Clinical Impact of Comprehensive Genomic Profiling in Early-Stage Non–Small Cell Lung Cancer

There is a growing recognition that comprehensive genomic profiling can better inform treatment decisions for esNSCLC and help identify patients eligible for clinical trial enrollment. Unfortunately, a significant proportion of patients with newly diagnosed esNSCLC do not undergo any molecular testing or are assessed for only one or a few alterations and thus may fail to receive the most appropriate therapy, resulting in suboptimal outcomes.8

The advent of genomic profiling and use of targeted agents against specific driver mutations or other alterations has improved outcomes and prolonged survival for many patients with advanced (stage IIIB–IV) non–small cell lung cancer (aNSCLC).1-4 Patients whose tumors bear oncogenic driver mutations may be eligible to receive a corresponding approved targeted therapeutic agent.5-6 The use and efficacy of these agents depends on accurate and timely detection of actionable alterations, preferably by means of comprehensive genomic profiling (CGP) that uses next-generation sequencing to simultaneously analyze a large number of oncogenic genomic alterations and other key tumor biomarkers.7 This technique may also provide clinical benefit for patients with early-stage (stage I–IIIA) NSCLC (esNSCLC), as discussed below.

Given the demonstrated benefit of comprehensive genomic profiling to inform treatment selection in aNSCLC, the increasing number of rare targetable mutations identified in patients with esNSCLC, and the rising use of adjuvant and neoadjuvant biomarker-informed therapy (including approved adjuvant therapies targeting EGFR and ALK alterations), there is a growing recognition that CGP can better inform treatment decisions in the neoadjuvant, adjuvant, and perioperative (neoadjuvant and adjuvant) settings and help identify patients eligible for clinical trial enrollment. Unfortunately, a significant proportion of patients with newly diagnosed NSCLC do not undergo any molecular testing or are assessed for only one or a few alterations and thus may fail to receive the most appropriate therapy, resulting in suboptimal outcomes.8

Genomic Profiling in Early-Stage NSCLC

Use of CGP in esNSCLC is gaining acceptance since it can aid in detection, molecular characterization, and prognostic assessment, including risk of recurrence and metastasis.9 Targetable oncogenic driver mutations are not limited to advanced-stage disease and can also occur in esNSCLC (Figure 1), although the frequency of individual oncogenic alterations varies across baseline patient and disease characteristics.10 Identification of actionable oncogenic drivers in patients with esNSCLC can inform selection of adjuvant targeted therapy or ICI-based perioperative therapy in patients lacking such alterations, and aid in clinical trial enrollment.

Figure 1. Prevalence of Actionable Gene Alterations in Advanced- and Early-Stage NSCLC

Adapted from Bruno et al.10 Licensed under the Creative Commons Attribution 4.0 License: http://creativecommons.org/licenses/by/4.0/.
Abbreviations: NSCLC = non–small cell lung cancer.

Numerous trials have demonstrated the clinical benefit of biomarker-informed adjuvant and neoadjuvant therapy for esNSCLC, resulting in several FDA-approved indications. In the adjuvant setting, osimertinib is approved for EGFR-mutated NSCLC, and alectinib is indicated for ALK-positive disease.11,12 Atezolizumab is approved as adjuvant therapy for PD-L1–positive NSCLC, while nivolumab in combination with chemotherapy is indicated as neoadjuvant therapy.13,14 Additionally, pembrolizumab is approved as adjuvant therapy, and as neoadjuvant/perioperative therapy in combination with platinum-based chemotherapy.15 Preliminary clinical data suggest that some tyrosine kinase inhibitors may also be effective in the neoadjuvant setting for patients whose tumors bear EGFR mutations or ALK/ROS1 fusions.16-18

CGP could help to identify genomic alterations in patients with esNSCLC that could be targeted with agents proven to be effective in the metastatic setting, and may suggest use of other biomarker-directed therapies currently in clinical trials for early-stage disease. In one study, 37.0% of patients with esNSCLC had oncogenic driver mutations for which targeted therapies have been approved for aNSCLC, while another 48.5% showed at least one mutation or rearrangement in other genes for which no targeted treatment option existed at the time of publication (in 2022).19

In addition to using CGP to positively select patients with targetable genomic alterations, it can also aid in the “negative selection” of individuals who lack targetable oncogenic driver mutations and may instead be candidates for perioperative chemoimmunotherapy.20 Inappropriate use of ICI-based neoadjuvant therapy in patients whose tumors bear certain actionable driver mutations can result in suboptimal outcomes.21

Umbrella clinical trials such as NAUTIKA1, LEADER, and ALCHEMIST have previously studied or are now evaluating how CGP can be applied to assess the frequency of actionable alterations in esNSCLC and better guide selection of biomarker-informed neoadjuvant or adjuvant therapy.22-26 Other adjuvant and neoadjuvant trials are evaluating agents targeting individual biomarkers for esNSCLC, following their prior approvals for treatment of advanced or metastatic disease.

CGP vs Single-Gene or Multi-Gene Panel Genomic Testing

Use of CGP (where available) is generally preferred over single- or multi-gene panel analysis since it has greater sensitivity and can simultaneously screen for multiple therapeutically relevant alterations.7,27,28 CGP is better able to detect less common actionable oncogenic alterations such as NTRK, RET, and ROS1 fusions as well as uncommon variants of regularly assessed oncogenic drivers that single-gene tests may miss.29-31 CGP can obviate the need for additional molecular testing and/or rebiopsy, thus preserving biopsy material and supporting tissue stewardship for any future biomarker testing that might be required (eg, for use of antibody-drug conjugates) or for determining enrollment in a clinical trial.32 Conversely, prior single-gene testing may consume limited tissue specimens, prolong CGP turnaround time, reduce the ability of CGP to detect therapeutically relevant genomic variants, and result in CGP failures. According to Martin Dietrich, MD, PhD, of The US Oncology Network, CGP can also inform decision-making regarding patient enrollment in biomarker-driven trials.33,34 “By testing comprehensively, we not only unlock today’s opportunities, but future opportunities. Because clinical trials increasingly depend on the availability of genomic information, I think this would be a major incentive to have patients tested comprehensively so we can offer them the full spectrum of opportunities,” he said.

By testing comprehensively, we not only unlock today’s opportunities, but future opportunities. MARTIN DIETRICH, MD, PhD

In addition to mutations like EGFR and ALK for which approved targeted adjuvant therapies are available, clinicians should consider CGP for detection of other actionable alterations (eg, KRAS, ERBB2, RET, ROS1, NTRK1/2/3) that could have prognostic value and inform selection of perioperative therapy.35 While many inhibitors are not yet approved as neoadjuvant therapy, agents that can block these targets in the perioperative setting are available or under investigation.36-38 Evaluation of other biomarkers such as PD-L1 status should also be considered for patients lacking driver alterations since they may be candidates for immunotherapy.

In my practice, if you have NSCLC and are considered for systemic therapy, CGP is a mandatory step. MARTIN DIETRICH, MD, PhD

CGP Timing

Timing of receipt of CGP results can have a major impact on esNSCLC treatment decisions. Prolonged turnaround time might result in delayed diagnosis or use of inappropriate (neo)adjuvant therapy, which may lead to poorer outcomes.21,39,40 In patients with aNSCLC and actionable driver mutations, starting therapy prior to receipt of molecular test results is associated with significantly worse survival.41,42 Timely biomarker testing can increase use of matched therapy in this setting and decrease risk for death, and may reduce inappropriate use of ICIs in patients with actionable driver mutations.43,44 Consequently, similar to the “test-wait-treat” approach in aNSCLC,42 patients with esNSCLC should undergo upfront molecular profiling, with a treatment plan developed only after biomarker testing results are received. Dr. Dietrich favors use of CGP regardless of tumor stage or histology. “In my practice, if you have NSCLC and are considered for systemic therapy, CGP is a mandatory step,” he emphasized.

Soo-Ryum Yang, MD, of the Memorial Sloan Kettering Cancer Center, supports this approach. “Because CGP is very comprehensive, you’re evaluating not only guideline-recommended biomarkers (EGFR and ALK) but also some of the less common oncogenic drivers such as ROS1 and RET fusions. These results could be helpful in clinical decision-making, and also for enrollment in clinical trials of neoadjuvant and adjuvant therapies,” he noted.

Because CGP is very comprehensive, you’re evaluating not only guideline-recommended biomarkers but also some of the less common oncogenic drivers. These results could be helpful in clinical decision-making, and also for enrollment in clinical trials of neoadjuvant and adjuvant therapies. SOO-RYUM YANG, MD

Barriers to Use of CGP in esNSCLC

While CGP in esNSCLC is increasing, several barriers to its regular use still exist. Biomarker testing may not be routinely ordered, and remaining tumor tissue may be insufficient.45 Limited clinician knowledge and experience with CGP and inadequate patient insurance coverage may also affect its use.40 According to Dr. Yang, turnaround time can be a significant barrier since protracted test results may delay initiation of perioperative therapy where timely treatment is critical. However, “newer, more rapid CGP assays that can provide answers in a matter of days, not weeks, have been very helpful in facilitating clinical decision-making,” he noted.

The NCCN Clinical Practice Guidelines in Oncology do not specifically endorse CGP for esNSCLC but do indicate it is the preferred testing methodology for NSCLC in general.5 Although to date only two biomarkers have been identified that can inform the use of adjuvant and neoadjuvant therapy for esNSCLC, additional biomarkers and emerging targeted agents are likely in the near future. The increasing use of biomarker-informed therapies suggests that CGP may soon become the most pragmatic approach for guiding such treatment decisions.46

We should encourage oncologists, surgeons, pathologists, and other providers on the multidisciplinary team to consider CGP for early-stage NSCLC, where possible… so that we can provide the most optimal neoadjuvant and adjuvant-based therapy. SOO-RYUM YANG, MD

Conclusion

Emerging evidence suggests that early CGP testing can improve outcomes for patients with esNSCLC, particularly those who may receive biomarker-informed adjuvant or neoadjuvant therapy. Prompt receipt of CGP results will allow for more complete analysis of molecular alterations present and can guide selection of perioperative systemic therapy. “We should encourage oncologists, surgeons, pathologists, and other providers on the multidisciplinary team to consider CGP for early-stage NSCLC, where possible, to ensure that our patients are getting the most comprehensive level of information, so that we can provide the most optimal neoadjuvant and adjuvant-based therapy,” Dr. Yang stressed. Additional education of providers and patients regarding the need for and clinical utility of biomarker testing in esNSCLC could also be helpful.

Disclosure

Dr. Dietrich reported honoraria from Amgen, AstraZeneca, Bayer, Blueprint, Bristol Myers Squibb Foundation, Caris Life Sciences, Daiichi Sankyo, Eli Lilly & Co, EMD Serono/Merck, Epizyme, Foundation Medicine, G1 Therapeutics, Genentech, Gilead Sciences, Janssen, Mirati Therapeutics, Myriad, Novartis, Pfizer, Puma Biotechnology, Regeneron, Sanofi, Stemline Therapeutics, and Takeda; a consulting or advisory role with Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, Caris Life Sciences, Daiichi Sankyo, Eli Lilly & Co, EMD Serono/Merck, Epizyme, Foundation Medicine, G1 Therapeutics, Genentech, Gilead Sciences, Janssen Oncology, Mirati Therapeutics, Myriad Genetics, Novartis, Pfizer, Puma Biotechnology, Regeneron, Sanofi, Stemline Therapeutics, and Takeda; speakers’ bureau participation with Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, Caris Life Sciences, Daiichi Sankyo, Eli Lilly & Co, EMD Serono, Epizyme, Foundation Medicine, G1 Therapeutics, Genentech, Gilead Sciences, Janssen Oncology, Mirati Therapeutics, Myriad Genetics, Novartis, Pfizer, Puma Biotechnology, Regeneron, Sanofi, Stemline Therapeutics, and Takeda; and travel, accommodations, and expenses from Amgen, AstraZeneca, Blueprint Medicines, Bayer, Bristol Myers Squibb Foundation, Caris Life Sciences, Daiichi Sankyo, Eli Lilly & Co, EMD Serono, Epizyme, Foundation Medicine, G1 Therapeutics, Genentech, Gilead Sciences, Janssen Oncology, Mirati Therapeutics, Myriad Genetics, Novartis, Pfizer, Puma Biotechnology, Regeneron, Sanofi, Stemline Therapeutics, and Takeda.

Dr. Yang reported honoraria from Medscape, OncLive/MJH Life Sciences, Medical Learning Institute, AstraZeneca, and Roche; a consulting or advisory role with AstraZeneca, AbbVie, Merus, Sanofi, and Amgen; and uncompensated relationships with Loxo/Lilly and Boehringer Ingelheim.

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