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Beyond Immunotherapy: New Targeted Agents for Advanced NSCLC

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The advent of PD-1 and PD-L1 checkpoint inhibitors has changed the treatment landscape of advanced non–small cell lung cancer (NSCLC), but only approximately 20% of patients treated with immunotherapy will be alive at 5 years. According to Melissa L. Johnson, MD, Director, Lung Cancer Research, Sarah Cannon Research Institute at Tennessee Oncology, Nashville, other treatment modalities are needed for the 80% of patients who develop disease progression on checkpoint inhibitors, especially those with oncogenic driver mutations. At the 2022 Community Oncology Alliance Annual Meeting, Dr. Johnson discussed new drugs under study in NSCLC, including tyrosine kinase inhibitors and antibody-drug conjugates.1

Melissa L. Johnson, MD

As Dr. Johnson reported, there is a growing list of molecular biomarkers in advanced NSCLC that have targeted inhibitors approved by the U.S. Food and Drug Administration (FDA). These targets include EGFR, ALK, ROS1, BRAF V600E, NTRK, RET, MET exon 14 skipping, and KRAS G12C mutations.

“When patients with driver oncogenes are treated with targeted therapies, they survive up to 3 years vs just 1 year,” said Dr. -Johnson. “It’s important to find these patients and find them early.”

Results of the NILE study, which compared cell-free circulating tumor DNA–based tumor genotyping with tissue-based genotyping to find targetable genomic alterations in advanced nonsquamous NSCLC, showed similar rates of detection of guideline-recommended biomarkers.2 Even in community-based centers, findings showed therapeutic outcomes based on plasma-based comprehensive genomic profiling were comparable to published targeted therapy outcomes with tissue profiling.

“If you don’t have enough tissue in the beginning, you should feel confident in your cell-free DNA results to find driver oncogenes,” said Dr. Johnson.

EGFR Exon 20 Insertions

Although EGFRexon 20 insertions comprise just 5% of all EGFR alterations and 2% of known oncogenic drivers, the FDA has approved two EGFR-directed agents in the past 18 months: amivantamab-vmjw and mobocertinib. Amivantamab, a bispecific antibody directed at EGFR and MET for adults with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, demonstrated a 40% response rate, an 11-month duration of response, and an 8-month progression-free survival in the phase I CHRYSALIS study.3 Mobocertinib, an oral tyrosine kinase inhibitor taken daily, yielded a 30% response rate in a phase I/II open-label nonrandomized clinical trial.4

Despite similar response rates, amivantamab and mobocertinib differ significantly with respect to administration and side effects, noted Dr. Johnson. The most common side effects with amivantamab, which is administered intravenously, were infusion reactions, occurring in approximately 60% of patients. For mobocertinib, however, diarrhea was the primary side effect, occurring in 90% of patients.

KRAS G12C Mutations

KRAS mutations comprise approximately 30% of all lung cancer cases, with KRAS G12C mutations representing 13% of all newly diagnosed NSCLC. There is currently one FDA-approved drug targeting KRAS G12C (sotorasib) and one drug with FDA Breakthrough Therapy designation (adagrasib). Both drugs have similar mechanisms of action and work by binding to the inactive state of KRAS. Progression-free survival and overall survival with sotorasib were 6.8 and 12.5 months, respectively.5 The data on adagrasib are still maturing, said Dr. Johnson, but both drugs are associated with similar amounts of nausea, vomiting, diarrhea, fatigue, and elevated liver enzymes.

“These drugs are tolerable enough that patients can stay on them for close to a year,” Dr. Johnson continued. “If that duration of response holds up over time, these agents will be a game-changer and will give chemotherapy a run for its money in patients who have a KRAS G12C mutation.”

Second-Line NSCLC: HER2/HER3 Mutations

For the 80% of patients with advanced NSCLC who experience disease progression on first-line therapy, antibody-drug conjugates have emerged as a viable second-line option. The DESTINY-Lung01 trial demonstrated durable anticancer activity with the HER2-directed antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) in patients with previously treated HER2-mutant NSCLC.6 The overall response rate was 61%, progression-free survival was 8 months, and overall survival was 17.8 months. “These are exciting single-arm data for trastuzumab deruxtecan that I believe will lead to an approval for lung cancer,” said Dr. Johnson.

Among patients with HER2-overexpressing NSCLC, however, the response rate was just 24%, and progression-free survival and overall survival were 5 months and 11 months, respectively. “Trastuzumab deruxtecan is still a great drug, but there needs to be significant HER2 expression [IHC 3+] for it to be effective,” Dr. Johnson added.

HER3 is expressed in most lung cancers, including approximately 80% of EGFR-mutated NSCLC, and overexpression of HER3 is associated with worse clinical outcomes. Patritumab deruxtecan, a novel HER3-directed antibody-drug conjugate, demonstrated a “respectable” response rate of 39% in patients with EGFR-mutated NSCLC who developed acquired resistance to osimertinib.7 Progression-free survival was 8 months, and the disease control rate was 72%.

Second-Line NSCLC: Trop-2 Expression

Finally, Trop-2, a transmembrane glycoprotein, is highly expressed in NSCLC and other solid tumors. High Trop-2 expression is associated with a poor prognosis, according to Dr. Johnson, making it a therapeutic target.

Two antibody-drug conjugates are currently being evaluated in this setting. Sacituzumab govitecan-hziy, which is approved in breast cancer, demonstrated a response rate of 20% in an open-label study of metastatic solid tumors.8 More recently, however, datopotamab deruxtecan demonstrated response rates in 34% of patients with relapsed or refractory advanced triple-negative breast cancer.9

“We’re going to have more and more choice in the second line, and we’re getting ready to see some of these drugs supplant docetaxel,” said Dr. Johnson. “We would prefer not to use docetaxel, but we use it because nothing else is available. Thankfully, other agents are coming soon.”

DISCLOSURE: Dr. Johnson reported institutional financial relationships with AbbVie, Acerta Pharma, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Carisma Therapeutics, Crovus Pharmaceuticals, CURIS, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax Technologies, Elicio Therapeutics, EMD Serono, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon Therapeutics, Helsinn Healthcare, Hengrui Therapeutics, Hutchinson MediPharma, IDEAYA Biosciences, IGM Biosciences, Immnocore, Incyte, Janssen, Kadmon Pharmaceuticals, Lilly, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, and Y-mAbs Therapeutics for research grants in which she served as PI for a study; has institutional financial relationships with Abbvie, Amgen, Astellas Pharma, AstraZeneca, Axelia Oncology, Black Diamond Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Checkpoint Therapeutics, CytomX, Daiichi Sankyo, EcoR1, Editas Medicine, Eisai, EMD Serono, G1 Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Ideaya Biosciences, iTeos, Janssen, Lilly, Merck, Mirati Therapeutics, Novartis, Oncorus, Regeneron, Revolution Medicines, Ribon Therapeutics, Sanofi, Turning Point, and WindMIL Therapeutics for consulting work.


1. Johnson M: Exciting new drugs in non-small cell lung cancer. 2022 Community Oncology Alliance Annual Meeting. Presented March 17, 2022.

2. Page RD, Drusbosky LM, Dada H, et al: Clinical outcomes for plasma-based comprehensive genomic profiling versus standard-of-care tissue testing in advanced non-small cell lung cancer. Clin Lung Cancer 23:72-81, 2022.

3. Park K, Haura EB, Leighl NB, et al: Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: Initial results rrom the CHRYSALIS phase I study. J Clin Oncol 39:3391-3402, 2021.

4. Zhou C, Ramalingam SS, Kim TM, et al: Treatment outcomes and safety of mobocertinib in platinum-pretreated patients with EGFR exon 20 insertion-positive metastatic non-small cell lung cancer. JAMA Oncol 7:e214761, 2021.

5. Skoulidis F, Li BT, Dy GK, et al: Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med 384:2371-2381, 2021.

6. Li BT, Smit EF, Goto Y, et al: Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med 386:241-251, 2022.

7. Jänne PA, Baik C, Su WC, et al: Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated non-small cell lung cancer. Cancer Discov 12:74-89, 2022.

8. Heist RS, Guarino MJ, Masters G, et al: Therapy of advanced non-small-cell lung cancer with an SN-38-anti-Trop-2 drug conjugate, sacituzumab govitecan. J Clin Oncol 35:2790-2797, 2017.

9. Krop I, Juric D, Shimizu T, et al: Datopotamab deruxtecan in advanced/metastatic HER2 negative breast cancer. 2021 San Antonio Breast Cancer Symposium. Abstract GS1-05. Presented December 7, 2021.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.