Targeted therapies and immunotherapies for non–small-cell lung cancer (NSCLC), the main type of lung cancer, have changed the prognosis of patients diagnosed with this type of lung cancer, increasing survival even for those diagnosed with metastatic disease, reducing chemotherapy-related side effects, and improving patients’ quality of life.
These newer therapies have increased, in many cases by years, the length of disease remission by significantly shrinking lung cancer tumors and giving patients new options that were not available a few years ago.
Becoming familiar with new treatment options can be beneficial for patients, because many cancers stop responding to a specific treatment after some time, and switching to another treatment becomes necessary.
If you are not sure, ask your oncologist if you have had a biomarker testing, whether your lung cancer is associated with a specific mutation, and if any newer treatment may be appropriate for you, if your lung cancer is driven by a biomarker.
The following is a quick overview of the many targeted therapies and immunotherapies that were approved by the FDA in the past 3 years for patients with NSCLC that is associated with a genomic biomarker or with PD-1/PD-L1 protein expression.
HER2 Mutation
Until recently, treatment for tumors with HER2 mutations was only available for patients with breast or ovarian cancer, but HER2 mutations are also found in lung cancer.
In August 2022, the HER2 inhibitor Enhertu (fam-trastuzumab deruxtecan-nxki) became the first HER2 inhibitor to be approved by the FDA for the treatment of adults with unresectable or metastatic NSCLC that is driven by a HER2 mutation.
“The approval of trastuzumab deruxtecan [Enhertu] in non–small-cell lung cancer is an important milestone,” said Bob T. Li, MD, PhD, MPH, of Memorial Sloan Kettering Cancer Center, New York City. “After 2 decades of research into the role of targeting HER2 in lung cancer, the approval of the first HER2-directed treatment option validates HER2 as an actionable target in lung cancer.”
EGFR Mutations
About 15% of patients with NSCLC have some type of EGFR mutation. Tyrosine kinase inhibitors (TKIs) were the first targeted therapies approved for EGFR or other mutations found in NSCLC, such as Xalkori (crizotinib), a first-generation TKI approved in 2011 for NSCLC and ALK mutation. The second- and third- generation TKIs have significantly improved survival for patients.
In May 2021, Rybrevant (amivantamab-vmjw), an intravenous antibody, was the first drug approved by the FDA for the treatment of adults with NSCLC and EGFR exon 20 insertion mutations. About 2% to 3% of patients with NSCLC have EGFR exon 20 insertion mutations. “for the first time, patients with non–small-cell lung cancer with EGFR exon 20 insertion mutations will have a targeted treatment,” said Julia Beaver, MD, Chief of Medical Oncology in the FDA’s Oncology Center of Excellence.
In September 2021, Exkivity (mobocertinib), a second-generation oral TKI, was the second drug approved for patients with locally advanced or metastatic NSCLC and EGFR exon 20 insertion mutations. “EGFR exon 20 insertion-positive NSCLC is an underserved cancer that we have been unable to target effectively with traditional EGFR TKIs,” said Pasi A. Jänne, MD, PhD, of Dana-Farber Cancer Institute, in Boston.
In December 2020, the FDA approved Tagrisso (osimertinib) for adjuvant therapy after surgical removal of the tumor in patients with NSCLC and EGFR exon 19 deletions or exon 21 (L858R) mutations. Tagrisso was previously approved for first-line treatment of patients with these mutations, as well as for second-line treatment of patients with metastatic NSCLC and EGFR T790M mutation.
In May 2020, the FDA approved the combination of Cyramza (ramucirumab) plus Tarceva (erlotinib) for first-line treatment of patients with metastatic NSCLC and EGFR exon 19 deletions or exon 21 (L858R) mutations. Cyramza and Tarceva were each previously approved alone for patients with metastatic NSCLC.
ALK Mutation
In March 2021, the third-generation TKI Lorbrena (lorlatinib) was approved for first-line treatment of patients with metastatic NSCLC and ALK mutation. Lorbrena was previously approved for the second- or third-line treatment of patients with ALK-positive NSCLC. “Lorbrena can significantly improve outcomes in the first-line treatment of ALK-positive non–small-cell lung cancer, including those who present with brain metastases,” said Benjamin Solomon, MD, of Peter MacCallum Cancer Centre.
In May 2020, the FDA approved Alunbrig (brigatinib), a second-generation TKI, for first-line treatment of patients with metastatic NSCLC and ALK mutation.
KRAS Mutation
About 30% of patients with NSCLC have KRAS mutations, and about 13% of these are KRAS G12C mutations. Until recently, it was thought that the KRAS mutation was a type of mutation that was resistant to any drug therapy.
In May 2021, the FDA approved Lumakras (sotorasib), an oral KRAS inhibitor, for locally advanced or metastatic NSCLC and KRAS G12C mutation. Lumakras is the first drug ever to be approved for any type of cancer with KRAS mutation. “KRAS mutations have long been considered resistant to drug therapy, representing a true unmet need....Today’s approval represents a significant step toward a future where more patients will have a personalized treatment,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence.
MET Mutations
In May 2020, the FDA approved Tabrecta (capmatinib), an oral TKI, for adults with metastatic NSCLC and MET exon 14 skipping mutations, a biomarker often involved in metastatic cancer. “Tabrecta is the first approval specifically for the treatment of patients with non–small-cell lung cancer whose tumors have mutations that lead to MET exon 14 skipping,” said Dr. Pazdur.
In February 2021, the FDA approved Tepmetko (tepotinib), the second oral TKI for adults with metastatic NSCLC harboring MET exon 14 skipping alterations.
“METex14 skipping occurs in approximately 3% to 4% of NSCLC cases, and patients with this aggressive lung cancer are often elderly and face a poor clinical prognosis,” said Paul K. Paik, MD, Clinical Director, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York City.
“The availability of a new precision medicine for NSCLC with METex14 skipping alterations…underscores the importance of routine comprehensive biomarker testing,” said Andrea Ferris, LUNGevity President.
RET Mutations
About 1% to 2% of people with NSCLC have RET genetic fusions or mutations. A fusion biomarker is a gene that fuses to another unrelated gene, which can lead to cancer.
In May 2020, the FDA approved Retevmo (selpercatinib), an oral TKI, for metastatic NSCLC with RET fusions or mutations, making it the first drug to be approved for this patient population. The FDA turned its accelerated approval into regular approval in September 2022.
In September 2020, the FDA approved Gavreto (pralsetinib), an oral TKI, as the second RET inhibitor for adults with metastatic NSCLC and RET fusions or mutations.
Immunotherapies
The PD-L1 biomarker responds to anti–PD-1 or anti–PD-L1 immunotherapies. In 2016, the PD-1 inhibitor Keytruda (pembrolizumab) was the first immunotherapy to be approved specifically for metastatic NSCLC and PD-L1 expression. More recently, immunotherapies were also approved for advanced NSCLC with no regard to PD-L1 expression.
In November 2022, the FDA approved the combination of 2 immunotherapies, Imjudo (tremelimumab), a TCLA-4 inhibitor, and Imfinzi (durvalumab), a PD-L1 inhibitor, plus chemotherapy for metastatic NSCLC without EGFR or ALK mutations. In 2018, Imfinzi was the first immunotherapy to be approved specifically for unresectable, stage III NSCLC.
In November 2022, the FDA approved Libtayo (cemiplimab), a PD-1 inhibitor, in combination with chemotherapy, for patients with advanced NSCLC and no EGFR, ALK, or ROS1 mutations.
And in February 2021, the FDA approved Libtayo (cemiplimab), a PD-L1 inhibitor, for first-line treatment of patients with advanced or metastatic NSCLC whose tumors have a high level of PD-L1 expression, but without EGFR, ALK, or ROS1 mutations.
In March 2022, the FDA approved Opdivo (nivolumab), a PD-1 inhibitor, in combination with chemotherapy, as the first neoadjuvant (before surgery) treatment for adults with early-stage NSCLC.
In October 2021, the FDA approved Tecentriq (atezolizumab), a PD-L1 inhibitor, for adjuvant treatment of patients with early-stage (II-IIIA) NSCLC and PD-L1 expression, after removal of the tumor and chemotherapy.
In May 2020, the FDA approved the combination of the PD-1 inhibitor Opdivo (nivolumab) plus the CTLA-4 inhibitor Yervoy (ipilimumab) for first-line treatment of patients with metastatic NSCLC whose tumors express PD-L1, but with no EGFR or ALK genomic mutations.
A few days later, the FDA approved the combination of Opdivo plus Yervoy and 2 cycles (only) of chemotherapy for first-line treatment of patients with recurrent or metastatic NSCLC, regardless of PD-L1 expression, and with no EGFR or ALK genomic aberrations.
“We have come a long way in understanding the role of dual immunotherapy-based approaches in cancer and the potential impact on patients’ long-term outcomes,” said David P. Carbone, MD, PhD, Director of James Thoracic Oncology Center, Ohio State University. “These positive findings…demonstrate the benefit of combining dual immunotherapy with limited chemotherapy for NSCLC patients regardless of PD-L1 status.”
