Year in Review – NSCLC - Physician's Weekly

2024 Year in Review: Therapeutics, Diagnostics, and Deep Learning Models 

NSCLC

Alecensa Receives FDA Approval for ALK+ NSCLC

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The recommended dosage of alectinib is 600 mg orally twice daily with food for 2 years or until disease recurrence or unacceptable toxicity.

On April 18, the FDA approved alectinib (Alecensa, Genentech, Inc.) as adjuvant treatment following tumor resection in patients with anaplastic lymphoma kinase (ALK)−positive non-small cell lung cancer (NSCLC).₁₋₃

Approval was based on results demonstrated in the ALINA study, which included patients with ALK-positive NSCLC who had complete tumor resection. Patients were required to have resectable stage IB (tumors ≥4 cm) to IIIA NSCLC with ALK rearrangements. A total of 257 patients were randomized 1:1 to receive either alectinib 600 mg twice daily for 24 months or four 21-day cycles of platinum-based chemotherapy.

Alectinib significantly improved disease-free survival, particularly in patients with stage II or IIIA disease. After 2 years, 93.8% of patients who received alectinib were disease-free compared with 63% who received platinum-based chemotherapy. Alectinib also demonstrated a marked increase in CNS disease-free survival.

NSCLC

Neoadjuvant/Adjuvant Imfinzi Receives FDA Approval for Resectable NSCLC

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On August 15, the FDA approved durvalumab (Imfinzi, AstraZeneca) with platinum-containing chemotherapy as neoadjuvant treatment, followed by single-agent durvalumab as adjuvant treatment after surgery for adults with resectable (tumors ≥4 cm and/or node positive) NSCLC and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements.₄₋₅

Efficacy was determined in the AEGEAN study, which included 802 patients with previously untreated and resectable squamous or nonsquamous NSCLC (stage IIA to select stage IIIB). Patients were randomized 1:1 to receive either durvalumab or placebo, with platinum-based chemotherapy, every 3 weeks for up to 4 cycles (neoadjuvant treatment), followed by either continued single-agent durvalumab or placebo, every 4 weeks for up to 12 cycles (adjuvant treatment).

The pathologic complete response rate was 17.0% for durvalumab and 4.3% for placebo. Event-free survival was observed in 73.4% of patients who received durvalumab plus chemotherapy compared with 64.5% of patients who received placebo plus chemotherapy.

For patients with a body weight of 30 kg or more, the recommended durvalumab dosage is 1,500 mg every 3 weeks (neoadjuvant treatment) and every 4 weeks (adjuvant treatment). For patients with a body weight of less than 30 kg, the recommended dosage is 20 mg/kg. Durvalumab should be administered before chemotherapy when administered on the same day.

NSCLC

New FDA Approval of Opdivo for Patients With Resectable NSCLC

The study demonstrated an event-free survival (EFS) benefit with neoadjuvant nivolumab followed by adjuvant single-agent nivolumab. Eighteen-month EFS was 70.2% in the nivolumab group and 50% in the chemotherapy group. There was a pathologic complete response in 25.3% of patients in the nivolumab group and 4.7% of patients in the chemotherapy group, along with a major pathologic response in 35.4% and 12.1%, respectively.

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The recommended dosage of nivolumab is 360 mg every 3 weeks (neoadjuvant treatment) and 480 mg every 4 weeks (adjuvant treatment). Nivolumab should be administered before chemotherapy when administered on the same day.

On October 3, the FDA approved nivolumab (Opdivo, Bristol Myers Squibb Company) with platinum-doublet chemotherapy as neoadjuvant treatment, followed by single-agent nivolumab after surgery as adjuvant treatment, for adults with resectable stage IIA-IIIB disease (tumors ≥4 cm and/or node positive) NSCLC and without known EGFR mutations or anaplastic lymphoma kinase (ALK) rearrangements.₆₋₈

Approval was based on findings in the CHECKMATE-77T trial, which included 461 patients with previously untreated and resectable NSCLC (stage IIA to select stage IIIB). Researchers randomized patients 1:1 to receive either nivolumab or placebo, with platinum-based chemotherapy, every 3 weeks for up to 4 cycles (neoadjuvant treatment), followed by either single-agent nivolumab or placebo every 4 weeks for up to 13 cycles (adjuvant treatment).

NSCLC

FDA Approves Tagrisso for Locally Advanced or Metastatic NSCLC and for Unresectable (Stage III) NSCLC

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Osimertinib also received approval on September 25 for adults with locally advanced, unresectable (stage III) NSCLC whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy and whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations. Efficacy was evaluated in the LAURA trial, which included 216 adults randomized 2:1 to receive either osimertinib 80 mg orally once daily or placebo until disease progression or unacceptable toxicity. Median PFS was 39.1 months in the osimertinib arm and 5.6 months in the placebo arm.₁₁₋₁₂

For both approvals, the recommended dosage of osimertinib is 80 mg once daily, with or without food, until disease progression or unacceptable toxicity.

On February 16, the FDA approved osimertinib (Tagrisso, AstraZeneca Pharmaceuticals LP) with platinum-based chemotherapy for patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations. Approval was based on findings in the FLAURA 2 trial, which included 557 patients randomized 1:1 to receive either osimertinib (80 mg once daily) with chemotherapy (pemetrexed) plus either cisplatin or carboplatin or to receive osimertinib monotherapy (80 mg once daily). Median progression-free survival (PFS) was 25.5 months for osimertinib plus platinum-based chemotherapy and 16.7 months for osimertinib monotherapy. At 24 months, 57% of the patients in the osimertinib-chemotherapy group and 41% in the osimertinib group were alive and progression-free.₉₋₁₀

NSCLC

FDA Approves Amivantamab for Locally Advanced or Metastatic NSCLC

On March 1, the FDA approved amivantamab-vmjw (Rybrevant, Janssen Biotech, Inc.) with carboplatin and pemetrexed for the first-line treatment of locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations as detected by Guardant360 CDx (Guardant Health, Inc.), as well as for those patients whose disease has progressed on or after platinum-based chemotherapy. Approval was based on findings in the PAPILLON trial, which randomized 308 patients 1:1 to receive amivantamab-vmjw with carboplatin and pemetrexed or carboplatin and pemetrexed. Progression-free survival (PFS) was significantly longer in the amivantamab-chemotherapy group than in the chemotherapy group (median, 11.4 months and 6.7 months, respectively). The recommended amivantamab-vmjw dosage is based on body weight and administered as an intravenous infusion after dilution.₁₃₋₁₄

The FDA granted several approvals for amivantamab in 2024, as follows:

On August 19, the FDA approved lazertinib (Lazcluze, Janssen Biotech, Inc.) in combination with amivantamab-vmjw for the first-line treatment of locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations. Approval was based on findings in the MARIPOSA trial, which included 1,074 patients randomized 2:2:1 to receive lazertinib in combination with amivantamab-vmjw, osimertinib monotherapy or lazertinib monotherapy (unapproved regimen for NSCLC) until disease progression or unacceptable toxicity. Median PFS was 23.7 months in the amivantamab–lazertinib group versus 16.6 months in the osimertinib group. The recommended dosage of lazertinib is 240 mg orally once daily, administered with amivantamab-vmjw with or without food. The recommended amivantamab-vmjw dosage is based on baseline body weight and administered as an intravenous infusion after dilution.₁₅₋₁₇

On September 19, the FDA approved amivantamab-vmjw with carboplatin and pemetrexed for adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor. Efficacy was evaluated in the MARIPOSA-2 trial, which included 657 patients who were randomized 1:2:2 to receive amivantamab-vmjw with carboplatin and pemetrexed, carboplatin and pemetrexed, or amivantamab-vmjw as part of another combination regimen. PFS was significantly longer for amivantamab-chemotherapy and amivantamab–lazertinib–chemotherapy versus chemotherapy (median of 6.3 months, 8.3 months, and 4.2 months, respectively). The recommended amivantamab-vmjw dosage is based on baseline body weight and administered as an intravenous infusion after dilution.₁₈₋₁₉

NSCLC

Tepotinib Approved for Adults With NSCLC

On February 15, the FDA approved tepotinib (Tepmetko, EMD Serono, Inc.) for adult patients with metastatic NSCLC harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations. Efficacy was demonstrated in a study of 313 patients who received 450 mg of tepotinib once daily until disease progression or unacceptable toxicity. The objective response rate was 51.4% , with a median response duration of 18 months.₂₀₋₂₂

Thirty of 69 patients (43%) with NSCLC who had not been previously treated and received Tepmetko experienced complete or partial shrinkage of their tumors. Tumor shrinkage lasted more than 6 months for 67% of those patients.₂₃

Thirty-six of 83 patients (43%) with NSCLC who had been previously treated and received tepotinib experienced partial shrinkage of tumors. Tumor shrinkage lasted more than 6 months for 75% of those patients.

The recommended tepotinib dosage is 450 mg orally once daily with food.₂₃

NSCLC

NCCN Clinical Practice Guidelines on NSCLC

The National Comprehensive Cancer Network released guidelines on non-small cell lung cancer (NSCLC), including the following:₂₄

Single-agent osimertinib is recommended as preferred treatment for patients with advanced or metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R mutations.

Afatinib or osimertinib is recommended as preferred first-line therapy for patients with advanced or metastatic NSCLC with EGFR S768I, L861Q, and/or G719X mutations.

Amivantamab-vmjw is recommended in combination with carboplatin and pemetrexed as a category 1 and preferred treatment for patients with advanced or metastatic nonsquamous EGFR exon 20 insertion mutation-positive NSCLC.

Alectinib, brigatinib, or lorlatinib is recommended as preferred first-line therapy for patients with advanced or metastatic NSCLC and ALK rearrangements.

Entrectinib, crizotinib, or repotrectinib are preferred first-line treatments for patients with ROS1-positive advanced or metastatic NSCLC.

Dabrafenib plus trametinib or encorafenib plus binimetinib is recommended as preferred first-line therapy for patients with BRAF V600E mutation-positive advanced or metastatic NSCLC.

Capmatinib, tepotinib, or crizotinib is recommended as first-line treatment for patients with advanced or metastatic NSCLC and METex14 skipping mutation.

Larotrectinib or entrectinib is recommended as preferred first-line therapy for patients with NTRK1/2/3 gene fusion-positive advanced or metastatic NSCLC.

Selpercatinib or pralsetinib is recommended as preferred first-line therapy for patients with advanced or metastatic NSCLC and RET rearrangements.

NSCLC

American Radium Society Releases Guidelines for Unresectable Locally Advanced NSCLC

The American Radium Society (ARS) published guidelines for NSCLC that include the following:₂₅₋₂₆

The ARS guidelines recommend standard care for patients with good prognosis, which involves concurrent platinum-based chemoradiation (60-70 Gy) followed by consolidation durvalumab immunotherapy, especially for patients without disease progression.

Advanced radiotherapy techniques, such as intensity-modulated radiotherapy (IMRT), are preferred for their precision. Different fractionation schedules are available based on the patient’s performance and pulmonary status. To minimize toxic effects, sequential therapy or radiation alone is advised for patients with poor prognoses.

For patients with bulky disease where radical radiotherapy is not feasible upfront, sequential chemotherapy followed by radiotherapy is recommended; in cases of epidermal growth factor receptor (EGFR)−positive, unresectable, locally advanced NSCLC, concurrent chemoradiation remains standard, but consolidation immunotherapy is generally considered inappropriate, suggesting a potential role for tyrosine kinase inhibitors instead.

In symptomatic patients with poor performance status, the ARS considers palliative radiotherapy schedules such as 30 Gy in 10 fractions or 40-45 Gy in 15 fractions to be appropriate. For radical treatment, doses such as 50-55 Gy in 20 fractions are favored.

For asymptomatic patients with poor performance status, treatment may include radiation therapy alone or in combination with systemic therapies, avoiding concurrent chemoradiation because of its potential adverse effects.

2. FDA Approves Alectinib as Adjuvant Treatment for ALK-Positive Non-Small Cell Lung Cancer. FDA.gov. April 18, 2024. Accessed November 22, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-alectinib-adjuvant-treatment-alk-positive-non-small-cell-lung-cancer

NSCLC

References

1. Alecensa Approved as First and Only ALK Inhibitor for Non-Small Cell Lung Cancer. Physician’s Weekly. April 23, 2024. Accessed November 22, 2024. https://www.physiciansweekly.com/alecensa-approved-as-first-and-only-alk-inhibitor-for-non-small-cell-lung-cancer/

3. Arter ZL, Nagasaka M. Redefining Recovery: The Transformative Impact of the ALINA Trial on Adjuvant Therapy for ALK-Positive Non-Small Cell Lung Cancer. Lung Cancer (Auckl). 2024;15:129-133. Published 2024 Aug 28. doi:10.2147/LCTT.S478054

4. FDA Approves Neoadjuvant/Adjuvant Durvalumab for Resectable Non-Small Cell Lung Cancer FDA.gov. August 15, 2024. Accessed November 18, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvantadjuvant-durvalumab-resectable-non-small-cell-lung-cancer

5. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med. 2023;389(18):1672-1684. doi:10.1056/NEJMoa2304875

6. FDA Approves Neoadjuvant/Adjuvant Nivolumab for Resectable Non-Small Cell Lung Cancer. FDA.gov. October 3, 2024. Accessed November 22, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvantadjuvant-nivolumab-resectable-non-small-cell-lung-cancer

7. Cascone T, Awad MM, Spicer JD, et al. Perioperative Nivolumab in Resectable Lung Cancer. N Engl J Med. 2024;390(19):1756-1769. doi:10.1056/NEJMoa2311926

8. Perioperative Nivolumab Beneficial for Resectable NSCLC. Physician’s Weekly. September 13, 2024. Accessed November 22, 2024. https://www.physiciansweekly.com/perioperative-nivolumab-beneficial-for-resectable-nsclc/

10. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434

NSCLC

References

9. FDA Approves Osimertinib With Chemotherapy for EGFR-Mutated Non-Small Cell Lung Cancer. FDA.gov. February 16, 2024. Accessed November 22, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer

11. FDA Approves Osimertinib for Locally Advanced, Unresectable (Stage III) Non-Small Cell Lung Cancer Following Chemoradiation Therapy. FDA.gov. September 28, 2024. Accessed November 22, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-locally-advanced-unresectable-stage-iii-non-small-cell-lung-cancer

12. Lu S, Kato T, Dong X, et al. Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC. N Engl J Med. 2024;391(7):585-597. doi:10.1056/NEJMoa2402614

13. FDA Approves Amivantamab-vmjw for EGFR Exon 20 Insertion-Mutated Non-Small Cell Lung Cancer Indications. FDA.gov. March 1, 2024. Accessed November 18, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-amivantamab-vmjw-egfr-exon-20-insertion-mutated-non-small-cell-lung-cancer-indications

14. Zhou C, Tang KJ, Cho BC, et al. Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. N Engl J Med. 2023;389(22):2039-2051. doi:10.1056/NEJMoa2306441

15. FDA Approves Lazertinib with Amivantamab-vmjw for Non-Small Cell Lung Cancer. FDA.gov. August 29, 2024. Accessed November 22, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lazertinib-amivantamab-vmjw-non-small-lung-cancer

16. Amivantamab and Lazertinib in Untreated EGFR-Mutated Advanced NSCLC. Physician’s Weekly. July 20, 2024. Accessed November 18, 2024. https://www.physiciansweekly.com/amivantamab-and-lazertinib-in-untreated-egfr-mutated-advanced-nsclc/

17. Cho BC, Lu S, Felip E, et al. Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498. doi:10.1056/NEJMoa2403614

19. Passaro A, Wang J, Wang Y, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024;35(1):77-90. doi:10.1016/j.annonc.2023.10.117

NSCLC

References

18. FDA Approves Amivantamab-vmjw With Carboplatin and Pemetrexed for Non-Small Cell Lung Cancer With EGFR Exon 19 Deletions or L858R Mutations. FDA.gov. September 29, 2024. Accessed November 22, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-amivantamab-vmjw-carboplatin-and-pemetrexed-non-small-cell-lung-cancer-egfr-exon-19

20. FDA Approves Tepotinib for Metastatic Non-Small Cell Lung Cancer. FDA.gov. February 15, 2024. Accessed November 22, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tepotinib-metastatic-non-small-cell-lung-cancer

21. 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

22. Mazieres J, Paik PK, Garassino MC, et al. Tepotinib Treatment in Patients With MET Exon 14-Skipping Non-Small Cell Lung Cancer: Long-term Follow-up of the VISION Phase 2 Nonrandomized Clinical Trial [published correction appears in JAMA Oncol. 2023 Sep 1;9(9):1300. doi: 10.1001/jamaoncol.2023.2810]. JAMA Oncol. 2023;9(9):1260-1266. doi:10.1001/jamaoncol.2023.1962

23. Drug Trials Snapshot: TEPMETKO. FDA.gov. November 14, 2022. Accessed November 19, 2024. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-tepmetko

24. Riely GJ, Wood DE, Ettinger DS, et al. Non-Small Cell Lung Cancer, Version 4.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2024;22(4):249-274. doi:10.6004/jnccn.2204.0023

25. Guidelines Address Specific Clinical Scenarios in Unresectable, Locally Advanced NSCLC. Physician’s Weekly. June 14, 2024. Accessed November 22, 2024. https://www.physiciansweekly.com/guidelines-address-specific-clinical-scenarios-in-unresectable-locally-advanced-nsclc/

26. Rodrigues G, Higgins KA, Rimner A, et al. American Radium Society Appropriate Use Criteria for Unresectable Locally Advanced Non-Small Cell Lung Cancer. JAMA Oncol. 2024;10(6):799-806. doi:10.1001/jamaoncol.2024.0294

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