New targeted therapy options in advanced NSCLC

There have been interesting developments in targeted therapy options for non-small cell lung cancer (NSCLC) over the past two years. New drugs have been approved for both existing targets and new targets where there were previously no targeted options. In 2021 and 2022, the FDA approved several new drugs for advanced or metastatic NSCLC with targeted mutations.

EGFR-targeted agents

In May 2021, amivantamab-vmjw (Rybrevant), a bispecific antibody for EGFR and MET receptors, received accelerated approval for patients with advanced or metastatic NSCLC following progression following platinum-based chemotherapy. CHRYSALIS (NCT02609776) was a phase 1, multicenter, non-randomized, open-label, multicohort clinical trial that included 81 patients with advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.1 The overall response rate was 40% with a median duration of response (DOR) of 11.1 months. The most common grade 3 or 4 adverse events (AEs) were hypokalemia and rash.

Another drug target EGFR exon 20 insert, mobocertinib (Exkivity), received FDA accelerated approval in September 2021 based on a phase 1/2 dose escalation/expansion study, Study 101 (NCT02716116).two It involved 114 patients with advanced NSCLC with EGFR exon 20 insertions in the platinum-pretreated cohort; the objective response rate (ORR) was 28% by the independent review board, with a median DOR of 17.5 months. The most common AEs were diarrhea and rash.

KRAS-targeted agents

Sotorasib (Lumakras), a small molecule inhibitor of KRAS The G12C mutation found in approximately 13% of lung adenocarcinomas received accelerated approval in May 2021 based on CodeBreaK 100 (NCT03600883), a phase 1/2 study in patients with advanced NSCLC with a KRAS G12Cmutation.3 At a median follow-up of 15.3 months in 124 patients, there was an ORR of 37.1% and a median DOR of 11.1 months.

The subsequent CodeBreak 200 phase 3 clinical trial (NCT04303780) comparing sotorasib to docetaxel in KRAS NSCLC with G12C mutation was presented at the 2022 European Society for Medical Oncology (ESMO) Annual Congress.4 After 17.7 months of median follow-up, a significant improvement in ORR of 28.1% was observed with sotorasib versus 13.2% with docetaxel (P < 0.001).MET-targeted agents

The highly selective and potent MET inhibitor capmatinib (Tabrecta) received a regular FDA approval in August 2022 due to activity in tumors with MET exon 14 skipping mutation. Previously received accelerated approval in 2020 based on findings from the GEOMETRY mono-1 study (NCT02414139).5 A total of 364 patients were included, both naïve and previously treated. Of the 28 treatment-naïve patients with MET exon 14 skipping mutation, 68% had an overall response rate with a DOR of 12.6 months. Of the 69 previously treated patients, 41% had an overall response rate with a DOR of 9.7 months. Common AEs included peripheral edema and nausea, mostly grades 1 and 2; the drug was generally well tolerated.

In addition, tepotinib (Tepmetko), which targets MET exon 14 skipping mutation, received FDA accelerated approval in February 2021. Approval was based on a phase 2 VISION study (NCT02864992).6 Included 152 patients with advanced or metastatic NSCLC harboring MET exon 14 skipping mutation, with an ORR of 46% and a median DOR of 11.1 months. The most common AE was peripheral edema, of which grade 3 events were seen in 7% of patients.

HER2-targeted agents

Another exciting development was the approval in August 2022 of the antibody targeting HER2 onend topoisomerase inhibitor conjugate, fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with unresectable or metastatic NSCLC with HER2 mutation after prior systemic therapy. Efficacy was proven in DESTINY-Lung02, a randomized phase 2 dose optimization trial (NCT04644237) presented at the 2022 EMSO Annual Congress.7 There was an ORR of 53.8% and a median DOR was not reached in 52 patients who received a dose of 5.4 mg/kg every 3 weeks. Treatment-related interstitial lung disease of any grade occurred in 5.9% of patients in the safety analysis set (n = 101). This approval is expected to become the standard of care for HER2-mutated NSCLC upon progression from prior systemic therapies.

promising targets

Several new targets and new drugs for existing targets are being evaluated in several clinical trials and show promise in the evolution of the targeted therapy scenario for the treatment of NSCLC.

Recently, results were reported from the phase 2 arm of the KRYSTAL-1 study (NCT03785249) which explores the activity of the selective and irreversible KRAS G12C inhibitor, adagrasib (MRTX849).8 mutations in KRAS G12C are estimated to account for approximately 14% of adenocarcinomas and 0.5% of squamous cell NSCLC. Compared to sotorasib, adagrasib has a longer half-life. In the study, 116 patients received treatment, most of whom had previously received systemic chemotherapy and immunotherapy. These patients were treated with adagrasib 600 mg orally twice daily. At a median follow-up of 15.6 months, 112 evaluable patients had an ORR of 42.9%, median DOR of 8.5 months, and median overall survival of 12.6 months. The drug has also shown promising activation in patients with central nervous system (CNS) metastases.

A phase 3 clinical trial (KRYSTAL-12; NCT04685135) comparing adagrasib with docetaxel in patients previously treated with KRAS NSCLC with G12C mutation and a phase 2 study (KRYSTAL-7; NCT04613596) evaluating the combination of adagrasib with pembrolizumab (Keytruda) compared to adagrasib monotherapy for first-line treatment in patients with advanced NSCLC with a KRAS G12C mutation are In progress.

For HER2 exon 20 insertion mutations, poziotinib, a tyrosine kinase inhibitor, is another drug with potential as a treatment option in advanced NSCLC. It was evaluated in the open-label phase 2 study ZENITH20 (NCT03318939) of previously treated patients. Of the 90 patients enrolled in the study, 27.8% achieved an overall response and median DOR of 5.1 months at 9.0 months of follow-up.9 Clinical benefit was also seen in patients with CNS metastases. Common AEs were diarrhea, stomatitis, and rash. It was granted an expedited designation by the FDA, however, in September 2022, the FDA’s Oncology Drugs Advisory Committee determined that the agent does not provide substantial benefits relative to its risks.10 Compared to other targeted therapies, the lower overall response rates seen among drugs that target HER2 exon 20 are of concern and subject to further review.

Pritonib, a pan-HER tyrosine kinase inhibitor with known activity in combination with capecitabine in breast cancer, was evaluated in a phase 2 clinical trial (ChiCTR1800020262) in China.11 The study included 78 patients with the majority harboring HER2 exon 20 insertion mutations. An ORR of 19.2% and a DOR of 9.9 months have been reported.

Irreversible oral EGFR inhibitor CLN-081 with broad spectrum of activity against EGFR mutations, including exon 20 mutations, have a breakthrough therapy designation from the FDA. A phase 1/2 dose escalation study (NCT04036682) of CLN-081 in patients with advanced and heavily pretreated NSCLC with documented EGFR exon 20 insertional mutation, demonstrated an ORR of 41% and a higher median DOR to 21 months with an acceptable toxicity profile.12 Plans are under way for expansion trials in patients with active CNS metastases.

Finally, the NRG1 (neuroregulin 1) fusion mutation, first described in 2014 in lung adenocarcinoma, is an oncogenic driver mutation and a promising target for future drug development. It is an unusual mutation, and its understanding is still in the early stages. Agents targeting HER2 and EGFR may be active in patients with NRG1 fusions. Afatinib is being explored as a potential drug in advanced NSCLC with NRG1 fusion mutation.13

Practice points for community oncologists

The field of advanced NSCLC is rapidly evolving with drugs against new targets and new therapies for existing targets showing promising activity. Additionally, combining targeted therapies with other systemic therapies such as immunotherapy is being explored. With the availability of multiple targeted therapies, optimal sequencing and drug selection when more than one option is available remains an issue of great interest.


1. Park K, Haura EB, Leighl NB, et al. Amivantamab in non-small cell lung cancer with EGFR exon 20 insertion mutation progressing on platinum chemotherapy: initial results from the phase I chrysalis study. J Clin Oncol. 2021;39(30):3391-3402. doi:10.1200/JCO.21.00662

2. Zhou C, Ramalingam SS, Kim TM, et al. Treatment outcomes and safety of mobocertinib in platinum-pretreated patients with EGFR exon 20-positive metastatic non-small cell lung cancer: an open-label non-randomized phase 1/2 clinical trial. JAMA Oncol. 2021;7(12):e214761. doi:10.1001/jamaoncol.2021.4761

[ PubMed ]3. Skoulidis F, Lee BT, Dy GK, et al. Sotorasib for lung cancer with KRAS p.G12C mutation. N Engl J Med. 2021;384(25):2371–2381. doi:10.1056/NOMoa2103695

4. Johnson ML, De Langen J, Waterhouse DM, et al. LBA10 – Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS G12C mutation: CodeBreaK 200 phase III study. Ana Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089

5. Wolf J, Seto T, Han JY, et al. Capmatinib in non-small cell lung cancer with MET exon 14 mutation or amplified by MET. N Engl J Med. 2020;383(10):944-957. doi:10.1056/NEJMoa2002787

6. Paik PK, Felip E, Veillon R, et al. Tepotinib in non-small cell lung cancer with MET exon 14 skipping mutations. N Engl J Med. 2020;383(10):931-943. doi:10.1056/NEJMoa2004407

7. Goto K, Sang-We K, Kubo T, et al. LBA55 – Trastuzumab deruxtecan (T-DXd) in patients (Pts) with HER2-mutant metastatic non-small cell lung cancer (NSCLC): Interim results from the phase 2 study DESTINY-Lung02. Ana Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089

8. Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in non-small cell lung cancer with KRASG12C mutation. N Engl J Med. 2022;387(2):120-131. doi:10.1056/NEJMoa2204619

9. Le X, Cornelissen R, Garassino M, et al. Poziotinib in non-small cell lung cancer with HER2 Exon 20 insertion mutations after prior therapies: the ZENITH20-2 study. J Clin Oncol. 2022;40(7):710-718. doi:10.1200/JCO.21.01323

10. Oncology Medicines Advisory Committee (ODAC) meeting, September 22-23, 2022 (Day 1). Streamed live September 22, 2022. Accessed November 18, 2022.

11. Song Z, Li Y, Chen S, et al. Efficacy and safety of pirotinib in advanced lung adenocarcinoma with HER2 mutations: a multicenter, single-arm phase II study. BMC Med. 2022;20(1):42. Published February 1, 2022. doi:10.1186/s12916-022-02245-z

12. Yu HA, Tan DS-W, Smit EF, et al. Phase (Ph) 1/2a study of CLN-081 in NSCLC patients (pts) with EGFR exon 20 insertion mutations (Ins20). J Clin Oncol. 2022;40(suppl 16):abstr 9007. doi:10.1200/JCO.2022.40.16_suppl.9007

13. Wu X, Zhang D, Shi M, et al. Successful targeting of NRG1 fusion reveals durable response to afatinib in lung adenocarcinoma: case report. Ann Transl Med. 2021 Oct;9(19):1507. doi: 10.21037/atm-21-3923

New targeted therapy options in advanced NSCLC

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