Systemic Therapy for Locally Advanced and Metastatic Non-Small Cell Lung Cancer

Lung cancer

Improved understanding of the biology and molecular subtypes of non-small cell lung cancer (NSCLC) has led to the development of several biomarker-targeted therapies for patients with locally advanced and metastatic disease.

Cytotoxic chemotherapy remains an essential component of systemic therapy, but regimens that forgo chemotherapy in favor of molecularly targeted therapy or immunotherapy are now the standard first-line approach for about 50 percent of patients. (1)

These new therapies and novel combinations have resulted in improved overall survival (OS). Today, five-year OS exceeds 25 percent for patients with tumors that have high PD-L1 expression and 40 percent for those with ALK-positive tumors. Until the last decade, the five-year OS for patients with metastatic NSCLC was less than 5 percent. (1)

In our review paper, published recently in JAMA, we summarize the clinical presentation and characterization of the disease and the evidence for currently approved systemic therapies. (1)

Clinical Presentation and Classification of NSCLC

In 2019, an estimated 228,000 Americans will be diagnosed with lung cancer. (2) NSCLC represents 85 percent of lung cancer cases. (3) Unfortunately, more than half of newly diagnosed patients have metastatic disease, (4) presenting with cough or dyspnea, and sometimes also with symptoms related to the most common sites for metastases: the lungs, brain, adrenal glands, bones, and liver. (5)

The two most common subtypes of NSCLC are adenocarcinoma (60 percent) and squamous cell carcinoma (15 percent). The safety and efficacy of some systemic therapies vary by histology. For example, bevacizumab, an antibody to the vascular endothelial growth factor (VEGF), is contraindicated for squamous cell carcinoma; clinical trials have found a higher risk of fatal or life-threatening hemoptysis. (6) Pemetrexed, a cytotoxic chemotherapy commonly used to treat adenocarcinoma, is associated with inferior OS when used in combination with cisplatin compared to gemcitabine and cisplatin in patients with squamous cell NSCLC (median OS was 9.4 versus 10.8 months, respectively: hazard ratio [HR], 1.23 [95 percent CI, 1.00–1.51]; p = 0.05). (7)

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Characterizing Metastatic NSCLC

Molecular testing of tumor tissue at the time of diagnosis informs the choice of treatment options. At MSK, we use MSK-IMPACT™, a next-generation DNA-sequencing platform that can detect hundreds of gene mutations, amplifications, and deletions, as well as genomic signatures, including microsatellite instability and tumor mutation burden.

Plasma circulating tumor DNA (ctDNA) analysis may identify molecular alterations in patients for whom insufficient tissue is available. (8) With some platforms, plasma ctDNA has a detection rate higher than 75 percent and a concordance rate with tissue-sequencing results higher than 95 percent. (9) If actionable mutations are found with ctDNA, another tissue biopsy, beyond the one performed at initial diagnosis, may not be required. However, 20 percent of patients with negative ctDNA results have molecular alterations that do respond to drug treatment in tumor samples. (10) Therefore, a combination of tissue and plasma testing provides the most robust information.

Landmark clinical trials of antibodies targeting the programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) pathways have shown that patients with a higher PD-L1 tumor proportion score are more likely to respond to single-agent immune checkpoint inhibitors. As a result, tissue testing for a PD-L1 tumor proportion score is recommended for all patients with metastatic NSCLC.

A greater number of nonsynonymous tumor mutations have been associated with improved clinical outcomes after treatment with PD-1 inhibitors and have been studied in patients who received PD-1 and PD-L1 antibodies. (11) Large-panel next-generation sequencing testing allows us to accurately estimate tumor mutational burden using clinical assays so we can identify patients who may achieve a durable response to a PD-1 and PD-L1 blockade despite a low PD-L1 tumor proportion score. (12) However, this biomarker is not yet a standard approach.

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Molecularly Targeted Therapies

Several approved agents target specific gene mutations or rearrangements in NSCLC, including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS proto-oncogene receptor tyrosine kinase 1 (ROS1), BRAF V600E, and neurotrophic receptor tyrosine kinase (NTRK) gene fusions. (13), (14)


About 20 percent of NSCLC cases have somatic EGFR mutations. (15) Patients with the two most common mutations, EGFR L858R and EGFR exon deletion 19, are treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs), which include erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib. These targeted therapies have prolonged progression-free survival (PFS) compared to platinum-based chemotherapy. (16), (17), (18)

Among those treated with a first-generation (erlotinib or gefitinib) or second-generation (afatinib or dacomitinib) EGFR-TKI, the emergence of the EGFR T790M mutation has been associated with resistance to treatment in 60 percent of patients. (19), (20), (21), (22) Osimertinib, a third-generation agent, has demonstrated that it can overcome this resistance. (23) In a clinical trial testing it in the first-line setting in patients with this mutation, osimertinib achieved a PFS of 18.9 months, significantly longer than the 10.2 months for patients in the comparison cohort, who received gefitinib or erlotinib (HR, 0.46 [95 percent CI, 0.37–0.57]; p < 0.001). (24), (25) Based on these results, the US Food and Drug Administration (FDA) approved osimertinib for the initial treatment of patients with EGFR-mutant NSCLC. Dacomitinib, a TKI that targets both EGFR and HER2, also significantly outperformed initial treatment with gefitinib, in patients with an EGFR mutation (median OS was 34.1 versus 26.8 months, respectively; p = 0.04) in a recent phase III trial. (26)

Research efforts are now focusing on understanding the mechanisms of resistance to third-generation EGFR-TKIs. (27), (28)

Cytotoxic chemotherapy remains an essential component of systemic therapy, but regimens that forgo chemotherapy in favor of molecularly targeted therapy or immunotherapy are now the standard first-line approach for about 50 percent of patients.
Kathryn C. Arbour

ALK-Positive NSCLC

About 5 percent of patients with metastatic NSCLC have gene fusions that result in the overexpression of the ALK protein. Crizotinib, a TKI that targets both ALK and MET receptor tyrosine kinases, was the first drug to achieve tumor responses in patients with ALK-positive NSCLC. (29) Further data showed that crizotinib was superior to combination therapy with pemetrexed and either cisplatin or carboplatin as first-line therapy (response rate of 74 versus 45 percent, respectively; and median PFS of 10.9 versus 7.0 months; p < 0.001). (30) As a result, ALK-TKIs were adopted as initial therapies for these patients, highlighting the need for molecular testing at diagnosis.

Second-generation ALK-TKIs (alectinib, ceritinib, and brigatinib) have a greater and more specific kinase inhibition effect, and can be effective in patients with resistance to crizotinib. Early-phase trials demonstrated responses for all three agents. (31), (32), (33)

In the first-line setting for patients with ALK-positive lung cancer, alectinib and brigatinib demonstrated superiority to crizotinib. Alectinib showed significantly improved PFS compared to crizotinib (34.8 versus 10.9 months, respectively; HR, 0.47 [95 percent CI, 0.34–0.65]; p < 0.001) in a phase III randomized trial. (34) Improvements in disease control were seen in the central nervous system (CNS), a common site for metastases. Similarly, brigatinib showed improved efficacy compared to crizotinib (12-month PFS rate of 69 versus 40 percent, respectively; p < 0.001), with less progressive disease in the CNS. (35) Based on these results, the FDA approved both drugs as initial therapy for patients with ALK-positive NSCLC.

Alectinib and brigatinib can achieve a median period of disease control lasting longer than two years, but drug resistance remains a challenge. Lorlatinib, a third-generation ALK inhibitor, was recently approved for treating patients with ALK-positive NSCLC who progressed following treatment with two prior ALK-TKIs, based on results from a global phase II trial. (36)

ROS1-Rearranged NSCLC

Rearrangements of the gene encoding ROS1 are found in about 1 percent of patients with NSCLC. (37)ALK and ROS1 mutations share substantial characteristics. As a result, some ALK-TKIs are effective for ROS1 mutations. (38) Crizotinib treatment achieved a 72 percent response rate and a median PFS of 19 months in a study of 50 patients with ROS1-rearranged NSCLC. Other agents have shown tumor responses; however, at present, crizotinib is the only approved treatment for this indication. (39), (40), (41)


BRAF V600E mutations are found in 1 to 2 percent of patients with lung adenocarcinoma. Responses to the single-agent BRAF inhibitors vemurafenib and dabrafenib have been short-lived. (42), (43) In a more recent phase II trial of 59 patients with metastatic BRAF V600E-mutant NSCLC who were treated with a combination of dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor), the response rate was 64 percent, with a median PFS of 11 months. (44) These findings support a molecularly targeted approach for treating patients with BRAF-mutant NSCLC.

Finding Additional Actionable Molecular Targets

Scientists are working on identifying additional molecular aberrations in smaller subsets of patients with NSCLC. Clinical trials are assessing newly identified alterations with existing drugs that are approved for other subtypes. For example, preliminary evidence suggested that crizotinib may decrease tumor size in patients with MET exon 14 skipping deletions, which occur in about 4 percent of patients with NSCLC. (45), (46)

Likewise, trastuzumab emtansine, the HER2-targeted antibody-drug conjugate, has achieved a tumor response rate of 44 percent and a median PFS of five months in a study of 18 patients with HER2-mutated NSCLC, which is found in about 2 percent of patients. (47) The results suggest that HER2 mutation status may be a better biomarker for selecting HER2-directed agents than protein overexpression.

NTRK mutations account for less than 1 percent of all NSCLC tumors. The targeted therapy larotrectinib demonstrated a tumor response rate of 75 percent and a 12-month PFS rate of 55 percent in a clinical trial of 55 patients with the NTRK rearrangement regardless of the primary tumor site. The case series included four patients with lung cancer. (48) Based on these results, the FDA approved the drug for NTRK-altered cancers regardless of the tumor site.

RET rearrangements occur in 1 to 2 percent of patients with NSCLC. Multiple RET-TKIs have shown modest efficacy: Cabozantinib showed a response rate of 28 percent and median PFS of 5.5 months, (49) and vendatinib showed a response rate of 18 percent and median PFS of 4.5 months. (50) More specific RET inhibitors are in development. (51), (52)

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Immunotherapy in NSCLC

The advent of immune checkpoint inhibitors has radically changed how we treat patients with metastatic NSCLC.

Single-Agent PD-1 and PD-L1 Inhibition

Following the approval of PD-1 and PD-L1 therapy for use after initial treatment with platinum-based chemotherapy, anti-PD-1 and anti-PD-L1 therapies were evaluated in the first-line setting. Pembrolizumab achieved the best results:

  • KEYNOTE-024, a phase III randomized trial, found that patients with a PD-L1 score of 50 percent or greater who did not have EGFR or ALK mutations and were treated with pembrolizumab achieved a significantly greater response rate versus patients treated with platinum-based chemotherapy (45 versus 28 percent respectively), an improved median PFS (10.3 versus 6.0 months, respectively; HR, 0.50 [95 percent CI, 0.37–0.68]; p = < 0.001), and an improved median OS (30.0 versus 14.2 months, respectively; HR, 0.63 [95 percent CI, 0.47–0.86]; one-sided nominal p = 0.002). Pembrolizumab was also associated with a lower frequency of severe adverse events. (53)
  • In the KEYNOTE-042 trial, 1,274 patients with metastatic NSCLC and a PD-L1 tumor proportion score of 1 percent or greater were randomized to receive pembrolizumab or platinum-based chemotherapy. OS improved, and benefits were greatest among patients with a tumor proportion score of 50 percent or higher. Those with a score from 1 to 49 percent saw no difference in OS compared to patients treated with platinum doublet chemotherapy (13.4 versus 12.1 months, respectively; HR, 0.92 [95 percent CI, 0.77–1.11]). (54) Following this evidence, the FDA expanded the approval of pembrolizumab to include first-line treatment of metastatic NSCLC for patients with tumors that have PD-L1 expression of 1 percent or greater. The approval has reinforced the need for routine testing of PD-L1 at the time of diagnosis for metastatic NSCLC.

Combination Chemotherapy and PD-1/PD-L1 Inhibition

The combination of chemotherapy and immune checkpoint inhibitors has proven to be the most effective regimen for patients with a PD-L1 tumor proportion score of less than 50 percent. Chemotherapy is thought to provide a cytotoxic effect and, at the same time, may boost immunologic activity by enhancing the presentation of tumor antigens. (55) Combining first- and second-line therapies may also confer benefits, since many patients with NSCLC have rapidly progressing cancer and are ineligible for further treatment due to functional decline.

Three large randomized trials have resulted in the incorporation of immunotherapy into the first-line setting for all patients with NSCLC who do not have molecular alterations that respond to targeted therapies:

  • The randomized phase III KEYNOTE-189 trial tested pembrolizumab plus chemotherapy (pemetrexed plus cisplatin or carboplatin) compared to chemotherapy alone in patients with nonsquamous NSCLC. The combination group showed an improved response of 48 versus 19 percent for the chemotherapy alone group (p < 0.001), median PFS was 8.8 versus 4.9 months, respectively (p < 0.001), and the 12-month OS rate was 69 versus 49 percent, respectively (HR, 0.49 [95 percent CI, 0.38–0.64]; p <0.001). These benefits occurred regardless of the tumor proportion score. (56)
  • A similar benefit was seen in the randomized phase III KEYNOTE-407 trial in patients with squamous NSCLC who received a combination of carboplatin, pembrolizumab, and either paclitaxel or albumin-bound paclitaxel versus chemotherapy alone. Median OS was 15.9 versus 11.3 months for the combination group versus the chemotherapy alone group, respectively (HR, 0.64 [95 percent CI, 0.49–0.85]; p = 0.001). (57)
  • Atezolizumab, an anti-PD-L1 antibody, showed benefit when combined with chemotherapy as a first-line treatment in the IMpower 150 study. Patients treated with quadruplet therapy (atezolizumab, paclitaxel, carboplatin, and bevacizumab) were compared to patients treated with triplet therapy (the same agents as the quadruplet group minus bevacizumab). The quadruplet group had improved median PFS compared to the triplet group (8.3 versus 6.8 months, respectively; HR, 0.62 [95 percent CI, 0.52–0.74]; p < 0.001), as well as improved OS (19.2 versus 14.7 months; HR, 0.78 [95 percent CI, 0.64–0.96]; p = 0.02). Benefits were irrespective of the tumor PD-L1 proportion score. (58)

The substantial body of evidence over the past few years guides treatment choice. For patients without molecular alterations that respond to targeted therapies, those with a PD-L1 tumor proportion score of less than 50 percent usually receive combination chemotherapy and PD-L1 blockade. Patients with a tumor proportion score greater than 50 percent receive single-agent pembrolizumab or chemotherapy combined with a PD-1 or PD-L1 inhibitor.

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Advancing NSCLC Research

Despite substantial advances, long-term durable responses remain uncommon for patients with NSCLC. We need to continue exploring and understanding the mechanisms of resistance in patients with advanced disease as well as test novel approaches in the early-disease setting to increase cure rates.

At MSK, our multidisciplinary lung cancer experts treat patients with the most-advanced therapies. We collaborate to develop an individualized treatment plan for each patient, to maximize their potential for the best possible outcome while minimizing side effects.

We are currently conducting 53 clinical trials for patients with NSCLC, testing a wide range of systemic therapies, including single agents and novel combinations.

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