Frontline Osimertinib/Chemotherapy Combination Improves PFS in EGFR-Mutated NSCLC

Pasi A. Jänne, MD, PhD

Osimertinib (Tagrisso) in combination with platinum-based therapy and pemetrexed demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs osimertinib monotherapy in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC). Pasi A. Jänne, MD, PhD, presented findings from the phase 3 FLAURA2 study (NCT04035486) during the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer.

The median PFS via investigator assessment with the osimertinib combination (n = 279) was 25.5 months (95% CI, 24.7-not calculable [NC]) vs 16.7 months (95% CI, 14.1-21.3) with osimertinib monotherapy (n = 278) translating to a 48% reduction in the risk of disease progression (HR, 0.62; 95% CI, 0.49-0.79; P < .0001). The 12-month PFS rates were 80% and 66%, respectively, and the 24-month PFS rates were 57% vs 41% respectively.

When investigated by blinded independent central review (BICR), the median PFS was 29.4 months (95% CI, 25.1-NC) with osimertinib in combination with pemetrexed/chemotherapy vs 19.9 months (95% CI, 16.6-25.3) with osimertinib alone (HR, 0.62; 95% CI, 0.48-0.80; P = .0002).

The 12-month PFS rates were 80% and 67%, respectively, and the 24-month PFS rates were 62% vs 47% respectively.

The PFS benefit was observed across all subgroups.

“Osimertinib plus platinum/pemetrexed offers a new first-line treatment option for patients with advanced EGFR-mutant NSCLC,” said Jänne who is director of the Lowe Center for Thoracic Oncology, the Belfer Center for Applied Cancer Science, the Chen-Huang Center for EGFR Mutant Lung Cancers, and a senior physician at Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School, in Boston, Massachusetts.

Jänne, who is also a 2021 Giant of Cancer Care® winner in the lung cancer category, added that EGFR-TKIs are a standard first-line treatment for patients with EGFR-mutant advanced NSCLC, yet most patients will progress following treatment, and clinical factors associated with poor prognosis include central nervous system (CNS) metastases as well as the L858R mutation.

“Osimertinib, a third-generation, CNS active EGFR-TKI, is the preferred first-line treatment for EGFR-mutant advanced NSCLC based on superior PFS/OS benefit with osimertinib vs gefitinib [Iressa] or erlotinib [Tarceva] in the FLAURA study [NCT02296125].”

Following a safety run-in, patients with untreated, locally advanced, metastatic EGFR-mutant NSCLC were randomly assigned in FLAURA2 to the experimental arm which included osimertinib 80 mg once daily plus pemetrexed 500 mg/m2 in combination with carboplatin area under the curve 5 or cisplatin 75 mg/m2 given once every 3 weeks for 4 cycles, or to maintenance osimertinib 80 mg once daily plus pemetrexed once every 3 weeks.

To be included patients must be aged at least 18 years or at least 20 years if residing in Japan with pathologically confirmed nonsquamous NSCLC with either an exon 19 deletion or L858R mutation, a World Health Organization performance status of 0 or 1, and who had received no prior systemic therapy for advanced NSCLC. Those with stable CNS metastases were permitted and all patients had to undergo a CT/MRI scan at baseline.

The primary end point was PFS by investigator and BICR using RECIST 1.1 criteria, and secondary end points included overall survival (OS), progression-free survival (PFS), duration of response (DOR), disease control rate, health-related quality of life, safety, and time to second disease progression.

At baseline, patient characteristics were well balanced. In the osimertinib/platinum/pemetrexed arm the median age was 61 years (range, 26-83), most patients were women (62%), Chinese Asian (25%) or non-Chinese Asian (39%), had a WHO performance status of 1 (62%), were never smokers (67%), had adenocarcinoma (99%), had metastatic disease (95%), had extra-thoracic metastases (53%), and 42% of patients had CNS metastases. EGFR mutations were exon 19 deletions (61%) and L858R (38%). The baseline median tumor size was 57 mm (range, 10-284).

In the osimertinib monotherapy arm the median age was 62 years (range, 30-85), most patients were women (61%), Chinese Asian (25%) or non-Chinese Asian (38%), had a WHO performance status of 1 (63%), were never smokers (65%), had adenocarcinoma (99%), had metastatic disease (97%), had extra-thoracic metastases (54%), and 40% of patients had CNS metastases. EGFR mutations were exon 19 deletions (60%) and L858R (38%). The baseline median tumor size was 57 mm (range, 11-221).

At data cutoff, in the combination arm, 56% of patients (n = 154) and 25% of patients (n = 68) were still receiving treatment with osimertinib and pemetrexed, respectively. Discontinuation rates were as follows: osimertinib (44%; n = 122) platinum (23%; n = 64), and pemetrexed (75%; n = 208). In the monotherapy arm 45% of patients (n = 123) were still receiving treatment at data cutoff, with 55% discontinuing osimertinib.

Among patients with CNS metastases, those who received the osimertinib combination (n = 116) had a median PFS of 24.9 months (95% CI, 22.0-NC) vs 13.8 months (95% CI, 11.0-16.7) with osimertinib monotherapy (n = 110; HR, 0.47; 95% CI, 0.33-0.66). Patients without CNS metastases in the combination arm (n = 163) had a median PFS of 27.6 months (95% CI, 24.7-NC) vs 21.0 months (95% CI, 16.7-30.5) with osimertinib monotherapy (n = 168; HR, 0.75; 95% CI, 0.55-1.03).

The median PFS for patients with an EGFR exon 19 deletion who received the osimertinib/pemetrexed/platinum chemotherapy (n = 172) was 27.9 months (95% CI, 25.1-NC) vs 19.4 months (95% CI, 16.5-27.6) with osimertinib monotherapy (n = 169; HR, 0.60; 95% CI, 0.44-0.83). Among those with an L858R mutation, those in the combination arm (n = 106) had a median PFS of 24.7 months (95% CI, 19.5-27.4) vs 13.9 months (95% CI, 11.1-19.4) in the monotherapy arm (n = 107; HR, 0.63; 95% CI, 0.44-0.90).

For CNS and EGFR status, the reviews were conducted via investigator analysis.

Time to second disease progression and OS were immature at the time of the analysis, with 34% and 27% maturity, respectively. The median time to second disease progression was 30.6 months (95% CI, 29.0-NC) with osimertinib/pemetrexed/platinum chemotherapy vs 27.8 months (95% CI, 26.0-NC) with osimertinib alone (HR, 0.70; 95% CI, 0.52-0.93; P = .0132). The median OS was NR in either arm (HR, 0.90; 95% CI, 0.65-1.24; P = .5238).

At data cutoff the discontinuation rate among those who had received subsequent anticancer therapy was 46% in the osimertinib plus platinum/pemetrexed arm (n = 57 of 123) and
60% in the osimertinib monotherapy arm (n = 91 of 151). In both arms, cytotoxic chemotherapy was the most common second-line treatment which was administered in 65% and 82% of those who went on to receive anticancer treatment, respectively.

Tumor response was documented as best percentage change and objective response rate (ORR). Among 279 patients in the osimertinib/pemetrexed/platinum arm the median best percentage change in target lesion size was –52.6% (range, –100.0 to 20.0). In the osimertinib monotherapy arm (n = 278), the median change was –50.0 (range, –100.0 to 40.4).

The ORRs were 83.2% (95% CI, 78.2%-87.4%) vs 75.5% (95% CI, 70.1%-80.5%) in the combination and monotherapy arms, respectively (OR, 1.61; 95% CI, 1.06-2.44). One patient in the combination arm had a complete response (< 1%), and 83% had a partial response (PR). The complete and PR rates in the monotherapy arm were 1% and 75%, respectively. Stable disease lasting at least 35 days was reported in 12% and 18% of patients in the combination and monotherapy arms, respectively. Disease progression was observed in 3% and 4% of patients, respectively.

The median duration of response was 24.0 months (95% CI, 20.9-27.8) in the combination arm and was 15.3 months (95% CI, 12.7-19.4) in the monotherapy arm.

Investigators reported that the safety profiles were as expected for each treatment and were manageable with standard medical practice. The median total duration of osimertinib exposure was 22.3 months (range 0.1-33.8) in the osimertinib/platinum/pemetrexed arm and 19.3 months (range 0.1-33.8) in the osimertinib monotherapy arm. In the combination arm, the median number of pemetrexed cycles was 12 (range 1-48) and 212 patients (77%) completed 4 cycles of platinum-based chemotherapy.

In the combination arm (n = 276), adverse effects (AEs) of any cause occurred in all patients, with 64% of patients experiencing a grade 3 or higher AE, 7% having an AE resulting in death, 38% experiencing a serious AE, and 48% experiencing an AE leading to discontinuation. When broken up by treatment, 11%, 17%, and 43% of patients had an AE leading to discontinuation related to osimertinib, carboplatin or cisplatin, or pemetrexed, respectively.

In the monotherapy arm (n = 276), AEs of any cause occurred in 97% of patients, with 27% experiencing a grade 3 or higher AE, 3% having an AE resulting in death, 19% experiencing a serious AE, and 6% experiencing an AE leading to discontinuation.

AEs deemed possible causally related to treatment were reported among 97% and 88% of patients in the combination and monotherapy arms with 53% and 11% of AEs being grade 3 or higher. The grade 3 or higher events in the combination arm were reported among 81 (29%) events with osimertinib, 104 (38%) events with cisplatin or carboplatin, and 130 (47%) events with pemetrexed. AEs leading to death were reported among 5 patients in the combination arm and 1 patient in the monotherapy arm. Serious AEs causally related to treatment were reported in 19% and 5% of patients in the combination and monotherapy arms, respectively.

The most common grade 1/2 AEs in the combination arm were nausea (42%), diarrhea (41%), anemia (27%), constipation (29%), decreased appetite (28%), rash (28%), fatigue (25%), vomiting (25%), stomatitis (24%), and paronychia (23%). Grade 3 events included anemia (20%), neutropenia (19%), and thrombocytopenia (12%). Grade 4 events included neutropenia (4%), thrombocytopenia (2%), COVID-19 (< 1%), and white blood cell count decrease (< 1%).

In the monotherapy arm, the most common grade 1/2 AEs were diarrhea (40%), paronychia (26%), dry skin (24%), and rash (21%). Grade 3 events included decreased appetite (1%), neutropenia (1%), thrombocytopenia (1%), diarrhea (< 1%), fatigue (< 1%), stomatitis (< 1%), paronychia (< 1%), increase ALT level (< 1%), increase AST level (< 1%), and white blood cell count increase (< 1%). No grade 4 AEs were reported in the monotherapy arm.

Of note, any-grade interstitial lung disease, which was used as a grouped term, was reported in 8 patients (3%) in the osimertinib/platinum/pemetrexed arm and 10 patients (4%) in the osimertinib monotherapy arm.

Investigators noted that ongoing analyses include CNS response and progression, postprogression end points, patient-reported outcomes, and subsequent therapies. Additionally, circulating tumor DNA (ctDNA) analyses will be used to identify resistance mechanisms and ctDNA dynamics.

In a discussion of the data, Yi-Long Wu, MD, a professor at Guagndong Provincial People’s Hospital in China commended the investigators on the findings but cautioned the use of EGFR TKIs in combination with chemotherapy without OS data. “The data showed that a longer PFS benefit comes with higher toxicity,” Wu said. “If the OS is positive, the FLAURA2 strategy will be the new standard of care for the EGFR-mutant first line. If the OS is negative [in] FLAURA2, it means the patient experiences the chemotherapy [AEs] early or for longer.” Wu also noted that the CNS data are intriguing and that resistance mechanisms may affect OS and require more clarity.

In a final question, Wu asked, “What do physicians and patients think about osimertinib with chemotherapy?” In a survey study, results showed that physicians responded that chemotherapy would be tolerable but that most patients do not agree. Among 71 physicians, 84.5% said that they would opt for the monotherapy option if resistance with the combination was only delayed by 10 months.

As for how long they would expect to prolong resistance before choosing the combination, 38% answered 12 months, 37% answered 18 months, 9.9% answered 2 years, and 15.5% answered greater than 2 years. For patients (n = 170), 72% would opt for the combination if it delayed resistance for 10 months. Patients and family (n = 363) said they would expect delays of 12 months (18%), 18 months (10%), 2 years (15%), or more than 2 years (57%) before choosing the combination.

“Should we need combination treatment for EGFR-mutant advanced NSCLC in the first-line setting? Yes, we need it. We need the combination treatment with more efficacy and less toxicity and [that is] convenient for [patients with] this disease,” Wu said.

WATCH: Dr Jänne discusses findings from the phase 3 FLAURA2 trial in patients with EGFR-mutant non–small cell lung cancer.

Reference

Jänne PA, Planchard D, Cheng Y, et al. Osimertinib with / without platinum-based chemotherapy as first-line treatment in patients with EGFRm advanced NSCLC (FLAURA2). Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore. Abstract PL03.13.