Non–Small Cell Lung Cancer

Initial US Approval

• 2015¹

Indications

Adjuvant Therapy mEGFR NSCLC:

• Adjuvant therapy after tumor resection in adult patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.

Unresectable mEGFR NSCLC:

• The treatment of adult patients 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, as detected by an FDA-approved test.

Metastatic mEGFR NSCLC (1L):

• The first-line treatment of adult patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.
• In combination with pemetrexed and platinum-based chemotherapy, the first-line treatment of adult patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.
• The treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR TKI therapy.

Recommended Dose/Route

• Osimertinib, administered at a dose of 80 mg orally once daily with or without food, is indicated for advanced unresectable or metastatic NSCLC until disease progression or the development of unacceptable toxicity.¹
• In early-stage NSCLC, it is approved as adjuvant therapy for a duration of up to 3 years.¹

Dose Reductions for Adverse Reactions

• No dose reduction is recommended; however, when restarting osimertinib after specific adverse reactions that have improved to Grade 0-2 within 3 weeks, dose should be resumed at 80 mg or 40 mg.¹

Pivotal Studies

ADAURA² (NCT02511106)

• Treatment Setting: Adjuvant Therapy, Early Stage EGFR Mutation-Positive NSCLC
• Key Inclusion: Eligible patients with resectable tumors (stage IB – IIIA according to American Joint Commission on Cancer [AJCC] 7th edition) were required to have predominantly non-squamous histology and EGFR exon 19 deletions or exon 21 L858R mutations identified prospectively from tumor tissue in a central laboratory by the cobas® EGFR Mutation Test.
• Treatment: Osimertinib 80 mg once daily or placebo for three years or until disease recurrence, or unacceptable toxicity.

ADAURA: Efficacy Data

LAURA⁶ (NCT03521154)

• Treatment Setting: Locally Advanced, Unresectable (Stage III) EGFR Mutation Positive NSCLC
• Key Inclusion: Patients with locally advanced, unresectable stage III NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations whose disease had not progressed during or following definitive platinum-based chemoradiation therapy.
• Treatment: Eligible patients had completed concurrent or sequential platinum-based chemoradiotherapy within 6 weeks before undergoing randomization and were without investigator-assessed disease progression during or after definitive chemoradiotherapy. After completing chemoradiotherapy, patients underwent randomization in a 2:1 ratio to receive either oral osimertinib at a dose of 80 mg once daily or placebo, until disease progression was shown by means of objective radiologic confirmation, as assessed by blinded independent central review.

LAURA: Efficacy Data

FLAURA³ (NCT02296125)

• Treatment Setting: Previously Untreated, Metastatic EGFR Mutation-Positive NSCLC
• Key Inclusion: Patients who had not received previous systemic treatment for metastatic disease were required to have measurable disease per RECIST v1.1, a WHO performance status of 0-1, and EGFR exon 19 deletions or exon 21 L858R mutation in tumor prospectively identified by the cobas® EGFR Mutation Test in a central laboratory or by an investigational assay at a CLIA-certified or accredited laboratory.
• Treatment: Osimertinib 80 mg, gefitinib 250 mg, or erlotinib 150 mg orally once daily until disease progression or unacceptable toxicity.

FLAURA: Efficacy Data

FLAURA2⁴ (NCT04035486)

• Treatment Setting: Previously Untreated, EGFR Mutation-Positive Locally Advanced or Metastatic NSCLC
• Key Inclusion: Patients who had not received previous systemic treatment for advanced disease were required to have measurable disease per RECIST v1.1, a WHO performance status of 0-1, and EGFR exon 19 deletions or exon 21 L858R mutations as identified by the cobas® EGFR Mutation Test v2 performed prospectively in tissue samples in a central laboratory or by a local test performed in a CLIA-certified or accredited laboratory.
• Treatment: Osimertinib 80 mg orally once daily (monotherapy) or osimertinib 80mg orally once daily with pemetrexed (500 mg/m2) and investigator’s choice of cisplatin (75 mg/m2) or carboplatin (AUC5) administered intravenously on Day 1 of 21-day cycles for 4 cycles, followed by osimertinib (80 mg) orally once daily and pemetrexed (500 mg/m2) administered intravenously every 3 weeks (combination therapy).

FLAURA2: Efficacy Data

AURA3⁵ (NCT02151981)

• Treatment Setting: Previously Treated EGFR T790M Mutation-Positive Metastatic NSCLC
• Key Inclusion: Patients who had progressed on prior systemic therapy, incusing an EGFR TKI were required to have EGFR T790M mutation-positive NSCLC identified by the cobas® EGFR Mutation Test performed in a central laboratory prior to randomization.
• Treatment: Osimertinib 80 mg orally once daily until intolerance to therapy, disease progression, or investigator determination that the patient was no longer benefiting from treatment or pemetrexed 500 mg/m2 with carboplatin AUC5 or pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 on Day 1 of every 21-day cycle for up to 6 cycles. Patients whose disease had not progressed after four cycles of platinum-based chemotherapy could have received pemetrexed maintenance therapy (pemetrexed 500 mg/m2 on Day 1 of every 21-day cycle).

AURA3: Efficacy Data

Safety

ADAURA^1,2

• Common Adverse Reactions (≥20%): The most frequently reported any grade adverse events (AEs) were diarrhea (47%), rash (40%), nail toxicity (37%), stomatitis (32%), and dry skin (29%).
• Common Laboratory Abnormalities (≥20%): The most frequently reported any grade laboratory abnormalities were leukopenia (54%), thrombocytopenia (47%), lymphopenia (44%), anemia (30%), neutropenia (26%), hyperglycemia (25%), hypermagnesemia (24%), and hyponatremia (20%).
• Dosage Reductions Due to AEs: 9%
• Permanent Discontinuation Due to AEs: 11%

LAURA^1,6

• Common Adverse Reactions (≥20%): The most frequently reported any grade AEs were ILD/pneumonitis (56%), rash (39%), diarrhea (36%), nail toxicity (23%), musculoskeletal pain (20%), and cough (20%).
• Common Laboratory Abnormalities (≥20%): The most frequently reported any grade laboratory abnormalities were lymphopenia (70%), leukopenia (66%), thrombocytopenia (51%), and neutropenia (42%).
• Dosage Interruption Due to AEs: 56%
• Dosage Reductions Due to AEs: 8%
• Permanent Discontinuation Due to AEs: 13%

FLAURA^1,3

• Common Adverse Reactions (≥20%): The most frequently reported any grade AEs were diarrhea (58%), rash (58%), dry skin (36%), nail noxicity (35%), stomatitis (32%), fatigue (21%), and decreased appetite (20%).
• Common Laboratory Abnormalities (≥20%): The most frequently reported any grade laboratory abnormalities were leukopenia, lymphopenia (63%), anemia (59%), thrombocytopenia (51%), neutropenia (41%), hyperglycemia (37%), hypermagnesemia (30%), hyponatremia (26%), increased AST (22%), and increased ALT (21%).
• Dosage Reductions Due to AEs: 2.9%
• Permanent Discontinuation Due to AEs: 13%

FLAURA2^1,4

• Common Adverse Reactions (≥20%): The most frequently reported any grade AEs were rash (49%), diarrhea (43%), stomatitis (31%), nail toxicity (27%), and dry skin (24%).
• Common Laboratory Abnormalities (≥20%): The most frequently reported any grade laboratory abnormalities were leukopenia (88%), thrombocytopenia (85%), neutropenia (85%), lymphopenia (78%), and blood creatine increased (22%).
• Dosage Interruption Due to AEs: 44%
• Permanent Discontinuation Due to AEs: 11%

AURA3^1,5

• Common Adverse Reactions (≥20%): The most frequently reported any grade AEs were diarrhea (41%), rash (34%), dry skin (23%), nail toxicity (22%), and fatigue (22%).
• Common Laboratory Abnormalities (≥20%): The most frequently reported any grade laboratory abnormalities were lymphopenia (63%), thrombocytopenia (46%), anemia (43%), neutropenia (27%), hypermagnesemia (27%), hyponatremia (26%), and hyperglycemia (20%).
• Dosage Reductions Due to AEs: 2.9%
• Permanent Discontinuation Due to AEs: 7%

Osimertinib: Most Common Adverse Events of Grade 3 or 4

References

1. Tagrisso (Osimertinib). Prescribing information. AstraZeneca Pharmaceuticals; 2024. Accessed December 2, 2024. https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/52503580-1192-44f7-a05e-5743159ed19b/52503580-1192-44f7-a05e-5743159ed19b_viewable_rendition__v.pdf
2. Wu Y-L, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071
3. Soria J-C, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi: 10.1056/NEJMoa1713137
4. 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
5. Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376(7):629-640. doi:10.1056/NEJMoa1612674
6. Lu S, Kato T, Dong X, et al.; LAURA Trial Investigators. Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC. N Engl J Med. 2024;391(7):585-597. doi: 10.1056/NEJMoa2402614.
7. Vogel WH, Jennifer P. Management strategies for adverse events associated with EGFR TKIs in non-small cell lung cancer. J Adv Pract Oncol. 2016;7(7):723-735