

Non-small cell lung cancer (NSCLC), which represents about 80 % of all lung cancers, is a molecularly heterogenous disease [4] with over half of all adenocarcinomas harboring variants in specific genes that drive oncogenesis (driver mutations) [5]. Identification of these driver mutations by single gene mutation testing or next generation sequencing (NGS) has changed the therapeutic landscape, as matching them with an FDA-approved targeted therapy has significantly improved therapeutic efficacy while reducing treatment-related toxicity [6].

Genomic profiling in NSCLC is necessary to identify driver mutations and select corresponding targeted therapies. Besides determining patient eligibility for targeted therapy, it should significantly influence the clinician's selection of first-line treatment Accordingly, the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) guidelines strongly recommend driver mutation testing by NGS at diagnosis [7,8].

However, adherence to these guidelines varies across clinical practices. Studies demonstrate that molecular testing is often not completed in a significant number of NSCLC patients prior to first line treatment, or at any time during their disease course [9,10]. Limitations of NGS testing include lengthy turnaround times, high tissue failure rates from suboptimal tissue quantity or quality, and cost, all of which may affect its use in clinical practice [[11], [12], [13], [14]] While other studies have addressed these limitations to improve the rates at which NGS testing is ordered [14], a major aim of this study was to characterize whether clinicians who had ordered NGS testing at diagnosis waited for the availability of NGS results to inform first line treatment decisions in patients within advanced NSCLC.

2 Methods

2.1 Study design, participants, and setting

This cross-sectional study included adult patients (≥18 years) diagnosed with stage IV (metastatic) NSCLC who underwent NGS testing via StrataNGS over a three-year period between May 2019 and June 2021. Patients were tested in accordance with institutional guidelines that recommended NGS testing for any patient with metastatic disease. Patients with localized disease or lung cancers not classified as NSCLC were excluded from the study. A total of 964 patients with test referrals met these criteria.

All study participants were members of KPSC, which serves over 4.7 million members through a network of 17 medical centers with over 8000 primary and specialty care physicians [15]. The KPSC Internal Review Board waived the requirement for written or verbal informed consent as study data were based on electronic health records (EHR).

2.2 Data sources

StrataNGS is a 429-gene comprehensive genomic profiling (CGP) assay that identifies single nucleotide variants (SNVs), microsatellite instability (MSI) status, tumor mutational burden (TMB), copy number alterations (CNAs), programmed death-ligand 1 (PD-L1) status, and RNA fusion events [16]. Patient NGS results were extracted from KPSC's StrataNGS database, which tracks information on the NGS testing workflow (date of provider referral, date of sample submission, result date), samples (histology), and results (targetable mutations, success/failure status for each sub-assay). This study focused on NSCLC driver mutations within seven genes (EGFR, ALK, ROS-1, BRAF, KRAS, RET, and MET).

Patient demographic data (biologic sex, age at diagnosis, race/ethnicity, smoking status), NSCLC diagnosis dates, use of systemic therapies, and use of hospice care were obtained through KPSC's EHR.

2.3 Cancer treatment

NSCLC treatment was defined as any initial intravenous (IV) (chemotherapy, immunotherapy, or a combination) or oral targeted therapy given between 30 days prior to the receipt of NGS results and up to 120 days after NGS results were received. This was further divided into three groups: patients who received treatment prior to NGS results; those who received treatment up to 120 days after NGS results; and those who did not receive any treatment up to 120 days after NGS results.

2.4 Independent variables and covariates

We first examined the baseline characteristics closest to and within one year of the index date (date of NGS testing referral). The variables assessed included biologic sex, age, race/ethnicity, smoking status, Elixhauser comorbidity index (ECI) score (0–2, 3–4, 5–6, 7+), and histology [adenocarcinoma, squamous cell carcinoma, adenosquamous, large cell carcinoma, other, not otherwise specified (NOS)]. Histology was aggregated into the three distinct categories of adenocarcinoma, squamous cell carcinoma, and other. We defined driver mutations as variants in the genes EGFR (exon 19, 20, 21), ALK fusions, ROS-1 fusions, BRAF, KRAS p. G12C, RET fusions, or MET (amplifications or exon 14 deletions).

2.5 Outcomes

The main outcomes assessed were the frequency of patients who initiated systemic therapy or enrollment into hospice before NGS results were complete. We additionally assessed timing of these outcomes relative to each patient's date of NGS referral and date of NGS test result. These outcome measures were further divided into patients who were or were not subsequently found to have a targetable mutation.

2.6 Statistical analysis

Time to results was calculated from both NGS referral date and sample submission date. Differences in socio-demographics, driver mutations, baseline comorbidities, and tumor characteristics were compared by treatment status up to 120 days after test results were received. Categorical data (e.g., demographic data) were summarized as frequencies using Chi-square test or Fisher's exact test to examine differences. Continuous variables (e.g. time to treatment initiation) were evaluated via means with standard deviation (SD) or medians with interquartile ranges (IQR).

We calculated adjusted odds ratios (OR) and 95 % confidence intervals (CI) using multivariable logistic regression to identify the association between receiving treatment and the aforementioned variables: race/ethnicity, age, biologic sex, smoking status, ECI, and histology.

Mean (SD) and median (IQR) days to treatment were determined from referral or result dates. We also examined the frequencies and percent distributions for IV, oral, and combined treatment, by all driver mutations including EGFR, ALK, ROS-1, BRAF, KRAS, RET (fusion), MET (amplification), MET (exon 14 deletions), in addition to TMB and PD-L1. All analyses were performed using SAS Version 9.4 (SAS Institute, Cary NC).

3 Results

3.1 Study population

A total of 964 patients with stage IV NSCLC completed NGS testing. Of these, 204 (21.2 %) patients were excluded because they received treatment 30 days prior to the NGS testing. These patients were not considered first line stage IV patients. Therefore, 760 (78.8 %) patients were considered treatment naïve at the time of NGS testing referral, which comprises the analytic sample (Fig. 1 displays the study flow diagram).Fig. 1 Study Schema.

*These patients were not considered de novo metastatic (stage IV) or first line patients, so they were excluded from the rest of the analysis.

**Spot testing leading to increased healthcare costs.

***Spot testing positive, NGS negative.

****Potentially inappropriate treatment, fatal complications in case of EGFR therapy after PD1/PDL1 therapy.

Fig. 1

The mean (SD) age at the date of referral for NGS testing was 70 years (SD = 10.9), with 17.8 % of patients aged 80 years and older. In the sample, 50.5 % of patients were male, and 49.5 % were female. This diverse study sample included 46.3 % non-Hispanic White patients, 20.4 % Hispanic patients, 13.3 % African American/Black patients, and 20.0 % Asian/Pacific Islander patients.

3.2 Time to NGS results

The mean time from NGS referral to receiving results was 25 days (SD = 16). Stratified further, the mean time from NGS referral to sample submission was 10 days (SD = 11.7), while the mean time from sample submission to result was 15 days (SD = 10.4). All measurements represent calendar days.

3.3 Driver mutation profile of cohort

Of the 760 total patients, 323 (42.5 %) had at least one driver mutation based on NGS testing [including 193 (25.3 %) with an EGFR, ALK, or ROS-1 mutation].

3.4 Treated patients (n = 546)

Of the 760 patients, 546 (71.8 %) received some form of first line treatment. Within this subgroup, 284 (52 %) patients received first line treatment prior to NGS results being reported, suggesting the treatment decision was based on factors other than NGS results. The remaining 262 (48 %) received their first line treatment after NGS results were reported. The median time from referral date to treatment initiation was 21 (IQR = 9.0, 36.0) days for IV treatment, and 19 (IQR = 0.5, 29.5) days for oral treatment. In the group treated after NGS results were received, the median time was 36 (IQR = 26.0, 50.0) days for IV treatment and 29 (IQR = 23.0, 40.0) days for oral treatment (Table 1).Table 1 Time to treatment initiation relative to NGS referral date or result date.

Table 1	Total treated	Treatment prior to NGS results	Treatment after NGS results	
IV (N = 410)	Oral (N = 136)	IV (N = 220)	Oral (N = 64)	IV (N = 190)	Oral (N = 72)	
Referral to treatment initiation (days)	
 Median	21	19	10	0	36	29	
 Q1, Q3	9.0, 36.0	0.5, 29.5	2.0, 17.0	−14.0, 13.0	26.0, 50.0	23.0, 40.0	
Results to treatment initiation (days)	
 Median	0	1	−13	−25	14	8	
 Q1, Q3	−14.0, 14.0	−23.5, 8.0	−26.0, −5.5	−39.0, −15.0	7.0, 27.0	3.0, 18.0	
Negative values indicate that treatment was initiated prior to referral date or result date.

Patients who were ≥80 years old were 2.4 times less likely to receive treatment compared to younger patients (<60 years of age) [OR (95 % CI) = 2.44 (1.31–4.53)]. Past smokers were 1.6 times less likely [OR (95 % CI) = 1.57 (1.00–2.44)] to be treated compared to never smokers. Patients with more comorbidities were less likely to be treated than those with a lower comorbidity index, with the likelihood decreasing as the score increases [OR 7+ score (95%CI) = 2.50(1.43–4.37)]. Patients without driver mutations were 1.7 times as likely to not be treated than those with mutations [OR (95 % CI) = 1.70 (1.16–2.48)] (Table 2).Table 2 Demographic distribution of patients treated vs patients not treated.

Table 2	Treated (N = 546)	No treatment up to 120 days after result (N = 214)	Total (N = 760)	Adjusted odds ratioa (95 % CI)	p-valuea	
N (%)	N (%)	N (%)	
Biologic Sex					0.682	
 Male	273 (50)	111 (51.9)	384 (50.5)	0.97 (0.69–1.37)		
 Female	273 (50)	103 (48.1)	376 (49.5)	1.00 (ref)		
Age at Index (yrs)					<0.001	
 < 60	98 (18)	23 (10.8)	121 (15.9)	1.00 (ref)		
 60-69	170 (31.1)	57 (26.6)	227 (29.9)	1.20(0.68–2.12)		
 70-79	206 (37.7)	71 (33.2)	277 (36.5)	0.99(0.56–1.76)		
 >80	72 (13.2)	63 (29.4)	135 (17.8)	2.44(1.31–4.53)		
Race/Ethnicity					0.051	
 Non-Hispanic White/Other	236 (43.2)	116 (54.2)	352 (46.3)	1.00 (ref)		
 Non-Hispanic Black	75 (13.7)	26 (12.2)	101 (13.3)	0.68(0.40–1.16)		
 Hispanic	120 (22.0)	35 (16.)	155 (20.4)	0.80(0.50–1.29)		
 Asian/PI	115 (21.1)	37 (17.3)	152 (20.0)	1.04(0.64–1.69)		
Smoking Status, 1 year prior/at index					<0.001	
 Current smoker	67 (12.3)	30 (14)	85 (11.2)	1.65(0.92–2.97)		
 Past smoker	287 (52.6)	128 (59.8)	386 (50.8)	1.57(1.00–2.44)		
 Never smoker	192 (35.2)	41 (19.2)	231 (30.4)	1.00 (ref)		
Elixhauser Comorbidity Group at Index					<0.001	
 0-2	131 (24)	27 (12.6)	158 (20.8)	1.00 (ref)		
 3-4	154 (28.2)	44 (20.6)	198 (26.1)	1.15(0.66–2.01)		
 5-6	148 (27.1)	58 (27.1)	206 (27.1)	1.46(0.84–2.54)		
 7+	113 (20.7)	85 (39.7)	198 (26.1)	2.50(1.43–4.37)		
Histology					0.139	
 Adenocarcinoma	341 (62.5)	117 (54.7)	458 (60.3)	1.00 (ref)		
 Squamous cell carcinoma	62 (11.4)	31 (14.5)	93 (12.2)	0.94(0.56–1.58)		
 Other	143 (26.2)	66 (30.8)	209 (27.5)	1.23(0.84–1.81)		
Driver Mutations						
 No	290 (53.1)	147 (68.7)	437 (57.5)	1.70(1.16–2.48)		
 Yes	256 (46.9)	67 (31.3)	323 (42.5)	1.00 (ref)	<0.001	
a Based on Chi-square or Fisher's Exact test.

3.5 Treated prior to NGS results (n = 284)

In the subgroup of 284 patients who initiated first line treatment prior to NGS results, 137 (48.2 %) were subsequently found to have a targetable mutation (Fig. 1), including 98 who had EGFR, ALK, or ROS mutations. Of these 137 patients, 81 (59.1 %) initiated first line treatment with chemotherapy and/or immunotherapy (including 44 who had an EGFR, ALK, or ROS mutation (Table 3)], and 56 (40.8 %) initiated first line treatment with an oral targeted tyrosine kinase inhibitor (TKI) (including 54 who had an EGFR, ALK, or ROS mutation).Table 3 Treatment initiation of patients relative to mutation status results.

Table 3Driver Mutation	Treated prior to NGS results	Treated after NGS results	No treatment after results	
IV	Oral	IV	Oral	
EGFR (ex 19, 20, 21)	31	50	6	56	21	
ALK fusion	11	4	1	8	2	
ROS-1 fusion	2	0	1	0	0	
BRAF	12	3	10	0	3	
KRAS p.G12C	17	0	26	0	28	
RET fusions	5	0	0	0	4	
MET ex 14 skipping/amplification	7	0	7	4	10	
Total patientsa	81	56	51	68	67	
a Some patients had multiple driver mutations (co-mutations).

Within this same subgroup of 284 patients who initiated first line treatment prior to NGS results, 147 (51.8 %) patients did not have a driver mutation based on NGS results. Of these 147 patients, 139 (94.6 %) initiated first line treatment with chemotherapy and/or immunotherapy and 8 (5.4 %) with an oral targeted TKI.

3.6 Treated after NGS results (n = 262)

In the subgroup of 262 patients who initiated first line treatment within 120 days after NGS results, 119 (45.4 %) were found to have a driver mutation by NGS (Fig. 1), including 72 who had an EGFR, ALK or ROS mutation. Of these 119 patients, 51 (42.9 %) initiated first line treatment with chemotherapy and/or immunotherapy [8 of whom had an EGFR, ALK, or ROS mutation (Table 3)], and 68 (57.1 %) initiated first line treatment with an oral targeted TKI.

Of the 72 patients with an EGFR, ALK, or ROS mutation, 64 (88.9 %) received an oral TKI (Table 3). Of the 143 patients who did not have targetable mutation, 139 (97.2 %) initiated first line treatment with chemotherapy and/or immunotherapy, while 4 (2.8 %) received an oral TKI.

3.7 Untreated patients (n = 214)

A subgroup of 214 (28.2 %) patients did not receive treatment up to 120 days after NGS results were reported. Within this subgroup, 67 (31.3 %) had a driver mutation on NGS (Fig. 1). Only 5.6 % of this subgroup received first line treatment with chemotherapy alone or in combination with immunotherapy after 120 days from NGS results being reported (none received targeted therapy).

4 Discussion

In this sample of patients with advanced NSCLC, all of whom had NGS ordered at the time of diagnosis, three-quarters received first line treatment with either a tyrosine kinase targeting a specific driver mutation or a non-targeted systemic therapy. Most (52 %) treated patients underwent first line treatment prior to NGS results becoming available, highlighting that clinicians often did not use NGS results, which might have contributed to the suboptimal care [17].

We recognize treatment prior to NGS results may have been influenced by either a patient's desire or the clinician's judgement for more timely initiation of first line therapy. Perhaps lengthy turnaround times for NGS results affected clinicians' decisions. To support this, we found that 41 % of patients with a driver mutation received targeted therapy before NGS results were obtained. Clinicians likely ordered a series of single gene mutation tests, or reflex single gene testing in parallel with NGS, because such results were available earlier than NGS results. An advantage to single gene testing is more timely turnaround times and time to treatment initiation with a tyrosine kinase inhibitor. Disadvantages include lower detection rates compared to NGS testing, increased tissue consumption, and additional costs incurred to healthcare systems [18,19] The mean time to NGS results in this study was 25 days which is in line with other commercially available NGS platforms during this period [20]. Moreover, clinicians were able to initiate treatment within 11 days from NGS results. Previous studies have reported that allocating time for pretreatment assessments is more beneficial to patients with advanced stage NSCLC than rushing treatment [21]. A 2020 survey done by ASCO targeting US oncologists indicated that TAT exceeding 2 weeks often results in empiric non-TKI therapy [22]. Improvements in tissue processing and verification of tissue integrity prior to NGS referral, NGS testing methodology, and alternatives to tissue NGS (e.g., liquid biopsies) may reduce the number of patients initiating treatment prior to molecular testing in the future.

We were surprised to find that 59 % of patients treated with chemotherapy and/or immunotherapy prior to NGS results, did in fact have a targetable mutation (as evidence by the NGS results). These patients may have been candidates to receive a targeted therapy in the first line. We recognize that during the study period targeted therapies may not have been commercially available for some of the alterations reported in this paper, and in particular, targeted therapies may not have been considered the recommended first line standard of care treatment. However, since 2018, EGFR or ALK targeted therapies have been considered the standard of care first line treatment for patients harboring these mutations [8]. Accounting for this, roughly a third of patients treated with non-targeted systemic therapy prior to NGS had an EGFR or ALK mutation. This illustrates that a substantial number of patients did not receive the first line treatment recommended by our health plan and NCCN guidelines.

Treatment decisions rely on upfront tissue molecular testing results identifying driver mutations in patient tumor samples. Therefore, patients treated after NGS results were obtained would be more likely to have received targeted therapy if a driver mutation was present. Indeed, most (57 %) patients treated after NGS results who had a driver mutation received oral targeted therapy, compared to just 41 % of those with a driver mutation who were treated prior to NGS results. Many patients (43 %) who initiated treatment after NGS results were found to have a driver mutation and yet did not receive a first line targeted therapy, however, only 6 % of these patients had EGFR or ALK mutations.

Over a quarter (28 %) of the sample did not receive treatment within 120 days following receipt of NGS results. This rate of non-treatment among patients with NSCLC is similar to rates published by other studies [23,24]. In our sample, older age, higher comorbidity index, smoking history, and lack of an identifiable driver mutation were correlated with no treatment. Among the untreated, were 67 patients (23 with EGFR, ALK or ROS1 variants) who had driver mutations. Even with evidence of lower functional status (e.g., higher comorbidity index, older age), these patients would have potentially benefited from targeted therapies that generally have lower toxicity, and better efficacy compared to immunotherapy and/or conventional chemotherapy. However, during our study period, our internal treatment pathways did not recommend oral therapy for patients with lower functional statuses harboring driver mutations.

Our study has certain limitations: It is possible that some patients who did not receive oral therapy despite having a driver mutation may have chosen to forgo treatment because they had metastatic disease or lower functional status, which were not captured in our study. This scenario reflects shared decision-making, as opposed to suboptimal treatment. Another limitation of our study is that it defines treatment as medical therapies and did not account for other forms of intervention such as surgery or radiotherapy, which could contribute to delays in timely initiation of targeted treatment.

A key strength of this study is that it is set in a large, vertically integrated care system in which insurance status is less likely to act as a barrier to accessing medical treatment within our cohort. This may not be true for other real-world settings, in which patients may face greater difficulty navigating coverage and care coordination, both of which further delay or even block timely guideline-adherent treatment.

5 Conclusion

Although NCCN guidelines recommend initiating treatment for NSCLC based on the tumor's molecular profile, and all patients in the study had NGS testing ordered at time of diagnosis, clinicians prescribed first line therapy prior to obtaining the NGS tests for just over half of treated patients. This finding illustrates the less-than-optimal use of NGS testing to inform first line treatment decisions for patients with advanced stage NSCLC in this health plan. Nearly half of those patients had a targetable driver mutation, but most did not receive a targeted therapy as their first line of treatment. Furthermore, during the study period, both health plan and NCCN guidelines recommended targeted therapy in one-third of those patients as their first line of treatment. Possible explanations include lengthy turnaround times for NGS testing and the availability of more timely, but less accurate, single gene testing. Strategies are needed to better maximize clinicians' use of NGS testing to guide treatment for NSCLC.

This project was reviewed and approved by the KPSC institutional review board. It was granted wavier of consent.

Funding

This work is supported by the 10.13039/100030924 Kaiser Permanente Southern California Care Improvement Research Team.

Data availability

The data used to create this work is not publicly available due to it being confidential data.

CRediT authorship contribution statement

Ahmed I. Megahed: Writing – review & editing, Writing – original draft, Visualization, Software, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Dominick Zheng: Writing – review & editing, Writing – original draft, Visualization, Project administration, Investigation. Lie Hong Chen: Writing – review & editing, Writing – original draft, Visualization, Validation, Software, Methodology, Formal analysis, Data curation. Reina Haque: Writing – review & editing, Writing – original draft, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. Eric C. McGary: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The authors thank the patients of Kaiser Permanente for helping to improve care with information collected through our electronic health record systems.
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