EGFR-Targeted TKIs Continue to Have Outsized Impact in NSCLC

Thomas J. Lynch Jr, MD

Since the initial discovery of EGFR mutations in non–small cell lung cancer (NSCLC) and the first FDA approvals of EGFR-directed TKIs in the early 2000s, these agents have redefined the treatment landscape in EGFR-mutated advanced NSCLC and continue to have an impact as they are moved into earlier lines of therapy, according to Thomas J. Lynch Jr, MD. During his presentation at the 21st Annual Winter Lung Cancer Conference^®, Lynch Jr detailed how treatments are evolving.¹

“In 2024, more than 2 million new cases are expected of cancer in the United States, and we’ll have 611,000 deaths,” Lynch Jr, president and director, as well as the Raisbeck Endowed Chair for the President and Director, at Fred Hutch Cancer Center in Seattle, Washington, said during the presentation. “The overall cancer adjusted death rate is 144 [deaths] per 100,000 [people]. Lung cancer is still the leading cause of cancer-related death—it accounts for 20% of all cancer deaths….[We feel] passionately about the idea of taking agents that work in metastatic disease and bringing them into the earlier setting where they can cure patients, [particularly those with] EGFR-mutated disease.”

Evaluating Osimertinib In FLAURA and FLAURA2

Lynch Jr began his discussion by reviewing findings from the phase 3 FLAURA trial (NCT02296125), which compared the third-generation EGFR-directed TKI osimertinib (Tagrisso) with the EGFR TKIs gefitinib (Iressa) or erlotinib (Tarceva) in patients with untreated, EGFR-mutated advanced NSCLC. The primary end point was investigator-assessed progression-free survival (PFS); secondary end points included objective response rate (ORR), duration of response (DOR), overall survival (OS), and safety.²

At the June 12, 2017, data cutoff, the median PFS in the osimertinib arm (n = 279) was 18.9 months (95% CI, 15.2-21.4) vs 10.2 moths (95% CI, 9.6-11.1) in the standard-of-care arm (n = 277; HR, 0.46; 95% CI, 0.37-0.57; P < .001). Moreover, findings from the final analysis of the study showed that, at the June 25, 2019, data cutoff, the median OS was 38.6 months (95% CI, 34.5-41.8) compared with 31.8 months (95% CI, 26.6-36.0), respectively (HR, 0.80; 95% CI, 0.64-1.00; P = .046).

Building off the positive findings from FLAURA, the phase 3 FLAURA2 study (NCT04035486) evaluated osimertinib plus chemotherapy vs osimertinib monotherapy in patients with EGFR-mutated advanced NSCLC. Adult patients who had not received systemic therapy for advanced disease were randomly assigned 1:1 to receive the combination (n = 279) or osimertinib monotherapy (n = 278). The primary end point was investigator-assessed PFS; secondary end points included OS, ORR, and safety.³

Updated findings from FLAURA2, presented during the 2023 IASLC World Conference on Lung Cancer, demonstrated that the median PFS in the combination arm was 29.4 months (95% CI, 25.1-not calculable [NC]) vs 19.9 months (95% CI, 16.6-25.3) in the monotherapy arm (HR, 0.62; 95% CI, 0.48-0.80; P = .0002). Additionally, the combination provided a significant PFS benefit over osimertinib monotherapy in both patients with (HR, 0.47; 95% CI, 0.33-0.66) and without (HR, 0.75; 95% CI, 0.55-1.03) central nervous system (CNS) metastases, as well as patients with ex19del (HR, 0.60; 95% CI, 0.44-0.83) or L858R (HR, 0.63; 95% CI, 0.44-0.90) EGFR mutations at baseline.

“There are more adverse effects [AEs] in the patients who get chemotherapy as one would expect, more hematologic AEs [and] more fatigue in this setting. The AE rate was slightly higher in the group that received osimertinib plus platinum. This brings up a couple of questions. I’ve heard the 2 places [clinicians] feel most enthusiastic about [the combination] is for patients with large volume and bulky disease where you want a response as quickly as possible, and possibly in the setting of brain metastasis. We don’t have final survival data on that yet, so that will be something to look at,” Lynch Jr noted.

Evaluating Amivantamab In The MARIPOSA Trial

During the 2023 ESMO Congress, investigators presented updated findings from the phase 3 MARIPOSA study (NCT04487080), which compared the safety and efficacy of the EGFR/MET bispecific antibody amivantamab-vmjw (Rybrevant) combined with lazertinib (Leclaza) as therapy for patients with advanced NSCLC harboring EGFR ex19del or L858R mutations. Patients were randomly assigned 2:2:1 to amivantamab plus lazertinib (n = 429), osimertinib alone (n = 429), or lazertinib alone (n = 216). The primary end point was PFS by blinded independent central review per RECIST 1.1 criteria for the amivantamab plus lazertinib arm compared with osimertinib. Secondary end points included OS, ORR, DOR, and safety.⁴

At a median follow-up of 22.0 months, the median PFS was 23.7 months (95% CI, 19.1-27.7) in the combination arm vs 16.6 months (95% CI, 14.8-18.5) in the osimertinib monotherapy arm (HR, 0.70; 95% CI, 0.58-0.85; P <.001). The 12- and 24-month PFS rates with the combination were 73% and 48%, respectively, vs 65% and 34% with osimertinib monotherapy. Additionally, the median PFS in the lazertinib monotherapy arm was 18.5 months (95% CI, 14.8-20.1).

A consistent PFS benefit was observed with the combination vs osimertinib monotherapy in patients with (HR, 0.69; 95% CI, 0.53-0.92) and without (HR, 0.69; 95% CI, 0.53-0.89) CNS metastases. The ORR in the combination arm vs the osimertinib monotherapy arm was 86% (95% CI, 83%-89%) vs 85% (95% CI, 81%-88%), respectively, including respective complete response rates of 7% and 4%. The median DOR was 25.8 months (95% CI, 20.1-not estimable [NE]) vs 16.8 months (95% CI, 14.8-18.5), respectively. Interim OS data favored the combination vs osimertinib monotherapy (HR, 0.80; 95% CI, 0.61-1.05; P = .11).

In terms of safety, grade 3 or greater AEs occurred at a rate of 75% in the combination arm vs 43% in the osimertinib monotherapy arm. Serious AEs occurred in 49% and 33% of patients and AEs leading to death occurred in 8% and 7% of patients, respectively. Venous thromboembolism represented an AE of special interest, occurring at a frequency of 37% overall in patients in the combination arm compared with 9% in the osimertinib monotherapy arm.

“This does look like an advance in the treatment of lung cancer and certainly an option to consider for patients. If you do comprehensive molecular profiling, there may be patients that emerge as those where this becomes a preferred treatment. Whether this will replace osimertinib, I leave to those of you to determine with time as we see the maturity of the OS data and get a sense of how that plays out, but it’s certainly not an unreasonable scenario,” Lynch Jr said.

A Role for Amivantamab Treating Exon 20 Insertions?

Lynch Jr then transitioned to highlight findings from the phase 3 PAPILLON trial (NCT04538664), which evaluated amivantamab plus chemotherapy (n = 153) vs chemotherapy alone (n = 155) in patients with EGFR exon 20 insertions who experienced disease progression during or after platinum-based chemotherapy. The primary end point was PFS; secondary end points included ORR, OS, DOR, and safety.⁵

At a median follow-up of 14.9 months, the median PFS was 11.4 months (95% CI, 9.8-13.7) in the amivantamab plus chemotherapy arm vs 6.7 months (95% CI, 5.6-7.3) in the chemotherapy alone arm (HR, 0.40; 95% CI, 0.30-0.53; P < .001). The ORR was 73% (95% CI, 65%-80%) vs 47% (95% CI, 39%-56%), respectively, and the median OS was NE vs 24.4 months (95% CI, 22.1-NE), respectively (HR, 0.67; 95% CI, 0.42-1.09; P = .11).

“There is 1 place where amivantamab plus chemotherapy makes sense and that’s in patients with exon 20 insertions. One type of [EGFR mutation] that is particularly difficult to treat, is the exon 20 insertion. This us not the type [of mutation] that has great response to osimertinib alone in this setting,” Lynch commented.

Further Examining Osimertinib in Adjuvant Disease

Lynch Jr concluded his presentation by discussing findings from the phase 3 ADAURA trial (NCT02511106), which evaluated adjuvant osimertinib vs placebo in patients with completely resected, EGFR-mutated stage IB to IIIANSCLC with or without adjuvant chemotherapy. The primary end point was disease-free survival (DFS) in patients with stage II/IIIA disease; secondary end points included DFS in the overall population, OS, and safety.⁶

The median DFS among patients with stage II/III disease who received osimertinib (n = 233) was not reached (NR; 95% CI, 38.8-NC) vs 19.6 months (95% CI, 16.6-24.5) in the placebo arm (n = 237; HR, 0.17; 99.06% CI, 0.11-0.26; P < .0001). In the overall population, the median DFS was NR (95% CI, NC-NC) vs 27.5 months (95% CI, 22.0-35.0) in the investigational vs control arm, respectively (HR, 0.20; 99.12% CI, 0.14-0.30; P < .0001).

Data from the final analysis for OS showed that, at the January 27, 2023, data cutoff, the 5-year OS rate was 85% (95% CI, 79%-89%) in the osimertinib arm (n = 233) vs 73% (95% CI, 66%-78%) in the placebo arm (n = 237) among patients with stage II to IIIA disease (HR, 0.49; 95.03% CI, 95% CI, 0.33-0.73; P < .001). Osimertinib also offered a significant OS benefit over placebo in patients with stage IB to IIIA disease (HR, 0.49; 95.03% CI, 0.34-0.70; P < .001), those who received adjuvant chemotherapy (HR, 0.49; 95% CI, 0.30-0.79), and those who did not receive adjuvant chemotherapy (HR, 0.47; 95% CI, 0.25-0.83).⁷

“[This study uses] the idea of taking an active drug from late disease and moving it into early disease,” Lynch said. “In the primary population, which was stage IIA to IIIA, you can see a clear benefit with osimertinib vs placebo. In the overall population, a benefit was seen as well. When one looks at patients with earlier stage disease [as well as] patients with later stage disease, you see a benefit. Looking at the survival graphs, the benefit is greater in patients with stage III disease compared with II compared with I….whether you got adjuvant chemotherapy or not didn’t seem to matter, there seemed to be a benefit to osimertinib in that setting. [I believe] this is an important advance.”

References

1. Lynch TJ. Giants of Cancer Care Lecture - 20 years of targeting EGFR: where are we in 2024? Presented at: 21st Annual Winter Lung Cancer Conference; February 2-4, 2024; Hollywood, FL.
2. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662
3. Janne P, PLanchard D, Cheng Y, et al. Osimertinib with/without platinum-based chemotherapy as first-line treatment in patients with EGFRm advanced NSCLC (FLAURA2). J Thorac Oncol. 2023;18(suppl 11):36-37. doi:10.1016/j.jtho.2023.09.009
4. Cho BC, Felip E, Spira AI, et al. Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results from MARIPOSA, a phase III, global, randomized, controlled trial. Ann Oncol. 2023;34(suppl 2):1306. doi:10.1016/j.annonc.2023.10.062
5. 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
6. Herbst RS, Wu YL, John T, et al. Adjuvant osimertinib for resected EGFR-mutated stage IB-IIIA non-small-cell lung cancer: Updated results from the phase III randomized ADAURA trial. J Clin Oncol. 2023;41(10):1830-1840. doi:10.1200/JCO.22.02186
7. Tsuboi M, Herbst RS, John T, et al. Overall survival with osimertinib in resected EGFR-mutated NSCLC. N Engl J Med. 2023;389(2):137-147. doi:10.1056/NEJMoa2304594