Early-Stage Lung Cancer: Assessment and Treatment

Introduction

Lung cancer is the third most common cancer and the leading cause of cancer-related death in the United States. 

Incidence

Lung cancer is categorized into small cell lung cancer (SCLC) comprising 15% of cases and non-small cell lung cancer (NSCLC) accounting for the remaining 85%.

• 30-40% of SCLC patients will be diagnosed as limited stage disease.
• Approximately, 16-20% of NSCLC patients are diagnosed with early-stage disease, T1-2, N0 and 30% with locally advanced stage III.
• Advances in diagnostics, including the introduction of low-dose computed tomographic (CT) screening algorithms, in combination with increased implementation of early lung cancer screening guidelines is continuing to increase the percent of patients diagnosed in earlier stages.

Diagnosis

Two of the main causes of high mortality rate observed with lung cancer are late stage of diagnosis (85% often diagnosed with locally advanced or metastatic stage) and biological phenotype of the cancer for those patients who have undergone radical surgical resection.

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Biomarker Assessment

Research has shown the presence of oncogenic driver mutations, like Epidermal growth factor receptor (EGFR) and Anaplastic lymphoma kinase (ALK), can have profound effects on NSCLC patient’s response to therapy and should be assessed prior to initiating any treatment plan. While biomarker assessment has been proven critical in advanced stage disease, the move to early-stage setting is slower to adoption in clinical decision making. Biomarkers hold the potential to play key role in clinical decision making including nodule characterization, prognosis, optimal treatment options and monitoring for recurrence.

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PD-1/L1 and CTLA-4 Levels:

Immunotherapy has proven effective in certain patients; however, similar results are not seen in those patients harboring oncogenic driver mutations.

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Outcomes

Lung cancer patient outcomes are closely correlated with the stage of disease at diagnosis with advanced stages being associated with the poorest outcomes. Lung cancer spreads quickly, highlighting the importance of diagnosis and treatment at earlier stages in the disease. The 5-year survival for a patient with localized lung or bronchus cancer is 60%, however, this drops significantly to 6.3% with advanced, metastatic stage.

Even when treated with curative intent, a high disease recurrence rate is still observed in early stages. More than 30-60% of patients stage IB-IIIA will experience recurrence with metastatic disease after surgical resection. Adjuvant chemotherapy has shown modest, but significant, improvements in 5-year survival ranging from 1-15%. The high rate of recurrence is potentially due to the presence of micrometastasis that are below the detection level threshold of current imaging techniques.

Treatment

Treatment for early-stage lung cancer is focused on curative intent as patient outcomes are the highest at this stage of disease.

• The standard of care for early-stage resectable disease is surgical intervention typically via lobectomy, bilobectomy, pneumonectomy, or video-assisted thoracic surgery (VATS).
• After surgery the risk of recurrence is significant. Approximately 40-50% of stage IB and 55-70% of stage II patients experience recurrent disease.
• For those patients who opt out of surgery or are deemed medically unfit for surgical intervention due to comorbidities, standard of care includes stereotactic body radiotherapy (SBRT) and chemo-radiotherapy (CRT).
• SBRT: Non-invasive, high precision irradiation technique that provides ablative doses to lesion. It requires a reduced number of sessions with higher efficacy compared to standard radiation therapy (RT). SBRT in early-stage NSCLC has shown a benefit with reported two-year overall survival rates of 65-70% and 30-65% at five years.
• CRT: CRT is the standard of care for medically inoperable stage II NSCLC that are not suitable for SBRT.

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Standard Adjuvant Treatment Options

Patients diagnosed with resectable early-stage NSCLC receive adjuvant chemotherapy as the mainstay treatment regimen to reduce the risk of recurrence and improve outcomes. Adjuvant radiotherapy is not recommended for stage I and II NSCLC due to increased mortality risk. However, recent clinical trials have highlighted the benefits of immunotherapy and targeted therapy in early-stage lung cancer patients. To optimize outcomes, clinicians must assess the risk level of recurrence post-surgical intervention to prescribe the best therapy while minimizing potential adverse side effects and toxicity of current therapies.

Stage IA

Research has shown stage IA patients do not benefit from adjuvant chemotherapy, with a potential decrease in survival observed in some studies.

Stage IB

While adjuvant chemotherapy is used in stage IB disease, it remains controversial and is usually only recommended for high-risk patients.

• Lack of definitive evidence exists that there is a survival benefit in these patients.

Stage II-III

Patients who have been completely resected are typically given adjuvant systemic therapy with cisplatin-based regimens.

• Cisplatin is often given in a doublet with vinorelbine, gemcitabine, docetaxel, etoposide, or pemetrexed.
• Research has shown a 4-5% 5-year survival benefit with adjuvant cisplatin-based therapy.
• LACE Meta-Analysis showed while adjuvant chemotherapy did show modest improvements in 5-year overall survival, it varied by stage and benefits were mainly observed in stage II and III patients.

Adjuvant Radiation

Currently, RT is reserved for patients with early-stage disease who undergo incomplete resections. A lack of scientific evidence exists showing benefit in patients with a complete resection.

Personalized Adjuvant Therapy

While treatment of advanced NSCLC has evolved to include targeted therapy and immunotherapy, these treatment options are still new to early-stage disease. Assessment of molecular markers in patients with early-stage NSCLC are being investigated to better understand the risk of recurrence after resection in this patient population and who may benefit from adjuvant targeted therapy or immunotherapy.

Targeted Therapy

Early studies of targeted therapy utilizing EGFR tyrosine kinase inhibitors (TKIs) in unselected stage IB-IIIA NSCLC did not result in survival benefit. However, after the success of targeted therapy in the advanced setting, more recent studies have focused on utilization of TKIs for early-stage NSCLC patients harboring specific oncogenic mutations.

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• Adjuvant erlotinib (1^st generation EGFR TKI) :Phase II SELECT trial was the first to test the efficacy of adjuvant erlotinib for two years post- adjuvant chemotherapy +/- radiotherapy in resected EGFR-mutated stage IA-IIIA NSCLC.
• Two-year disease-free survival (DFS) of 88% was observed compared to 76% with historical controls.
• Adjuvant osimertinib (3^rd generation EGFR TKI): Osimertinib was the first adjuvant targeted therapy approved by the FDA in 2020 for patients with resectable EGFR exon 19del or L858 mutation positive NSCLC with or without adjuvant chemotherapy based on the results of ADAURA study.
• The ADAURA study investigated adjuvant osimertinib therapy versus placebo with or without adjuvant chemotherapy in primary non-squamous resectable EGFR exon 19del or L858 mutated NSCLC. Patients were treated with osimertinib or placebo for up to three years or disease recurrence or discontinuation criteria were met.
• A significant benefit of 89% DFS was shown at 24 months in those treated with osimertinib compared to 52% with placebo.
• The benefit to DFS was seen regardless of adjuvant chemotherapy or disease stage.
• Updated data demonstrated three-year DFS of 85% compared to 44% in placebo. In addition, a benefit for central nervous system (CNS) DFS was observed with osimertinib compared to placebo.
• Additional ongoing trials are assessing EGFR and ALK TKIs in the adjuvant setting. EGFR mutations are estimated to comprise up to 15% and ALK rearrangements less than 5% of early-stage NSCLC Caucasian patients. Other driver mutations are estimated to be more rare in early-stage disease and thus have not been the main focus of targeted therapy clinical trials in early-stage disease, at this time.

Immunotherapy

If no driver mutations are identified, immunotherapy is another treatment option utilized in advanced stages that has recently emerged in the early-stage setting. Two immunotherapies are FDA approved in the adjuvant setting and one is approved in the neoadjuvant setting. Research and clinical trials have shown immunotherapy in early-stage disease provides benefit in prevention of post-operative recurrence and improvement in survival outcomes.

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• Durvalumab (anti-PD-L1 immune check point inhibitor): Durvalumab was approved by the FDA in 2021 for patients with stage III unresectable NSCLC after concurrent chemoradiation based on the PACIFIC trial. This regimen has become the standard of care for patients with unresectable, stage III NSCLC post-CRT.
• PACIFIC trial compared durvalumab versus placebo in patients with unresectable, stage III NSCLC post concurrent chemoradiation with no disease progression. Initial analysis showed durvalumab significantly prolonged progression free survival (PFS) with a median duration of 16.8 months compared to 5.6 months with placebo. Updated 5-year overall survival (OS) analysis demonstrated 42.9% with durvalumab compared to 33.4% with placebo and 33.1% versus 19.0% for PFS.
• Adjuvant atezolizumab (anti-PD-L1 immune check point inhibitor): Atezolizumab was approved by the FDA in 2021 for adjuvant therapy following resection and platinum-based chemotherapy in stage II-IIIA NSCLC patients with PD-L1 expression of >1% based on the Impower010 trial.
• Impower010 was the first major study to demonstrate benefit of immunotherapy in the adjuvant setting. This study assessed adjuvant atezolizumab in resected stage IB-IIIA NSCLC patients for one year versus observation post-standard adjuvant chemotherapy. Superior DFS was observed with adjuvant atezolizumab independent of D-L1 expression, with greatest benefit seen in patients with PD-L1 >50%, compared to best supportive care.
• Adjuvant pembrolizumab (anti-PD-1 immune check point inhibitor): Pembrolizumab is under consideration by the FDA for approval for adjuvant treatment of completely resected patients with stage IB-IIIA NSCLC based on the PEARLS/KEYNOTE-091 trial.
• PEARLS/KEYNOTE-091 study assessed adjuvant pembrolizumab for one year compared to placebo in resected stage IB-IIIA NSCLC after standard CT, regardless of PD-L1 expression. Interim analysis demonstrated median DFS of 53.6 months with pembrolizumab compared to 42.0 months with placebo independent of PD-L1 expression.

Neoadjuvant Therapy

Preoperative therapy offers resectable NSCLC patients the opportunity for downstaging of the tumor prior to surgery, earlier elimination of micrometastases (small number of cancer cells that have spread from the original tumor to other areas of the body but are yet to be detectable by screening) and reduction in the risk of recurrence.

A large meta-analysis consisting of 15 trials showed neoadjuvant chemotherapy in stage I-III NSCLC followed by surgery statistically improved OS, time to distant recurrence and recurrence-free survival compared to surgery alone.

• Estimated 13-18% reduction in relative risk of death demonstrated with neoadjuvant chemotherapy and surgery alone resulting in 5-year OS benefit of 5-6% across stages.
• The major limitation associated with neoadjuvant chemotherapy is the risk of delay in time to surgery resulting from patients requiring additional time to recover from adverse events related to the treatment.

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Personalized Neoadjuvant Therapy

Targeted Therapy

Currently, there are no FDA approved targeted therapies in the neoadjuvant setting for early-stage NSCLC. However, there are several ongoing clinical trials assessing TKIs in the neoadjuvant setting including:

• Neoadjuvant osimertinib:
• NEOS is a multi-center, single arm study evaluating neoadjuvant osimertinib in stage I-IIIA EGFR del19 and L858R mutation positive NSCLC for six weeks prior to surgical resection. Current analysis showed an objective response rate (ORR) of 71.1% (27/38 patients) with 93.8% (30/32 resected patients) achieving R0 resection. Treatment-related adverse events were observed in 60% of patients during neoadjuvant therapy, however, no adverse events led to discontinuation of neoadjuvant treatment.
• NEOADAURA trial is assessing neoadjuvant osimertinib in stage II-IIIB resectable EGFR mutation positive NSCLC compared to osmimertinib plus chemotherapy and chemotherapy alone. Study results are ongoing.
• Neoadjuvant/adjuvant erlotinib:
• EMERGING-CTONG1103 trial assessed neoadjuvant/adjuvant erlotinib versus chemotherapy (gemcitabine plus cisplatin) in stage IIIA-N2 EGFR mutation positive NSCLC. Neoadjuvant therapy consisted of 6 weeks erlotinib or two cycles of chemotherapy followed by surgery and erlotinib for 12 months or progression or toxicity compared to chemotherapy for two cycles. The primary endpoint of ORR was not met, but a significant improvement was seen in PFS of 21.5 months with erlotinib compared to 11.4 months with chemotherapy.

Immunotherapy

Currently there is only one FDA approved immunotherapy in the neoadjuvant setting for resectable NSCLC. Additional ongoing trials have shown positive data with utilization of immune checkpoint inhibitors prior to surgical resection.

• Neoadjuvant Nivolumab: Nivolumab was approved by the FDA in 2022 as neoadjuvant therapy with platinum-doublet chemotherapy for resectable stage IB-IIIA NSCLC based on the CheckMate-816 study.
• CheckMate-816 trial investigated neoadjuvant nivolumab plus platinum-doublet chemotherapy compared to platinum-doublet chemotherapy alone in newly diagnosed resectable stage IB-IIIA NSCLC with no known EGFR or ALK mutations and optional adjuvant therapy following resection. Median event-free survival was shown to be 31.6 months with nivolumab plus chemotherapy compared to 20.8 months in chemotherapy alone. Additionally, pathological complete response (pCR) rate was 24% with the combination compared to 2.2% with chemotherapy alone. Addition of neoadjuvant nivolumab did not cause frequent delay or cancellations in surgery.
• NADIM II trial assessed adjuvant nivolumab plus chemotherapy compared to chemotherapy alone for three cycles followed by surgery in resectable clinical stage IIIA NSCLC patients. Patients with R0 resection received adjuvant nivolumab for six months. Combination neoadjuvant nivolumab plus chemotherapy resulted in pCR rate of 36.2% compared to 6.8% with neoadjuvant chemotherapy alone.