Emerging Data Highlight Potential for Frontline Combinations in EGFR+ NSCLC

Ongoing research evaluating combination therapies for the frontline treatment of patients with EGFR-mutated non–small cell lung cancer (NSCLC) could help improve survival outcomes for this patient population, according to Julia Rotow, MD.¹

Prior to November 2023, the main first-line therapy utilized for the treatment of patients with EGFR-mutated lung cancer was osimertinib (Tagrisso) monotherapy, based on the phase 3 FLAURA study (NCT02296125). In FLAURA, treatment with osimertinib was superior compared with standard EGFR TKIs and a similar safety profile was observed with lower rates of serious adverse effects (AEs).

In 2018, the FDA expanded the approval of afatinib (Gilotrif) for patients with metastatic NSCLC who harbor EGFR mutations as detected by an FDA-approved test. This approval was based on findings from 3 clinical trials (LUX-Lung 2 [NCT00525148], LUX-Lung 3 [NCT00949650], and LUX-Lung 6 [NCT01121393]), which showed that durable responses were observed in a subset of 32 patients with metastatic NSCLC harboring non-resistant EGFR mutations who were treated with afatinib (S768I, L861Q, and/or G719X), other than exon 19 deletions or exon 21 L858R substitutions.

However, the treatment landscape has expanded within the past 2 months with new data presented at the 2023 ESMO Congress.

Rotow, a medical oncologist at the Dana-Farber Cancer Institute, discussed these impactful and emerging data on upfront therapies for patients with lung cancer harboring EGFR mutations in a presentation titled, “EGFR - Can We Do Better Upfront?”, at the 18th Annual New York Lung Cancers Symposium^®.

FLAURA2

The phase 3 FLAURA2 trial (NCT04035486) evaluated osimertinib with chemotherapy in patients with EGFR-mutated NSCLC with central nervous system (CNS) metastases.²

A total of 557 patients were enrolled and randomly assigned 1:1 to receive either first-line osimertinib with chemotherapy (n = 279) or frontline osimertinib alone (n = 278) until progression or treatment discontinuation.

Patients aged 18 years and older with pathologically confirmed, EGFR-mutated, advanced NSCLC who had not undergone previous treatments and an ECOG performance status of 0 or 1 were eligible for enrollment. Patients who had asymptomatic CNS metastases that either did not require steroids or were stable for at least 2 weeks after receiving definitive treatment or steroids were also eligible for inclusion.

Reports from the study have shown that first-line osimertinib plus chemotherapy significantly improved PFS vs osimertinib monotherapy. In patients with advanced EGFR-mutated NSCLC, the median PFS improved by 38% with the combination vs osimertinib alone. With the combination, the investigator-assessed median PFS was 25.5 months vs 16.7 months with osimertinib monotherapy (P < .0001). The PFS rates for the 2 treatment arms at 2 years were 57% and 41%, respectively.^1,2

Among patients in the osimertinib-treated group, the absolute improvement in PFS was 8.8 months favoring the combination, according to investigator assessment and by 9.5 months based on blinded independent central review (BICR).

This improvement in PFS was consistent across all subgroups, including those with brain metastases. In patients with CNS metastasis at baseline, the median PFS rate was 24.9 months vs 13.8 months with the combination and osimertinib alone, respectively. For patients without baseline CNS metastasis, median PFS rates were 27.6 months vs 21 months, respectively.

“The big takeaways are that the primary end point was PFS and there was a positive improvement in PFS from 16.7 months to 25.5 months with the addition of chemotherapy in the first-line setting,” said Rotow.

According to findings presented at ESMO Congress 2023, osimertinib plus chemotherapy reduced the risk for CNS progression in patients with EGFR-mutated NSCLC with CNS metastases with an estimated 9% risk of developing a CNS lesion at 24 months (95% CI, 4-16) vs an estimated 23% risk (95% CI, 14-33) with osimertinib alone. Further, adding chemotherapy to the EGFR TKI also led to a higher CNS objective response rate (ORR) and better complete response (CR) rate with durable responses compared with osimertinib alone, and the combination was tolerable with a manageable safety profile.

MARIPOSA

In the phase 3 MARIPOSA trial (NCT04487080), the combination of amivantamab-vmjw (Rybrevant) plus lazertinib (Leclaza) reduced the risk of disease progression or death by 30% vs osimertinib (Tagrisso) alone when used in the first-line for patients with advanced NSCLC with classical EGFR sensitizing mutations.³

MARIPOSA enrolled patients with treatment-naive, locally advanced or metastatic NSCLC who had a documented EGFR exon 19 deletion or L858R mutation and an ECOG performance status of 0 or 1. Once enrolled patients were given amivantamab 1050 mg (1400 mg if 80 kg) weekly for the first 4 weeks, then every 2 weeks with lazertinib 240 mg daily. Osimertinib was given to patients at the standard 80 mg once-daily dose.

Findings from the phase 1 CHRYSALIS trial (NCT02609776) previously revealed that amivantamab in combination with lazertinib led to a 100% ORR in 20 patients with treatment-naive, EGFR-mutant advanced NSCLC. Half of the patients were still receiving treatment at a median follow-up of 33.6 months.⁴

“Amivantamab is a bispecific antibody that is FDA-approved for previously-treated [NSCLC with] EGFR exon 20 insertions… Again, similar outcomes occurred with a PFS survival curve that showed again that if you do a combination upfront, you are going to get a better PFS, here 23.7 months vs 16.6 months,” said Rotow.

In MARIPOSA, findings from ESMO 2023 showed that the median PFS was 23.7 months (95% CI, 19.1-27.7) with the combination vs 16.6 months (95% CI, 14.8-18.5) with osimertinib alone at a median follow-up of 22.0 months (HR, 0.70; 95% CI, 0.58-0.85; P <.001). At 12 and 24 months, the PFS rates were 73% and 48% with the combination, respectively, vs 65% and 34% with osimertinib alone. When lazertinib was given alone, the median PFS was 18.5 months (95% CI, 14.8-20.1).

The risk of extracranial progression or death was also reduced with the combination by 32% vs osimertinib alone. Median extracranial PFS was 27.5 months (95% CI, 22.1-not evaluable [NE]) with amivantamab and lazertinib vs 18.5 months (95% CI, 16.5-20.3) with osimertinib alone (HR, 0.68; 95% CI, 0.56-0.83; P <.001). With the combination vs osimertinib monotherapy, the 12- and 24-month extracranial PFS rates were 77% and 53%, respectively, vs 67% and 38%.

Though not yet mature, the interim overall survival (OS) analysis demonstrated a trend favoring the combination of amivantamab and lazertinib (HR, 0.80; 95% CI, 0.61-1.05; P =.11) with estimated 24-month PFS rates of 74% vs 69% with osimertinib alone, respectively.

RAMOS

According to Rotow, it has been seen that EGFR TKIs plus VEGF agents offer benefits in PFS but not OS. Because of this, investigators thought to add an anti-VEGF therapy to third-generation EGFR TKI therapy.

“This is a story we have heard before for first-generation EGFR TKIs. They always improve PFS, but not overall survival. We’ve looked at this a little bit hesitantly over time and always wondered, if you’ve added it to third generation EGFR TKI therapy, what happens? The RAMOSE study looked at this,” Rotow explained.

The randomized, open-label, phase 2 RAMOS trial (NCT03909334) evaluated patients with metastatic EGFR-mutant NSCLC who were treated with oral osimertinib 80 mg daily with ramucirumab 10 mg/kg via intravenous infusion every 3 weeks (arm A) vs osimertinib alone (arm B).⁵

The primary end point was PFS with secondary end points of best response rates (BRR), disease control rate (DCR), overall survival (OS), and safety. Patients were stratified by EGFR mutation type and presence of CNS metastasis.

At the data cutoff date of August 29, 2023, 147 patients received treatment and 139 patients had at least 1 efficacy scan. At a median follow up was 16.6 months (range 1.4-46.1), the median PFS was 24.8 in arm A vs 15.6 months in arm B (HR, 0.55; 95%CI, 0.32-0.93; P = .023). At 12 months, the PFS rates were 76.7% vs 61.9% in arms A vs B (P =.026).

No differences were observed in regard to BRRs and DCRs. For safety, any-grade AEs were seen in 93% of arm A and 87% of arm B, and no grade 5 treatment-related AEs were noted.

“I’m kind of pausing and waiting to see overall survival data, but I do mention it here as something to watch in case there is an overall survival advantage because it is a relatively easy addition if you’re going to add a combination upfront,” added Rotow.

PAPILLON

In the phase 3 PAPILLON trial (NCT04538664), 308 patients with untreated, locally advanced or metastatic NSCLC with a documented EGFR exon 20 insertion mutation and an ECOG performance status of 0 or 1 were randomized in a 1:1 fashion to receive amivantamab plus chemotherapy (n = 153) or chemotherapy alone (n = 155).⁶

Amivantamab was given at a dose of 1400 mg (1750 mg if ≥80 kg) for the first 4 weeks, then 1750 mg (2100 mg if ≥80 kg) every 3 weeks, starting at week 7. Chemotherapy was administered on the first day of each 21-day cycle: carboplatin at an area under the curve of 5 for the first 4 cycles and pemetrexed (Alimta) at 500 mg/m² until disease progression. In the chemotherapy alone arm, patients were allowed to cross over to receive amivantamab monotherapy at the time of progression.

“This was a positive study with our first positive data for first-line treatment in the exon 20-targeted space,” said Rotow.

Findings showed that superior PFS results were observed with amivantamab plus chemotherapy, with a median PFS of 11.4 months (95% CI, 9.8-13.7) vs 6.7 months (95% CI, 5.6-7.3) with chemotherapy alone. At a median follow-up of 14.9 months, the BICR-assessed hazard ratio was 0.395 in favor of the combination (95% CI, 0.30-0.53; P <.0001). According to investigator assessment, a consistent benefit was also observed with a median PFS of 12.9 months with the combination of amivantamab plus chemotherapy vs 6.9 months with chemotherapy alone (HR, 0.38; 95% CI, 0.29-0.51; P <.0001). At 12 and 18 months, the PFS rates were 48% and 31% with the combination, respectively, vs 13% and 3% with chemotherapy alone.

For OS, a trend was also observed with the combination (HR, 0.675; 95% CI, 0.42-1.09; P =.106). In the combination arm, the median overall survival (OS) was not evaluable (NE; 95% CI, NE-NE) compared with 24.4 months (95% CI, 22.1-NE) with chemotherapy alone. For the combination vs chemotherapy alone, the 18- and 24-month OS rates were 74% and 72% vs 68% and 54%, respectively.

Further, the BICR-assessed ORR was 73% (95% CI, 65%-80%) with the combination vs 47% (95% CI, 39%-56%) with chemotherapy alone (odds ratio, 3.0; 95% CI, 1.8-4.8; P <.0001). Partial responses were predominantly the best responses in both arms, respectively (69% vs 47%), but CRs (4% vs 1%), and stable disease (19% vs 41%) were also observed.

For safety, grade 3 or greater AEs occurred in 75% of patients in the combination arm vs 54% of patients in the chemotherapy alone arm. EGFR- and MET-related AEs were seen more in patients treated with amivantamab and chemotherapy, and most were grade 1 or 2. The most common grade 3 or greater AEs associated with EGFR inhibition in the combination vs chemotherapy alone arms were rash (11% v 0%), paronychia (7% v 0%), and dermatitis acneiform (4% v 0%). Only 2 grade 3 or greater AEs were associated with MET inhibition, including hypoalbuminemia (4% v 0%) and peripheral edema (1% v 0%).

Other grade 3 or greater AEs consisted of neutropenia (33% v 23%), anemia (11% v 12%), and leukopenia (11% v 3%), and pneumonitis was reported in 4 (3%) of patients given the combination.¹

“I now consider this to be our new emerging standard of care for this patient population,” added Rotow.

Looking Forward

Combination treatment regimens have improved progression-free survival in patients with NSCLC with classical EGFR mutations. Although overall survival data are still immature and shared decision making is needed when selecting what first-line regimen to use, combination therapies being explored in multiple trials have shown promise for this patient population.

“We don’t yet know overall survival data and a caution is needed integrating these combinations in appropriate patient populations. Lastly, amivantamab plus chemo is an emerging standard of care for EGFR exon 20 insertions and hopefully they can be used in the clinic shortly,” concluded Rotow.

References

1. Rotow J. EGFR- Can we do better upfront? Presented at: 18th Annual New York Lung Cancers Symposium; November 11, 2023; New York, NY.
2. Planchard D, Janne PA, Cheng Y, et al. FLAURA2: Safety and CNS outcomes of first-line (1L) osimertinib (osi) ± chemotherapy (CTx) in EGFRm advanced NSCLC. Presented at: European Society for Medical Oncology Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA68.
3. 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):S1306. doi:10.1016/j.annonc.2023.10.062
4. Cho BC, Lee SH, Han JY, et al. Amivantamab and lazertinib in treatment-naïve EGFR-mutant non-small cell lung cancer (NSCLC). J Thorac Oncol. 2022;17(suppl 9):S126. doi:10.1016/j.jtho.2022.07.210
5. Le X, Shum E, Gray JE, et al. LBA71 A multi-centre open-label randomized phase II study of osimertinib with and without ramucirumab in TKI-naïve EGFR-mutant metastatic NSCLC (RAMOSE trial interim analysis). Ann Oncol. 2023;34 (suppl 2):S1313-S1314. doi:10.1016/j.annonc.2023.10.07
6. Girard N, Park K, Tang K, et al. Amivantamab plus chemotherapy vs chemotherapy as first-line treatment in EGFR exon 20 insertion–mutated advanced non-small cell lung cancer (NSCLC). Ann Oncol. 2023;34(suppl 2):S1304. doi:10.1016/j.annonc.2023.10.060