Lung Cancer Awareness Month: New Targeted Therapy Options in Advanced NSCLC

Surabhi Pathak, MD

There have been exciting developments in the targeted therapy options for non-small cell lung cancer (NSCLC) within the last couple of years. New drugs have been approved both for existing targets and for novel targets where there were previously no targeted options. In 2021 and 2022, the FDA approved multiple 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, was granted accelerated approval for patients with advanced or metastatic NSCLC following progression after platinum-based chemotherapy. CHRYSALIS (NCT02609776) was a phase 1, multicenter, nonrandomized, open-label, multicohort clinical trialwhich 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. Most common grade 3 or 4 adverse events (AEs) were hypokalemia and rash.

Another drug targeting EGFR exon 20 insertion, mobocertinib (Exkivity), was granted accelerated approval by FDA in September 2021 based on a phase 1/2 dose-escalation/expansion trial, Study 101 (NCT02716116).² 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 independent review committee, with 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 G12Cmutation found in approximately 13% of lung adenocarcinomas, was granted accelerated approval in May 2021 based on CodeBreaK 100 (NCT03600883) a phase 1/2 trial in patients with advanced NSCLC harboring a KRAS G12Cmutation.³ At 15.3-month median follow-up in 124 patients, there was an ORR of 37.1% and a median DOR of 11.1 months.

The subsequent phase 3 clinical trial CodeBreak 200 (NCT04303780) comparing sotorasib to docetaxel in KRAS G12C-mutated NSCLC 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 ORR was observed, at 28.1% with sotorasib versus 13.2% with docetaxel (P < .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. It was previously granted accelerated approval in 2020 based on findings from GEOMETRY mono-1 trial(NCT02414139).⁵ A total of 364 patients were enrolled, both treatment naïve and previously treated. Of the 28 treatment-naïve patients with MET exon 14 skipping mutation, 68% had overall response rate with a DOR of 12.6 months. Of the 69 previously treated patients, 41% had overall response rate with a DOR of 9.7 months. Common AEs included peripheral edema and nausea, mostly grade 1 and 2; the drug was generally well tolerated.

Additionally, tepotinib (Tepmetko), which targets MET exon 14 skipping mutation, received accelerated FDA approval in February 2021. Approval was based on a phase 2 VISION study (NCT02864992).⁶ It 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 has been the August 2022 approval of HER2 targeted antibody and topoisomerase inhibitor conjugate, fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with unresectable or metastatic HER2-mutated NSCLC after prior systemic therapy. Efficacy was proven in the DESTINY-Lung02, a phase 2 randomized 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 achieved in 52 patients receiving a dose of 5.4 mg/kg every 3 weeks. Treatment-related interstitial lung disease of any grade occurred in 5.9% of the patients in the safety analysis set (n = 101). This approval is expected to become the standard of care for NSCLC with HER2 mutation following progression after prior systemic therapies.

Promising Targets

Several novel targets and new drugs for existing targets are being evaluated in multiple clinical trials and hold promise in the evolution of the targeted therapy landscape for the treatment of NSCLC.

Recently, results from the phase 2 arm of the KRYSTAL-1 trial (NCT03785249) exploring activity of selective and irreversible KRAS G12C inhibitor, adagrasib (MRTX849) were reported.⁸ Mutations in KRAS G12C are estimated in about 14% of adenocarcinoma and 0.5% of squamous cell NSCLC. Compared with sotorasib, adagrasib has a longer drug half-life. In the trial, 116 patients received treatment, majority 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 also showed promising activating in patients with central nervous system (CNS) metastases.

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

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 ZENITH20 study (NCT03318939) of previously treated patients. Of the 90 patients included in the study, 27.8% achieved an overall response and a median DOR of 5.1 months at 9.0 months follow-up.⁹ Clinical benefit was noted in patients with CNS metastases as well. Common AEs were diarrhea, stomatitis, and rash. It was granted a fast track designation by FDA, however, in September 2022, FDA’s Oncologic Drug Advisory Committee determined that the agent does not provide substantial benefit relative to its risks.¹⁰ Compared to other targeted therapies the lower overall response rates observed among drugs targeting HER2 exon 20 is a cause for concern and subject to further analysis.

Prytonib, 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 trial included 78 patients with majority harboring HER2 exon 20 insertion mutations. An ORR of 19.2% and a DOR of 9.9 months were reported.

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

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

Practice Points for Community Oncologists

The field of advanced NSCLC is rapidly evolving with drugs against novel targets and newer therapies for existing targets showing promising activity. Additionally, combination of targeted therapies with other systemic therapies such as immunotherapy are being explored. With the availability of multiple targeted therapies, optimal sequencing and drug selection when more than 1 option is available remain a matter of active interest.

_References:

_{1. 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 from the chrysalis phase I 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 insertion-positive metastatic non-small cell lung cancer: a phase 1/2 open-label nonrandomized clinical trial. JAMA Oncol. 2021;7(12):e214761. doi:10.1001/jamaoncol.2021.4761}

_{3. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 2021;384(25):2371-2381. doi:10.1056/NEJMoa2103695}

_{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. Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089}

_{5. Wolf J, Seto T, Han JY, et al. Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. 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 DESTINY-Lung02 trial. Ann 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 harboring a 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 harboring HER2 Exon 20 insertion mutations after prior therapies: ZENITH20-2 trial. J Clin Oncol. 2022;40(7):710-718. doi:10.1200/JCO.21.01323}

_{10. Oncologic Drugs Advisory Committee (ODAC) Meeting, September 22-23, 2022 (Day 1). Streamed live September 22, 2022. Accessed November 18, 2022. https://bit.ly/3LNcW9a}

_{11. Song Z, Li Y, Chen S, et al. Efficacy and safety of pyrotinib in advanced lung adenocarcinoma with HER2 mutations: a multicenter, single-arm, phase II trial. BMC Med. 2022;20(1):42. Published 2022 Feb 1. 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 patients (pts) with NSCLC 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 the NRG1 fusion reveals durable response to afatinib in lung adenocarcinoma: a case report. Ann Transl Med. 2021 Oct;9(19):1507. doi: 10.21037/atm-21-3923}