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by Dr. C.H. Weaver M.D. updated 6/2022

When non-small cell lung cancer (NSCLC) has progressed or returned following an initial treatment it is said to be recurrent or relapsed.

Patients experiencing a recurrence of NSCLC are treated with precision cancer medicines or chemotherapy similar to treatment of Stage IV disease but with different medicines. Patients should strongly consider participation in a clinical trial evaluating novel treatment approaches.

If individuals with NSCLC have not previously had genomic biomarker testing is should be performed on tissue or blood. When and individual develops a recurrence genomic biomarker testing should be performed using a blood biopsy to determine the mechanism of resistance and whether the individual can benefit from another precision medicine.1-3

Lung CancerConnect 490

Recurrent NSCLC in Individuals Previously Treated with Chemotherapy Alone

Keytruda® (pembrolizumab) and other checkpoint inhibitors have been demonstrated to be superior to chemotherapy treatment when used as single agents in patients with advanced NSCLC regardless of whether they test positive for the PD-L1 ligand. A checkpoint inhibitor combined with chemotherapy is superior to treatment with chemotherapy alone and the benefit from treatment is greatest with higher levels of PD-L1.1-8

Tecentriq® (atezolizumab) improves survival in recurrent NSCLC compared to chemotherapy and may be most effective when combined with Avastin (bevacizumab) and chemotherapy.4,5

Opdivo (nivolumab) has been compared to Taxotere (docetaxel) chemotherapy in patients with recurrent NSCLC that have previously failed chemotherapy and found to improve the response to treatment, delay cancer progression and prolong a patients survival.6-8

Recurrent NSCLC in Individuals Previously Treated with Chemotherapy + Immunotherapy and No Driver Mutation

Patients with recurrent NSCLC are treated with chemotherapy to alleviate the symptoms of their disease and prolong their duration of survival. Chemotherapy is a systemic therapy that uses drugs that kill rapidly dividing cells, a hallmark of cancer. Unlike precision cancer medicine chemotherapy doesn’t target specific cancer cells. It may affect normal cells leading to many side effects of treatment.

Most treatments involve a combination (regimen) of two chemotherapy drugs. The most commonly used regimens include either cisplatin or carboplatin; combined with one of several other drugs approved for the treatment of NSCLC; Alimta® (pemetrexed), Taxol® (paclitaxel), Taxotere® , Gemzar® (gemcitabine), Camptosar® (irinotecan), or Navelbine® (vinorelbine).17

Anti-angiogenesis: Cyramza (ramucirumab) & Avastin® are a type of targeted therapy that slows or stops the growth of blood vessels that deliver blood to the cancer, effectively starving the cancer of the oxygen and nutrients it requires to survive and grow.

Cyramza™ when combined with Taxotere® chemotherapy or Keytruda extends overall survival in patients with NSCLC compared to standard second-line therapy with Taxotere alone and has become a standard treatment.11 Avastin® in combination with the chemotherapy drugs paclitaxel and carboplatin, is also FDA-approved for the treatment of advanced, non-squamous NSCLC.21

Targeting Specific "Driver" Mutations in Recurrent NSCLC

Individuals with EGFR, ALK, ROS1, BRAF, MET, RET, TRK and other mutations eventually develop resistance to their initial treatment. When resistance occurs its important to repeat genomic testing in order to determine if another precision cancer medicine is available to target their cancer. Individuals are typically treated with a "second line" or "next generation" precision cancer medicine that targets their specific mutation, or consider participation in a clinical trial.2,3

There are several known mechanisms of developing drug resistance to TKI's that can be identified by genomic testing; MET, HER2, EGFR amplification, BRAF, PIK3CA, KRAS, and development of C797S and T790M in Tagrisso treated patients have all been characterized and specific treatments or trials are available.

TKI's can also be combined with chemotherapy, Avastin or immunotherapy for the treatment of recurrent EGFR + NSCLC.

Avastin + Tecentriq Checkpoint Inhibitor Immunotherapy

The IMpower150 clinical trial compared Tecentriq immunotherapy in combination with chemotherapy with or without Avastin in individuals with stage IV or recurrent chemotherapy naive metastatic NSCLC in 1202 patients. Individuals were treated with either one of 3 regimens and directly compared.5

  • Tecentriq plus carboplatin and paclitaxel
  • Tecentriq and Avastin plus carboplatin and paclitaxel
  • Avastin plus carboplatin and paclitaxel

The result of the study demonstrated that individuals treated with Tecentriq in combination with Avastin and chemotherapy were more likely to respond to treatment and survive longer compared to Avastin and chemotherapy. Subgroup analyses of EGFR+ patients also revealed a survival benefit. The average survival duration was improved from 15 to 20 months.

The addition of Avastin to Tarceva (erlotinib) for treatment of EGFR + NSCLC has been demonstrated to improve the duration of survival without cancer recurrence from 17 to 13 months for Tarceva alone.9

Cyramza when combined with Tarceva in EGFR positive NSCLC delays cancer progression compared to Tarceva alone.(1,2) The combination therapy showed an objective response rate of 23% compared to 14% for Taxotere and delayed cancer progression and improved survival.10

​In June 2019 it was also announced that the phase 3 RELAY study of Cyramza met its primary endpoint of progression-free survival (PFS), when used in combination with Tarceva (erlotinib) compared to Tarceva alone as a first-line treatment in patients with metastatic NSCLC whose tumors have activating EGFR mutations.11

Anaplastic Lymphoma Kinase (ALK) gene: There are several precision cancer medicines that target ALK+ recurrent NSCLC. Alecensa (alectinib) is one of the more effective treatments and recent studies demonstrate that Lorbrena (lorlatinib) is effective in some individuals with recurrent disease.12-15

ROS-1+ Lung Cancer: The ROS-1 mutation is an uncommon mutation found in only 1% of individuals with NSCLC. Research has indicated that the ROS-1 mutation plays a role in the development and progression of some lung cancers, and patient characteristics are similar to those who have ALK+ NSCLC and can be targeted with similar medications.12

BRAF& MEKKinase Inhibitors: The BRAF and MEK genes are known to play a role in cell growth, and the BRAF V600E mutation occurs in ~ 2% of NSCLC patients, most commonly in smokers. If previously untreated with a BRAF/MEK inhibitor the Tafinlar® (dabrafenib) BRAF V600E kinase inhibitor and Mekinist®(trametinib) MEK V600 kinase inhibitor are FDA approved. For patients failing BRAF/MEK participation in a clinical trial or treatment with checkpoint inhibitor based therapy is recommended.16

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RET + Lung Cancer: Genetic alternations in the RET ( rearranged during transfection) receptor tyrosine kinase are present in 1-2% of NSCLC's and drive their development and growth.14

  • Vandatenib
  • Cabozantinib
  • BLU-667
  • LOXO-292

TRK + Lung Cancer: Tropomyosin receptor kinases (TRK) fusions are rare chromosomal abnormalities that occur when one of the NTRK genes (NTRK1, NTRK2, NTRK3) becomes abnormally connected to another, unrelated gene (e.g. ETV6, LMNA, TPM3). This abnormality results in uncontrolled TRK signaling that can lead to cancer.15,16

  • Vitrakvi (larotrectinib)
  • Entrectinib

Small Cell Transformation: EGFR-mutant NSCLC can undergo transformation to small cell lung cancer. This typically occurs at an average of 18 months after diagnosis and is often characterized by Rb1, TP53, and PIK3CA mutations. Responses to platinum-etoposide and taxane chemotherapy are frequent, but checkpoint inhibitors seem ineffective.17  Clinical trials are ongoing.

Treatment of Older Individuals

Many NSCLC cases occur in people over the age of 70, but there is limited information about how best to treat older patients. As a result of the limited information and concern that elderly patients will not be able to tolerate aggressive treatment, older patients may be treated with single-agent chemotherapy rather than the combination chemotherapy that is commonly used in younger patients. Studies have suggested, however, that although combination chemotherapy increases side effects, it also improves survival among elderly patients.

A study presented at the 2021 World Conference on Lung Cancer suggests age does not negatively impact survival benefit from Checkpoint Inhibitors with stage IV NSCLC. Researchers analyzed 86,173 patients with stage IV NSCLC--24,136 patients were age 75 and older and 62,037 patients were under age 75 and confirmed the survival benefit from ICIs for patients 75 years of age and older and that chronological age does not appear to impact the survival benefit of ICIs in stage IV NSCLC.26

Managing Bone Complications

NSCLC cells commonly spread to the bone, causing bone metastases. Bone metastases may cause pain, bone loss, increased risk of fractures, and a life-threatening condition characterized by a high level of calcium in the blood, called hypercalcemia.

Preventing or delaying these skeletal-related events (SREs) can preserve quality of life and reduce healthcare costs. Bisphosphonate drugs such as Zometa® (zoledronic acid) and a newer type of bone drug, Xgeva® (denosumab) can be used to reduce the risk of complications from bone metastases. Xgeva® is a drug that targets a protein known as the RANK ligand. This protein regulates the activity of osteoclasts (cells that break down bone). Xgeva® is approved for the prevention of bone complications such as fracture in patients with bone metastases from solid (not blood-related) cancers.

Xgeva® has been directly compared to Zometa® for the treatment of bone metastases in 702 with NSCLC and 109 with small-cell lung cancer (SCLC). Xgeva® is associated with a decrease in SREs and improved overall survival when directly compared with Zometa.19  To learn more about bone metastases and bone health, go to the Bone Information Center.

Managing Brain Metastases

When NSCLC spreads to the brain, it can cause symptoms such as headaches and seizures. Depending on the number, size, and location of the tumors in the brain, treatment may involve radiation therapy and/or surgery to remove the tumor.

Managing Pleural Effusion

In some patients with advanced NSCLC, fluid collects in the space around the lungs. This is called pleural effusion. The fluid can compress the lung and make it difficult to breath. If a patient is experiencing symptoms due to pleural effusion, the fluid may be drained using a catheter.

Strategies to Improve Treatment

The progress that has been made in the treatment of NSCLC has resulted from patient participation in clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of NSCLC.

Lung Cancer News: The Daily Cancer News reports on all advances in the management of lung cancer that are most important to patients; visit the news to stay current with developments in the treatment of lung cancer.

Precision Cancer Medicine: 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. Therapies directed at EGFR, ALK, PD-1, PD-L1, and BRAF have already improved the treatment of advanced NSCLC. How best to use these targeted medicines and the identification of new targets is ongoing. ALL NSCLC patients should undergo genomic testing in order to benefit from this area of active research.

The Lung-MAP Trial for Squamous Cell Carcinoma

In Lung-MAP (, researchers with several public institutions, including the National Cancer Institute (NCI), are working with pharmaceutical companies to study treatment for advanced squamous cell lung cancer. Though only a fraction (about a quarter) of all lung cancer diagnoses as squamous cell, it’s an important area of research, as there are few treatment options for these patients.

Lung-MAP will evaluate several investigational treatments and match patients with the therapy most likely to benefit them. Participants will undergo genomic profiling—a type of testing that provides information about all the genes in an organism, including variation, gene expression, and the way genes interact with each other and the environment. The drugs studied in Lung-MAP are designed to target genomic alterations involved in the growth of cancer, and researchers will use genomic profiling to match patients with the therapy designed to target the particular genomic alterations that their cancer expresses.

This more comprehensive approach marks a change in the typical clinical trial model for targeted therapies, in which separate studies for the same disease focus on particular genomic abnormalities and treatments. Potential participants are tested for that genomic biomarker (a molecule that is a sign of a normal or abnormal process or of a condition or disease), and only individuals who test positive are enrolled in the study. As a result, many patients are left out of each trial and—with multiple, separate trials—overall progress in treatment development is made less efficient.

In Lung-MAP, however, everyone who’s tested will be eligible for a therapy. And several treatments for advanced squamous cell lung cancer will be evaluated under one protocol in an effort to accelerate safe drug development.

Epacadostat is a novel drug that blocks an enzyme called IDO1, which is implicated in the growth and spread of cancer cells. Investigators have theorized that the combination may be more effective than the use of either drug as a single agent.19

Ensartinib (X-396) is a novel ALK inhibitor that is well tolerated and has antitumor activity in patients with ALK positive NSCLC. Ensartinib is being developed for the treatment of solid tumors where ALK is deregulated. Ensartinib has been validated in potency and selectivity assays indicating that it is more selective and up to 10 times more potent than competitive ALK inhibitors.

The interim results of one study have demonstrated that among 11 ALK positive patients evaluable for response 6 patients had a partial response (55%) and 2 had stable disease (18%). Of the three patients with progressive disease, all acquired resistance to Xalkori®.20

Ganetespib is an investigational drug that targets a protein known as heat shock protein (Hsp) 90. Hsp90 is necessary for the function of several other proteins that are known to play an important role in lung cancer. In a Phase II clinical trial, second-line treatment with a combination of chemotherapy and the investigational drug ganetespib improved overall survival among patients with advanced lung adenocarcinoma.21

Nintedanib is an angiokinase inhibitor that when combined with Taxotere® improves progression-free and overall survival in patients with NSCLC-adenocarcinoma.22

Lung Newsletter 490


  1. Merck’s KEYTRUDA® (pembrolizumab)Demonstrates Superior Progression-Free and Overall Survival Compared to Chemotherapy as First-Line Treatment in Patients with Advanced Non-Small Cell Lung Cancer [news release]. Merck website. Available at: June 16, 2016.
  2. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. New England Journal of Medicine. 2015;372(21):2018-20. Abstract. doi: 10.1056/ NEJMoa1501824.
  3. Leighl NB, Rekhtman N, Biermann WA, et al. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline. Journal of Clinical Oncology. 2014;32(32):3673-79. Available Molecular Testing for Selection of Patients With Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline. Accessed September 30, 2016.
  4. Barlesi F, Park K, Ciardiello F, et al. Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC. Proceedings from the annual meeting of the 2016 European Society for Medical Oncology (ESOM). (Abstract #LBA44) Oct. 9, 2016.
  5. Socinski M et al., Atezolizumab for First-Line Treatment of Metastatic non-squamous NSCLC. N Engl J Med. 2018; 378:2288- 2301.
  6. Brahmer J, Reckamp KL, Bass P, et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. New England Journal of Medicine. 2015;373(2):123-35. Abstract. doi: 10.1056/NEJMoa1504627.
  7. Borghaei H, Paz-Arez L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. New England Journal of Medicine. 2015;373(17):1627-39. doi: 10.1056/NEJMoa1507643.
  8. Bristol-Myers Squibb Announces Top-Line Results from CheckMate -026, a Phase 3 Study of Opdivo (Nivolumab) in Treatment-Naïve Patients with Advanced Non-small Cell Lung Cancer [news release]. Bristol-Myers Squibb website. Available at:–026-a-Phase-3-Study-of-Opdivo-nivolumab-in-Treatment-Nave-Patients-with-Advanced-Non-Small-Cell-Lung-Cancer/default.aspx. August 5, 2016.
  9. Zhou C, Wu Y-L, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomized, phase 3 study. Lancet Oncology. Early online publication July 22, 2011.
  10. Perol M, et al. REVEL: A randomized, double-blind, phase III study of docetaxel and ramucirumab versus docetaxel and placebo in the second-line treatment of stage IV non-small cell lung cancer following disease progression after one prior platinum-based therapy. ASCO 2014; Abstract LBA8006.
  11. Lilly's CYRAMZA® (ramucirumab) Phase 3 RELAY Trial Met Primary Endpoint, Significantly Improving Progression-Free Survival in First-Line Treatment of Patients with Metastatic EGFR-Mutated Non-Small Cell Lung Cancer
  12. Kwak EL, Bang Y-J, Camidge DR et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. New England Journal of Medicine. 2010;363:1693-1703.
  13. Ou SI, Ahn J, De Petris L, et al. Alectinib in crizotinib-refactory ALK-rearranged non-small cell lung cancer: A phase II global study. Journal of Clinical Oncology. Published online before print November 23, 2015, doi: 10.1200/JCO.2015.63.9443.
  14. FDA approves lorlatinib for second- or third-line treatment of ALK-positive metastatic NSCLC
  15. J Clin Oncol. 2019 Mar 20. Epub ahead of print
  16. Clinical Characteristics and Course of 63 patients with BRAF Mutant Lung Cancers
  17. EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes.
  18. Scagliotti GV, Hirsh V, Siena S, et al. Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: Subgroup analysis from a randomized phase 3 study. Journal of Thoracic Oncology. 2012; 7(12): 1823-1829.
  20. Horn L, Infante J, Blumenshcein G, et al. A phase I trial of X-396, a novel ALK inhibitor, in patients with advanced solid tumors. J Clin Oncol 32:5s, 2014 (suppl; abstr 8030)
  21. Ramalingam SS, Goss GD, Andric ZG et al. A randomized study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel versus docetaxel alone for second-line therapy of lung adenocarcinoma (GALAXY-1). Presented at the 49th Annual Meeting of the American Society of Clinical Oncology. May 31-June 4, 2013; Chicago, IL. Abstract CRA8007.
  22. Reck M, Kaiser R, Mellemgaard A, et al: Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomized controlled trial. The Lancet Oncology. 2014; 15(2): 143-155.
  24. FDA approves lorlatinib for second- or third-line treatment of ALK-positive metastatic NSCLC
  25. J Clin Oncol. 2019 Mar 20. Epub ahead of print