Treatment of Stage I - III Non-Small Cell Lung Cancer

by Dr. C.H. Weaver M.D. Medical Editor

Most stage I-III non-small cell lung cancers (NSCLC) are considered surgically resectable and should be treated with a combination of surgery and systemic chemotherapy, immunotherapy and/or precision cancer medicines. For effective treatment planning it is essential that molecular testing consisting of next generation sequencing (NGS) of ROS, ALK, EGFR, and PDL-1 biomarker testing be performed on the initial biopsy or surgically resected cancer. 

A blood based "liquid biopsy" can be used, but the combination of blood and tissue produces the best results. Recent clinical trial results suggest that systemic treatment with chemo-immunotherapy BEFORE surgical removal of the cancer may is more beneficial than treatment after surgery and a combination of pre and post operative therapy may produce the best outcomes overall.^29,30,31 All newly diagnosed patients should discuss the role of pre-surgical "neoadjuvant" therapy and ensure NGS-biomarker testing is performed as soon as possible.

Stage I cancers are located in only one lung and have not spread to the adjacent lymph nodes or outside the chest - surgical removal of the cancer results in over 60% of patients surviving without evidence of cancer recurrence within 5 years of treatment and some but not all patients with stage I disease can benefit from systemic therapy. 

Stage II and III cancers are more widely spread within but not outside the lungs. They are both treated with surgery combined with systemic therapy. While some early stage cancers can be treated with surgery followed by systemic (adjuvant) therapy, both stage II and III cancers may best be managed by combined systemic therapy BEFORE (neoadjuvant) and after (adjuvant) surgery.^29-31  Results of genomic-biomarker testing are essential for determining which systemic therapy should be used.^1,2,9,10

Precision Cancer Medicines & Immunotherapy

By performing genomic-biomarker testing on a biopsy of the cancer and/or from a blood sample doctors are able to define the genomic alterations in a cancers DNA that is driving the growth of that specific cancer. Once a genetic abnormality is identified, a precision medicine can be selected to target the specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities.

Surgery

For patients with NSCLC that is limited to the chest surgical resection is not only an important therapeutic modality, but in many cases, an effective method of controlling the disease. Patients with stages I-IIIA localized cancer are considered to have early stage disease and are almost always treated with surgery. The most recent clinical trial results increasingly support starting systemic treatment before surgery.

Surgical removal of the cancer may be accomplished by removing the entire lung (pneumonectomy), a lobe of the lung (lobectomy) or even a small segment of the lung (segmentectomy). In general, the less lung that is removed, the greater the preservation of lung function and the lower the risk of major side effects from the surgery. On the other hand, if too little lung is removed, there is an increased chance of a local cancer recurrence. Currently, most physicians recommend a lobectomy. A patient’s general overall condition, age and location of the cancer are all factors that may influence the type of surgery performed and the side effects associated with the surgery. 

• Learn more about surgery and lung cancer.

Systemic Therapy: Precision Cancer Medicine, Chemotherapy, and Immunotherapy

Systemic therapy is any treatment directed at destroying cancer cells throughout the body. Because most NSCLC patients with early stage cancer already have small amounts of undetectable cancer that have spread outside the lungs these cancer cells cannot be treated effectively with surgery alone.  Their eradication requires systemic treatment to decrease the chance of cancer recurrence. Systemic therapy can be administered before or after surgery. Most recently study results suggest that perioperative therapy (before and after) may produce the best outcomes.^29-31

The use of adjuvant cisplatin-based chemotherapy for approximately 4 cycles was a standard of care for more than a decade,^1,6 and is associated with an approximate 5% improvement in overall survival compared to treatment with surgery alone. The development of specific precision cancer medicines and immunotherapy have significantly improved upon these results. 

EGFR positive NSCLC

Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have epidermal growth factor receptor - mutated (EGFRm) NSCLC. These patients are particularly sensitive to treatment with precision cancer medicines known as EGFR-tyrosine kinase inhibitors (TKIs) which block the cell-signaling pathways that drive the growth of EGFR expressing lung cancer cells. 

Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI designed to inhibit both EGFR-sensitizing and EGFR T790M-resistance mutations, with clinical activity against cancer in the brain. In the Phase III ADAURA clinical trial Tagrisso treatment following surgical removal of the cancer is the standard of care.  Tagrisso when compared to placebo as adjuvant therapy in patients with stage IB, II and IIIA EGFRm NSCLC delays cancer progression and prolongs overall survival. Overall Tagrisso improved 5 year survival rates from 78% to 88%.

5 Year Survival for Tagrisso Compared to Placebo

• Stage IB   94% vs 88%
• Stage II    85% vs 78%
• Stage IIIA 85% vs 67%

Individuals with stage IA cancer may have high risk features and should discuss whether Tagrisso may be of benefit with their treating physician.

ALK positive NSCLC

Patients with ALK mutated NSCLC also benefit from initial treatment with the precision cancer medicine Alecensa. 

The ALINA clinical trial demonstrated that adjuvant treatment with Alecensa improved 3 year cancer free survival rates from 54% to 80%.

Immunotherapy in Individuals without cancer driving mutations:

Precision immunotherapy treatment of early stage NSCLC can reduce the risk of cancer recurrence and improve survival in patients without ALK or EGFR mutations and has become a standard treatment. PD-1 and PD-L1 are proteins that inhibit certain immune responses, allowing cancer cells to evade detection and attack by immune cells in the body.  Checkpoint inhibitor immunotherapy drugs can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the cancer cells. A diagnostic test to measure the level of PD-L1 is available and in general the higher the percentage of PD-L1 expressing cells, the more effective is immunotherapy. 

Combinations of chemotherapy with Tecentriq (atezolizumab), Keytruda (pembrolizumab), Opdivo (nivoluimab) and Imfinzi (durvalumab) checkpoint inhibitors have all been shown to delay cancer recurrence when used in combination with chemotherapy for treatment of early stage NSCLC.^19,20,29-31

What do the Trials Show?

The first clinical trials showed that systemic chemo-immunotherapy administered after (adjuvant) surgery improved outcomes. Subsequent clinical trials demonstrated that chemo-immunotherapy BEFORE surgery (neoadjuvant) appeared even more effective that adjuvant therapy and the most recent data suggest that combined neoadjuvant and adjuvant therapy may produce the best outcomes.  In the phase 3 Aegean trial the combination of Imfinzi and chemotherapy before surgery, followed by Imfinzi after surgery delayed cancer progression and improved survival for individuals with stage 2A to 3B NSCLC. Other trials of perioperative combinations of chemotherapy and immunotherapy shown similar benefit.^29-31

Adjuvant Immunotherapy for  early-stage NSCLC

Immunotherapy treatment for early stage NSCLC is a standard of care, especially for individuals with higher levels of PDL-1. All patients unable to receive perioperative chemo-immunotherapy should discuss the role of adjuvant immunotherapy with their surgeon and make sure their surgeon tests their cancer for PDL-1 and has NGS testing performed. Studies have demonstrated that adjuvant chemo-immunotherapy can prolong cancer free survival following surgery resection of early stage NSCLC.^18,19,27

Neoadjuvant Therapy 

Administering systemic treatment before surgery may be beneficial because it can reach the cancer before surgery has disrupted its blood supply and potentially shrink the cancer for easier surgical removal. Systemic treatment administered before surgery is referred to as neoadjuvant therapy.

The FDA approved neoadjuvant Opdivo immunotherapy combined with platinum-doublet chemotherapy for treatment off adult patients with surgically resectable NSCLC in 2022.^20-22  The CheckMate-816 clinical trial found that neoadjuvant Opdivo in combination with chemotherapy increases the number of patients with complete disappearance of their cancer from 2.2% to 24% without negatively impacting a patients ability to undergo timely surgery.¹⁷  Opdivo plus chemotherapy improved average survival without recurrence to 32 months compared with 21 months for treatment with chemotherapy alone.^17,19-24

Peri-Operative Therapy

Results from recent clinical trials directly comparing treatment strategies of neoadjuvant platinum-based chemo-immunotherapy combined with post-surgical immunotherapy maintenance to treatment with neoadjuvant chemotherapy alone appear to favor the combined neoadjuvant-adjuvant treatment approach.^29-31

The addition of peri-operative Imfinzi immunotherapy to neoadjuvant chemotherapy improves pathological complete response (pCR) rates and prolongs cancer free survival in patients with stage IB to III NSCLC, according to findings from the phase 3 AEGEAN clinical trial.

The AEGEAN clinical trial directly compared a treatment strategy of neoadjuvant Imfinzi + platinum-based chemotherapy and post-surgical Imfinzi maintenance to treatment with neoadjuvant chemotherapy alone in 802 patients. The initial trial results were released at the September 2023 World Lung Meetings.⁹

• Imfiniz improved the pCR rate from 4.3% to 17.2% leading to a modest improvement in R0 resection rates.
• The 12- and 24-month survival rates without cancer progression were in favor of Imfinzi-Overall survival data is still immature.

Neoadjuvant (preoperative) treatment with Opdivo plus chemotherapy followed by surgery and adjuvant Opdivo also improves the duration of cancer free survival when used as initial treatment for early-stage stage II to IIIB NSCLC

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Pancreatic Cancer Treatment

Zenocutuzumab - the first approved systemic therapy for patients with NRG1 fusion–positive NSCLC or pancreatic adenocarcinoma.

Zenocutuzumab targeted therapy approved for treatment of pancreatic ductal adenocarcinoma and non-small cell lung cancer with NRG1 fusions.

By Dr. C.H. Weaver M.D.Dec 5, 2024

Lung Cancer Treatment

Immunotherapy After Chemoradiotherapy Promising in Limited-Stage Small Cell Lung Cancer

Adjuvant therapy with Imfinzi (durvalumab) significantly improved survival outcomes for patients with limited-stage SCLC

By Dr. C.H. Weaver M.D.Nov 29, 2024

Breast Cancer Treatment

Breakthrough in Understanding Tamoxifen's Effectiveness in Breast Cancer: Gut Bacteria Play a Crucial Role

Since tamoxifen is taken orally and travels through the digestive system, variations in patient responses may be connected to the gut microbiome—the trillions of bacteria in our intestines that differ significantly from one person to another.

By Dr. C.H. Weaver M.D.Nov 26, 2024

In the trial 461 patients with stage IIA to IIIB previously untreated NSCLC, and no EGFR or known ALK alterations were treated with

• Odivo plus chemotherapy followed by surgery within 6 weeks followed by Opdivo administered 4 weeks for 1 OR
• Chemotherapy alone followed by surgery within 6 weeks and no additional post surgery treatment.

Neoadjuvant Opdivo produced a complete disappearance of cancer (pathologic complete remission pCR) assessed at the time of surgery in 25% of patients compared to only 5% of chemotherapy treated patients.

After a median follow-up of 25.4 months patients treated with perioperative Opdivo demonstrated a clinically meaningful improvement in their survival duration without cancer recurrence. Stage III patients treated with Opdivo survived 30.2 months on average without cancer recurrence compared to only 13.4 months if treated with chemotherapy alone. Similar results were reported for stage II disease but longer follow up is required. For all patients the 18-month cancer free survival rates were improved from 50% to 70% with the addition of perioperative Opdivo. 

Stage IIIB NSCLC

Historically the standard treatment for patients with surgically unresectable stage IIIA NSCLC was a treatment combination of platinum-based chemotherapy and radiation producing a 5 year survival rate of around 15%.^23,24

Based on encouraging results in stage IIIB NSCLC researchers evaluated a combination of targeted radiation therapy with immunotherapy in the PACIFIC clinical trial for individuals unable or unwilling to undergo surgery.

The Phase 3 Pacific clinical trial determined that the addition of Immunotherapy with Imfinzi (durvalumab) in patients with unresectable stage III NSCLC further improved patient survival. In the trial patients were initially treated with 2 or more cycles of platinum based chemoradiotherapy²⁵ and those with stable disease then received additional treatment with Imfinzi immunotherapy. ²⁶ Average survival duration was improved from 29 to 48 months with the addition of Imfinzi and the estimated 5-year survival rate increased to 43%.

The survival benefit for patients with unresectable stage III NSCLC harboring EGFR or ALK mutations with Imfinzi is unclear and further studies with target therapy is currently undergoing for this subgroup of patients.

Radiation Therapy

Some patients with lung cancer are not able to undergo surgery to remove their cancer. Advanced age and other medical conditions such as heart disease and diminished lung capacity make it more difficult for these patients to withstand surgery. For these patients, staging of their cancer may be relatively precise using newer scanning techniques, including positron emission tomography (PET) and they are often offered radiation therapy as treatment for their cancer.

Two studies have demonstrated that patients with early stage NSCLC who are not able to, or do not wish to undergo surgery may be treated with radiation therapy alone. One of these was an extensive review of the literature since the mid-1980’s and the other was a recently conducted clinical trial that evaluated the use of radiation administered twice-daily for approximately 5 weeks. Results indicated that radiation therapy alone produced an average survival time of over 30 and 34 months, respectively.^4,5

Treatment Follow-up

Although patients with NSCLC have a relatively high rate of long-term survival following treatment some patients are still at risk for developing a cancer recurrence, and others may still develop another lung cancer if lifestyle or other factors that increase their risk of developing cancer have not been changed. Researchers have been evaluating different screening methods and schedules for these patients in order to detect recurrent or second cancers early, when they are most treatable.

Researchers from the City of Hope National Medical Center recently determined that annual CT scans and chest x-rays three times per year may detect early second cancers in patients with previously treated NSCLC who appeared to be cured.⁸

Strategies to Improve NSCLC Treatment

Currently, there are several areas of active exploration aimed at improving the treatment of stage I - IIIA NSCLC which are mainly available in clinical trials. All individuals should undergoing genomic biomarker testing to see if their cancer has a "targetable" cancer driving mutation that can be treated with a precision cancer medicine.

Overcoming Resistance

There are currently several immunotherapy clinical trials that combine an established PD-1 or PD-L1 inhibitor with another drug designed to specifically overcome resistance with an emphasis on LAG-3 and TIGIT.²⁸

There are currently more than a dozen different LAG-3 inhibiting agents in development and just as many phase 3 studies that exploring anti-TIGIT therapy in combination with checkpoint inhibitors.

Precision Cancer Medicines

A targeted or precision therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Precision cancer medicines that “target” cancer cells offer the advantage of reduced treatment-related side effects and improved outcomes and have become standard treatment for more advanced NSCLC. Therapies directed at mutations in the epidermal growth factor receptor (EGFR) and the ALK gene have improved outcomes in the treatment of advanced NSCLC and are now being evaluated in stage I-IIIA disease.

• A clinical trial in 1000 early-stage lung cancer patients compared Keytruda immunotherapy to placebo and found that Keytruda reduced the risk of cancer recurrence or death by 24%. Data will be submitted to the FDA.

• ALCHEMIST- the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials – represents three integrated, precision medicine trials that are designed to identify people with early-stage lung cancer who have tumors that harbor EGFR and ALK gene alterations and evaluate whether drug treatments targeted against those molecular changes can lead to improved survival compared to current standard of care therapy alone.
• Epidermal growth factor receptor (EGFR): Mutations in the EGFR gene may affect how NSCLC responds to certain drugs. EGFR contributes to the growth of several types of cancer, and drugs that block the activity of EGFR can slow cancer growth. EGFR mutations are most common in people of Asian ethnicity, women, never-smokers, and those with a type of lung cancer known as adenocarcinoma. Researchers have reported that EFGR positive individuals treated with Tagrisso or Tarceva® plus chemotherapy have delayed time to cancer progression and improved survival compared to those treated with placebo or chemotherapy alone respectively.^9,10,16
• Anaplastic lymphoma kinase (ALK) gene: Up to 7% of NSCLC’s have an abnormal version of the ALK gene that contributes to the growth and development of cancer. Lung cancers with this abnormality typically occur in non-smokers. The abnormal gene contributes to the growth and development of cancer cells. Medicines have been developed that target the ALK gene mutation and produced very promising rates of response in more advanced cancers.^11,12

Cryotherapy: Cryotherapy is a technique that kills cancer cells by freezing them with sub-zero temperatures. During this procedure, hollow steel probes are placed inside and surrounding the cancer. Liquid nitrogen is then circulated through the probes, freezing the cancer cells and creating a ball of ice that surrounds the cancer. Once an adequate ice ball is formed, heated nitrogen is circulated through the probes. This process is then repeated.

Researchers from France conducted a clinical trial evaluating cryotherapy for the treatment of early stage lung cancer. Cryotherapy was performed through a rigid bronchoscope (a lighted tube that is placed into the bronchi). In this trial, 35 patients with early stage lung cancer received cryotherapy, 20% of whom had multiple locations of early stage lung cancer. One year following treatment, 91% of patients had a complete disappearance of cancer. Four years following treatment, only 10 patients experienced a local cancer recurrence. The treatment was well tolerated by these patients.¹⁵

Image-guided radiation therapy (IGRT): IGRT involves a computed tomography (CT) scanner and computer modeling to accurately determine the size and depth of the cancer. In addition, this technique determines the measurement of the cancer through all stages of respiration and can direct the radiation more precisely while the patient is breathing normally. Researchers from Japan recently concluded that IGRT appears to be an effective and well tolerated radiation technique for patients with inoperable stage I NSCLC with poor lung function. A distinct advantage of IGRT is that patients do not have to hold their breath during the treatment, which is necessary for standard radiation therapy. This is important because many patients with lung cancer have poor lung function and are not able to hold their breath during treatment.

Of the 21 patients with stage I NSCLC involved in this clinical trial, 5 experienced a complete disappearance of detectable cancer, 11 patients experienced at least a 50% reduction in the volume of their cancer, and one patient had progressive disease following therapy. Approximately two years following therapy, only 5 patients had experienced a cancer recurrence. The treatment was well tolerated with no major side effects reported. Further clinical trials will are necessary to determine the role of IGRT in the clinical setting and demonstrate whether chemotherapy prior to or following radiation therapy may further improve long-term outcomes.¹⁶

Adoptive Immunotherapy

Gut Microbiome: The NEOSTAR clinical trial tested the administration of Opdivo with or without Yervoy (ipilimumab), prior to surgery in 44 patients with with operable stage IA to IIIA NSCLC between June 2017 and November 2018. Overall, 41 patients completed the planned three doses of therapy prior to surgery. Eight of 21 treated patients (38%) achieved a pathological complete response following Opdivo-Yervoy compared to only 10%, treated with Yervoy alone.

The researchers analyzed the gut microbiome and found that pathologic response to combination therapy was associated with the presence of certain fecal microbes that also have been correlated with immunotherapy response in melanoma and other cancers.¹⁸

Next: Surgery for Non Small Cell Lung Cancer

Next: Radiation Therapy for Non Small Cell Lung Cancer

Next: Precision Cancer Medicine for Non Small Cell Lung Cancer

References:

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16. Tagrisso – First Precision Medicine Approved for Treatment of Early Stage NSCLC
17. Opdivo (nivolumab) Plus Chemotherapy Shows Statistically Significant Improvement in Pathologic Complete Response as Neoadjuvant Treatment of Resectable Non-Small Cell Lung Cancer in Phase 3 CheckMate-816 Trial [news release]. Princeton, NJ. Published October 7, 2020. Accessed October 7, 2020.

18. FDA approves atezolizumab as adjuvant treatment for non-small cell lung cancer. News release. October 15, 2021. Accessed October 15, 2021. https://bit.ly/3lHUgv

19. Wakelee HA, Altorki NK, Zhou C, et al. IMpower010: primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):8500. doi:10.1200/JCO.2021.39.15_suppl.8500.

20. US Food and Drug Administration approves Opdivo (nivolumab) with chemotherapy as neoadjuvant treatment for certain adult patients with resectable non-small cell lung cancer. News release. Bristol Myers Squibb; March 4, 2022. Accessed March 4, 2022. https://bit.ly/3sG3zQA

21. Spicer J, Wang C, Tanaka F, et al. Surgical outcomes from the phase 3 CheckMate 816 trial: nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):8503. doi:10.1200/JCO.2021.39.15_suppl.8503

22. Neoadjuvant Opdivo (nivolumab) plus chemotherapy significantly improves pathologic complete response in patients with resectable non-small cell lung cancer in phase 3 CheckMate -816 trial. News release. Bristol Myers Squibb; April 10, 2021. Accessed February 28, 2022. https://bit.ly/3HrBxw7

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26. Paz-Ares L, Spira A, Raben D, Planchard D, Cho BC, Özgüroğlu M, Daniel D, Villegas A, Vicente D, Hui R, Murakami S, Spigel D, Senan S, Langer CJ, Perez BA, Boothman AM, Broadhurst H, Wadsworth C, Dennis PA, Antonia SJ, Faivre-Finn C. Outcomes with durvalumab by tumour PD-L1 expression in unresectable, stage III non-small-cell lung cancer in the PACIFIC trial. Ann Oncol. 2020 Jun;31(6):798-806.

27. FDA approves Keytruda® (pembrolizumab) as adjuvant treatment following surgical resection and platinum-based chemotherapy for patients with stage IB (T2a ≥4 centimeters), II, or IIIA non-small cell lung cancer (NSCLC). News release. January 27, 2023. https://www.businesswire.com/news/home/20230127005078/en/FDA-Approves-KEYTRUDA%C2%AE-pembrolizumab-as-Adjuvant-Treatment-Following-Surgical-Resection-and-Platinum-Based-Chemotherapy-for-Patients-With-Stage-IB-T2a-%E2%89%A54-Centimeters-II-or-IIIA-Non-Small-Cell-Lung-Cancer-NSCLC

28. Peters S. ADCs: the mechanisms of resistance to immunotherapy and how to overcome them. Presented at: 24th Annual International Lung Cancer Congress; July 27-29, 2023; Huntington Beach, CA.

29. The addition of perioperative durvalumab to neoadjuvant chemotherapy is potential new treatment option for patients with resectable NSCLC. Mitsudomi T, Heymach JV, Reck et al. Surgical outcomes with neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in resectable NSCLC (AEGEAN). Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore. Abstract OA12.05.

30. Cascone T, Awad MM, Spicer J, et al. CheckMate 77T: Phase 3 study comparing neoadjuvant nivolumab plus chemotherapy with neoadjuvant placebo plus chemotherapy followed by surgery and adjuvant nivolumab or placebo for previously untreated, resectable stage II–IIIB NSCLC. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA1.

31. https://www.nejm.org/doi/full/10.1056/NEJMoa2302983