There has been a dramatic shift in the treatment of non-small cell lung cancer (NSCLC) in the last 5 to 10 years. Although the majority of patients diagnosed with NSCLC will receive immunotherapy with or without chemotherapy in the front-line setting, a growing percentage of patients are eligible to receive targeted agents, or those designed to take advantage of vulnerabilities in the patient’s specific tumor.
“The majority of NSCLC is related to smoking, though with smoking rates dropping, we are seeing the balance shift between smoking-related cancer and cancer that is caused by driver mutations, for which recent drugs have been made,” said Thomas U. Marron MD, PhD, director of the Early Phase Trials Unit, associate director of the Cancer Clinical Trials Office at the Mount Sinai Tisch Cancer Center, and associate professor of medicine (hematology and oncology) at the Icahn School of Medicine at Mount Sinai.
The most common driver mutation in NSCLC is EGFR, seen in about 20% to 25% of NSCLC worldwide, Dr. Marron said. Some of the earliest targeted therapies in NSCLC were EGFR tyrosine kinase inhibitors (TKIs)—gefitinib and erlotinib. Since then, the number of targets has continued to expand, offering more personalized options for patients.
Targeted Advances
Patients with advanced or metastatic NSCLC and targetable mutations are usually able to receive targeted therapies at some point during the course of treatment, according to Elaine Shum, MD, a medical oncologist at New York University (NYU) Langone Health’s Perlmutter Cancer Center and assistant professor of medicine at the NYU Grossman School of Medicine.
Whether that occurs during first-line or second-line treatment depends on the mutation. Any patient with detectable mutations in EGFR, ROS1, ALK, NTRK, RET, MET, or BRAF should receive targeted therapies as first-line treatment.
“Depending on geographical location, this typically accounts for 30% to 50% of patients with new diagnoses of NSCLC,” Dr. Marron said, adding that these therapies are currently used primarily in the stage IV setting.
“In recent years we have seen the use of targeted therapies expand to earlier stages of disease, with patients now after surgical resection potentially having the option to receive EGFR– or ALK-directed therapy in the adjuvant space,” Dr. Shum said.
The phase 3 ADAURA trial showed that adjuvant osimertinib significantly improved overall survival (OS) compared with placebo in patients with resected EGFR-mutated NSCLC (hazard ratio [HR], 0.49; 95.03% CI, 0.33-0.73; P<.001).1
“The use of osimertinib in the adjuvant setting in patients with EGFR-mutated lung cancer is certainly practice changing,” said Karen Yun, MD, an assistant clinical professor at the University of California, San Diego.
Similarly, results of the ALINA trial presented at the 2023 European Society for Medical Oncology (ESMO) Congress showed that adjuvant treatment with the oral ALK inhibitor alectinib resulted in a 76% reduced risk of recurrence or death compared with chemotherapy for patients with ALK-positive stage II-IIIA NSCLC (HR, 0.24; 95% CI, 0.13-0.45; P<.0001).2
“OS data from ALINA are still immature, but we are certainly excited to see how this trial pans out,” Dr. Yun said. “It looks promising, and hopefully we will have an adjuvant targeted therapy for patients with ALK fusion-positive lung cancers.”
Randomized data demonstrating the superiority of selpercatinib, which targets RET rearrangements, compared with standard chemotherapy in advanced NSCLC were also reported at ESMO 2023.3 Selpercatinib now has full approval from the US Food and Drug Administration (FDA), “with very durable responses seen and very tolerable side effects,” Dr. Marron said.
“The greatest story in the past few years has been the ability now to target KRASG12C,” according to Dr. Shum.
Updated results on KRASG12C inhibitors continue to look promising, but there are currently no data comparing them with frontline chemotherapies, qualified Edward B. Garon, MD, MS, a professor of medicine at the University of California, Los Angeles.
“There are two issues right now that impede using KRASG12C inhibitors as a monotherapy instead of standard chemoimmunotherapy,” Dr. Garon said. “One is that response rate and duration of response with KRASG12C inhibitors are not exactly what we currently see with EGFR inhibitors, but it is possible future generations of KRASG12C inhibitors will be better. Second is that there is a subset of patients who have KRASG12C mutations who are likely to have a durable response from chemoimmunotherapy-based approaches.”
Targeted therapies are generally associated with a cancer cell eventually figuring out a way around the blockage of the therapy, Dr. Garon said. Therefore, it makes more sense to start with immunotherapy and follow with the targeted therapy with the currently available data.
ADCs
There is also growing work being done to harness antibody-drug conjugates (ADCs) as a form of targeted therapy against NSCLC.
“I would consider [ADCs] targeted therapies because they consist of antibodies that target a specific protein—for example, HER3, which is commonly expressed in NSCLC—that is attached to a chemotherapy,” Dr. Yun said. “I like to call them targeted chemotherapy.”
Indeed, Dr. Shum said that the idea of an ADC is to target a specific receptor on a tumor cell in order for the drug to release chemotherapy to the tumor cell.
“We have seen that neighboring tumor cells can also be affected by a bystander effect,” Dr. Shum said. “The difference so far, however, compared with TKIs, is that there have not been any validated biomarkers to help us choose exactly who the ADC would be most effective for, if it is even needed, and so we await further information on that.”
Currently, the only ADC approved for NSCLC is trastuzumab deruxtecan-nxki (T-DXd), a HER2-directed antibody and topoisomerase inhibitor conjugate. Dr. Garon pointed out that, at least traditionally, there was trouble with TKIs directed against HER2 in NSCLC. T-DXd was approved for patients with HER2-mutant unresectable or metastatic NSCLC based on results of DESINTY-Lung02, which showed an overall response rate (ORR) of 58% with a median duration of response of 8.7 months.4
However, T-DXd is not without toxicity.
Results of the HERTHENA-Lung01 trial published in late 2023 detailed the use of the ADC patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC after EGFR TKI and platinum-based therapy. HER3-DXd is a fully human monoclonal antibody to human EGFR 3 (HER3) attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker.5
“HER3-DXd did show that it was effective, with an overall response in these pretreated patients of 30%, a median duration of response of 6.4 months, and a progression-free survival [PFS] of 5.5 months,” Dr. Yun said. “What is also interesting is that this agent demonstrated [central nervous system (CNS)] efficacy.”
The confirmed CNS ORR was 33.3%.
“HERTHENA-Lung01 has certainly demonstrated some exciting data, and we look forward to seeing what the long-term efficacy will be because this could address an unmet need in patients with EGFR-mutated lung cancer who progress on initial treatments,” Dr. Yun said.
The TROPION-Lung trials are looking at another exciting ADC: datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen-2 (Trop-2)-directed ADC. Data from TROPION-Lung01 presented at ESMO 2023 showed that Dato-DXd prolonged PFS compared with docetaxel in patients with previously treated advanced NSCLC. Median PFS was 4.4 months with Dato-DXd compared with 3.7 months with docetaxel (HR, 0.75; 95% CI, 0.62-0.91; P=.004).6
Results from TROPION-Lung01 showed that Dato-DXd plus pembrolizumab with or without chemotherapy had notable first-line activity in patients with advanced NSCLC.7 Dato-DXd is also being studied with immunotherapy with or without carboplatin in advanced metastatic NSCLC (TROPION-Lung04).
“Dato-DXd and other ADCs—including the HER3 ADC, an EGFR × HER2 ADC, and a HER2 × HER3 ADC—are all demonstrating promise as treatments in the second line and beyond,” Dr. Marron said. “Dato-DXd is likely the most promising of these agents, with particularly impressive response rates in patients with EGFR mutations whose cancer is progressing on osimertinib, and it will likely become a standard second- or third-line therapy in this patient population upon approval.”
However, the news has not been all good for ADCs in NSCLC. In January, the manufacturer of sacituzumab govitecan-hziy (SG), a Trop-2-directed ADC, announced that the phase 3 EVOKE-01 study testing SG against docetaxel failed to meet its primary end point of OS in patients with previously treated metastatic NSCLC.8 A press release noted a numerical improvement in OS favoring SG and a more than 3-month difference in median OS for SG in a subgroup of patients who were nonresponsive to the last prior anti–PD-L1 therapy. Data have not yet been publicly presented.
Dr. Shum noted that this was disappointing to hear, but she “looks forward to seeing the full results before deciding what this means for the future.”
Dr. Yun noted that data from EVOKE-2 are looking at SG in combination with pembrolizumab in patients with advanced or metastatic NSCLC not selected for driver mutations. Initial data from the trial show that in patients with higher PD-L1 expression the ORR was 69% with a 6-month disease control rate of 88%.9
“If the combination of SG and pembrolizumab does read out with positive findings, that will at least offer another option in the first-line setting,” Dr. Yun said.
Future Directions
In addition to the progress that has been made in targeted therapies in recent years, there are many more drugs currently in development.
“I think that KRASG12C is a very active area of research,” Dr. Garon said. “Although we already have two approved drugs, there are other drugs actively being developed, and there is a question of whether they could be even better.”
There also continues to be further evaluation in the ALK space, as well as research into multiple TKIs that are targeting both EGFRexon20 insertion and HER2 mutations, Dr. Garon said.
Dr. Marron is looking forward to more data on a novel polyclonal tumor-infiltrating lymphocyte therapy from Iovance, which is being researched in patients with advanced or metastatic NSCLC who have progressed on or after chemotherapy and anti–PD-1 therapy and have received at least one line of an FDA-approved targeted therapy, if indicated.
“This is a complex regimen and likely will only be an option for very robust patients progressing on first-line therapy who are treated at centers with cellular therapy experience, but, nonetheless, the potential for this novel approach to induce durable remissions is exciting,” Dr. Marron said.
Similarly, there are Fc-enabled CTLA4 blocking antibodies from OncoC4/BioNTech and Agenus that have demonstrated activity in the post–PD-1 setting, Dr. Marron said.
“I am very excited to see data from trials of [the soluble LAG-3 protein] eftilagimod alpha in the first-line setting, given the highly promising improvement in response rates over pembrolizumab alone in patients regardless of PD-L1 status,” Dr. Marron said.
Finally, it is possible there are still some targets that are not yet appreciated, Dr. Garon noted.
“We think of cancer as a genetic disease, but that doesn’t mean that every mutation will be druggable,” he said. “There is still a lot of progress to be made on a lot of fronts.”
Leah Lawrence is a health writer and editor based in Delaware.
References
Tsuboi M, Herbst RS, John T, et al. Overall survival with osimertinib in resected EGFR-mutated NSCLC. N Engl J Med. 2023;389:137-147. doi:10.1056/NEJMoa2304594
Solomon BJ, Ahn JS, Dziadziuszko R, et al. ALINA: efficacy and safety of adjuvant alectinib versus chemotherapy in patients with early-stage ALK+ non-small cell lung cancer (NSCLC). Abstract LBA2. Presented at the 2023 European Society for Medical Oncology Congress; October 20-24, 2023; Madrid, Spain.
Loong HHF, Goto K, Solomon BJ, et al. Randomized phase III study of first-line selpercatinib versus chemotherapy and pembrolizumab in RET fusion-positive NSCLC. Abstract LBA4. Presented at the 2023 European Society for Medical Oncology Congress; October 20-24, 2023; Madrid, Spain.
FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA. Accessed February 28, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung
Yu HA, Goto Y, Hayashi H, et al. HERTHENA-Lung01, a phase II trial of patritumab deruxtecan (HER3-DXd) in epidermal growth factor receptor–mutated non–small-cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitor therapy and platinum-based chemotherapy. J Clin Oncol. 2023;41(35):5363-5375. doi:10.1200/JCO.23.0147
Ahn M-J, Lisberg A, Paz-Ares L, et al. Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): results of the randomized phase III study TROPION-Lung01. Abstract LBA12. Presented at the 2023 European Society for Medical Oncology Congress; October 20-24, 2023; Madrid, Spain.
Goto Y, Su W-C, Levy BP, et al. TROPION-Lung02: datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) in advanced non-small cell lung cancer (aNSCLC). J Clin Oncol. 2023. doi:10.1200/JCO.2023.41.16_suppl.9004
Gilead provides update on phase 3 EVOKE-01 study. Gilead. January 22, 2024. Accessed February 28, 2024. https://www.gilead.com/news-and-press/press-room/press-releases/2024/1/gilead-provides-update-on-phase-3-evoke-01-study
Gilead’s phase 2 EVOKE-02 study of Trodelvy® (sacituzumab govitecan-hziy) in combination with KEYTRUDA® (pembrolizumab) demonstrates promising clinical activity in first-line metastatic non-small cell lung cancer. Gilead. September 10, 2023. Accessed February 28, 2024. https://www.gilead.com/news-and-press/press-room/press-releases/2023/9/gileads-phase-2-evoke02-study-of-trodelvy-sacituzumab-govitecanhziy-in-combination-with-keytruda-pembrolizumab-demonstrates-promising-clinica
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