Chemotherapy was once the only treatment available for metastatic or advanced non-small lung cancer (NSCLC). But the situation has changed dramatically in recent years. NSCLC may harbor mutations that drive cancer development, and many of these mutations can be targeted with precision drugs that inhibit specific mutant proteins. Targeted drugs not only often prolong survival of patients compared to chemotherapy, but they also improve quality of life during treatment.
Targetable mutations occur more often in adenocarcinoma, the predominant type of NSCLC, but they are also seen in squamous NSCLC. NSCLC patients who have never smoked are more likely to have tumors with targetable mutations.
Here, I outline the mutations and approved drugs that are now used to treat NSCLC.
The EGFR gene encodes one of the proteins known as receptor tyrosine kinases (RTKs). EGFR mutations come in many forms and are more common than other RTK alterations (see below), with a frequency of 14% to 35%, depending on a patient’s ethnicity.
In 2004, erlotinib (brand name Tarceva) became the first targeted drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of NSCLC with EGFR mutations. Approval of the drug gefitinib, also a “first-generation” EGFR inhibitor, followed. In clinical trials, neither erlotinib nor gefitinib prolonged overall survival compared to chemotherapy, but patients could still receive chemotherapy as a second-line option after treatment with one of these drugs, and live longer.
Afatinib (brand name Gilotrif), a “second-generation” EGFR inhibitor, became FDA approved in 2013. In clinical trials, this drug increased progression-free survival to about 11 months, and even longer in NSCLC with most the common kinds of EGFR mutations. Afatinib also has activity in the setting of the rare EGFR mutations known as G719X, S768I, and L861Q. What’s more, afatinib prolonged overall survival compared to chemotherapy.
Osimertinib, a “third-generation” RTK inhibitor, was approved by the FDA in 2018, based on the results of the AURA clinical trial, which showed progression-free survival of almost 19 months for patients who received osimertinib versus 10 months for patients who received standard treatment with erlotinib or gefitinib. Overall response rate (ORR) with osimertinib was 66%, and overall survival was much longer for patients treated with osimertinib—over 38 months, versus about 32 months for patients with standard treatment. One very important feature of osimertinib is that it can enter the brain and therefore works well in patients with brain metastases—a frequent feature of EGFR-mutant (EGFR+) NSCLC. Thus, osimertinib became a preferred first-line treatment option for EGFR+ NSCLC. However, not all mutations in EGFR are responsive to osimertinib. Tumors with the most common mutations in a portion of the EGFR gene known exon 21 (L858R, 43% of all mutations) and tumors with exon 19 deletions (48% of all EGFR mutations) respond very well to osimertinib, but tumors with less common EGFR mutations—namely, those in exons 18 and 20 (G719X, S768I, and L861Q, as mentioned above)—do not.
However, the situation has recently changed for NSCLC with EGFR exon 20 mutations: amivantamab (brand name Rybrevant), a kind of treatment known as an antibody drug, was approved by the FDA in May 2021. In a clinical trial, amivantamab treatment was associated with a 40% ORR and an 11-month duration of response (DOR) for patients previously treated with chemotherapy. In addition, a small-molecule drug called mobocertinib (Exkivity) showed good activity in patients with exon 20 mutations, and became FDA approved in September 2021. ORR for mobocertinib in patients who had previously received other treatment was 28%, and DOR was 17.5 months.
ALK is a RTK that is altered by an abnormal process known as chromosomal translocation (rather than typical “point” mutations) in about 5% to 7 % of NSCLC cases. In 2014, crizotinib (brand name Zalkori) became the first drug FDA-approved for ALK+ NSCLC. In a clinical trial, it produced responses in 74% of patients versus 45% with chemotherapy. Alectinib (Alcensa) became FDA approved in 2015 after showing an ORR of 83%. Updated results from that clinical trial later showed progression-free survival of 25.7 months with alectinib versus 10.2 months with crizotinib. Importantly, 80% of patients with brain metastases respond to alectinib. Alectinib also works in 40% of patients for whom crizotinib treatment failed.
Ceritinib (Zykadia) approval followed, as did approval of brigatinib (Alunbrig) and lorlatinib (Lorbrena). All of these newer drugs are superior to crizotinib. However, there is no full agreement on which is best to use as first-line treatment. Many oncologists prefer alectinib because of its great safety profile. Very recent data show that overall survival with alectinib is longer than with ceritinib in patients who have already received crizotinib.
ROS1 is another RTK that can become altered through a rare chromosomal translocation (0.9% to 2% of NSCLC cases). NSCLC tumors with ROS1 translocations respond remarkably well to targeted drugs. Crizotinib, already mentioned as a drug for ALK-rearranged NSCLC, has been in use since 2014, but the drug entrectinib (Rozyltrek) is now much preferred to crizotinib, mainly because it has fewer side effects and much better intracranial activity. ORR for entrectinib is 57%, and in a clinical trial, the DOR was 12 months or longer for almost half of the patients. At least one of the drugs approved for ALK+ NSCLC, ceritinib, may also be used for ROS1+ disease, but it is not yet FDA approved.
RET is an RTK that is in chromosomal translocations in 1% to 2% of NSCLC cases. In 2020, the FDA approved two targeted drugs for treatment of RET fusion–positive NSCLC. The first, selpercatinib (Retevmo), works astonishingly well. In a clinical trial, ORR was as high as 85% for patients who had not received prior treatment, and even in patients previously treated with chemotherapy, ORR was 64%. The other approved drug, pralsetinib (Gavreto), elicited an ORR of 61% in patients who were previously treated with chemotherapy, and an ORR of 70% in patients who had not received prior treatment (“treatment naïve).
Alterations in MET (also an RTK) are seen in about 3% to 4% of NSCLCs, and are most often one of two types: MET amplifications or MET exon 14 alterations leading to exon 14 skipping. Two drugs, capmatinib (Tabrecta) and tepotinib (Tepmetko), are FDA-approved for MET exon 14 skipping alterations. ORR for capmatinib in treatment-naïve patients was 68%, with DOR of 12.6 months. For tepotinib, ORR was 43% with a DOR of 10.8 months.
In patients who received capmatinib as their second- or third-line treatment, the ORR was 41%, with a median DOR of 9.7 months. With tepotinib, in these previously treated patients, the ORR was 43%, with a median DOR of 11.1 months. Although not yet FDA approved for this indication, responses to capmatinib were also noted in patients who had MET amplification.
NTRK, also an RTK, is involved in about 3% of NSCLC cases. Larotrectinib (Viktravi) was approved by the FDA in 2018 for all tumors with NTRK translocations, with an ORR of 75% and DOR of over 9 months for 63% of patients in a clinical trial. Entrectinib (Rozlytrek) was approved in 2019, with an ORR of 78% and DOR of 12 months or longer for 55% of patients in a clinical trial.
Yet another RTK, HER2 is mutated or amplified in 2% to 6% of NSCLC cases. Because HER2 has been investigated for a long time due to its involvement in 20% of breast cancers, there are numerous drugs that are approved for this indication, and they were or still are being explored in HER2+ NSCLC. Trastuzumab emtansine (Kadcyla) produced an ORR of 44% with DOR of 4 months, but now a newer drug, trastuzumab-deruxtecan (Enhertu), has shown significantly improved efficacy (ORR 63%, DOR 14 months); although it has yet to be approved for NSCLC.
BRAF is not an RTK, and is best known as a gene mutated in half of melanomas, with a number of drugs approved in this cancer. NSCLC cases with BRAF mutations are rare (no more than 3%), but development of BRAF inhibitors for melanoma has helped with treatment of BRAF-mutant NSCLC. Vemurafenib was the first FDA-approved drug for NSCLC with a specific kind of BRAF mutation known as V600E (based on clinical trial results showing a 40% ORR and DOR of 12 months). The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) was approved in 2017 for NSCLC with BRAF V600E based on clinical trial results that showed an ORR of over 60% in both treatment-naïve and patients who had received prior treatment, with a DOR of at least one year. Another combination, encorafenib (Braftovi) plus Mektovi was approved in 2018, with an ORR of 63% and DOR over 16 months.
The KRAS gene is mutated in at least 30% of NSCLC cases, mostly involving a part of the gene known as amino acid residue G12. Until very recently, KRAS was thought to be “undraggable” due to the extreme challenges involved in designing drugs to inhibit KRAS. This biochemical puzzle was solved not long ago for one mutated form of KRAS, namely G12C. (There are other mutations also affecting the G12 position of KRAS, and G12C is found in about 7% of NSCLC tumors). The FDA’s 2021 approval of sotorasib (Lumakras) for treating KRAS G12C-mutated NSCLC was based on an observed ORR of 36% with a DOR of 10 months. Next in line to be approved for KRAS G12C-positive NSCLC is adagrasib, with an ORR of 45%. Recent data indicate that combining sotorasib or adagrasib with other targeted drugs may increase ORR significantly.
The many forms of NSCLC
This post is simply a summary of FDA-approved targeted drugs in NSCLC, and the main purpose is to show how NSCLC is, in reality, a variety of different cancers when it comes to the molecular mechanisms that underly their development. Limited testing of newly diagnosed NSCLC for 1 or 2 “usual suspect” mutations (like EGFR and ALK) is no longer an acceptable option after diagnosis of NSCLC. In spite of the relative rarity of some targetable mutations, the remarkable efficacy of targeted drugs that are already approved absolutely warrants more extensive testing for patients. This is, unfortunately, not yet a fully accepted practice according to a recent survey, and change is overdue!
If you or a loved one have advanced NSCLC, and you want to know if any of the treatments discussed here are a good fit, I encourage you to request free, personalized help from Cancer Commons.