Tagrisso(osimertinib) combined with platinum-based therapy and pemetrexed (a type of chemotherapy) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS; time from treatment until death or disease worsening) compared with Tagrisso monotherapy in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC).
Tagrisso is a targeted medication that treats non-small-cell lung carcinomas with specific mutations.
Dr. Pasi A. 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, presented findings from the phase 3 FLAURA2 study during the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer.
Following a safety run-in, patients with untreated, locally advanced, metastatic EGFR-mutant NSCLC were randomly assigned to be treated with 80 mg of Tagrisso plus pemetrexed in combination with carboplatin, or to maintenance Tagrisso alone.
To be included, patients must be aged at least 18 or 20 years if residing in Japan with pathologically confirmed nonsquamous NSCLC with either an exon 19 deletion or L858R mutation, a World Health Organization (WHO) performance status of 0 or 1 and who had received no prior systemic therapy for advanced NSCLC. Those with stable central nervous system (CNS) metastases were permitted and all patients had to undergo a CT/MRI scan at baseline.
The median PFS via investigator assessment with the Tagrisso combination was 25.5 months vs 16.7 months with Tagrisso monotherapy translating to a 48% reduction in the risk of disease progression. The 12-month PFS rates were 80% and 66%, respectively, and the 24-month PFS rates were 57% vs 41% respectively.
The PFS benefit was observed across all subgroups.
“Tagrisso plus platinum/pemetrexed offers a new first-line treatment option for patients with advanced EGFR-mutant NSCLC,” explained Jänne.
Jänne 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 CNS metastases as well as the L858R mutation.
“Tagrisso, 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 Tagrisso vs (Iressa [gefitinib]) or (Tarceva [erlotinib]) in the FLAURA study.”
The primary end point was PFS, and secondary end points included overall survival (OS; time from treatment until death of any cause), 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 Tagrisso/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 Tagrisso 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 and 25% of patients were still receiving treatment with Tagrisso and pemetrexed, respectively. Discontinuation rates were as follows: Tagrisso (44%) platinum (23%), and pemetrexed (75%). In the monotherapy arm 45% of patients were still receiving treatment at data cutoff, with 55% discontinuing Tagrisso.
Among patients with CNS metastases, those who received the Tagrisso combination had a median PFS of 24.9 months vs 13.8 months with Tagrisso monotherapy. Patients without CNS metastases in the combination armhad a median PFS of 27.6 months vs 21.0 months with Tagrisso monotherapy.
The median PFS for patients with an EGFR exon 19 deletion who received the Tagrisso/pemetrexed/platinum chemotherapy was 27.9 months vs 19.4 months with Tagrisso monotherapy. Among those with an L858R mutation, those in the combination arm had a median PFS of 24.7 months vs 13.9 months in the monotherapy arm.
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 with Tagrisso/pemetrexed/platinum chemotherapy vs 27.8 months with Tagrisso alone. The median OS was non-reactive in either arm.
At data cutoff, the discontinuation rate among those who had received subsequent anticancer therapy was 46% in the Tagrisso plus platinum/pemetrexed arm and 60% in the Tagrisso monotherapy arm. 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 Tagrisso/pemetrexed/platinum arm the median best percentage change in target lesion size was –52.6% (range, –100.0 to 20.0). In the Tagrisso monotherapy, the median change was –50.0 (range, –100.0 to 40.4).
The ORRs were 83.2 vs 75.5% in the combination and monotherapy arms. One patient in the combination arm had a complete response, meaning that no cancer was found after treatment, 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 months in the combination arm and was 15.3 months 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 Tagrisso exposure was 22.3 months (range 0.1-33.8) in the Tagrisso/platinum/pemetrexed arm and 19.3 months (range 0.1-33.8) in the Tagrisso 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, side effects of any cause occurred in all patients, with 64% of patients experiencing a grade 3 or higher side effect, 7% having a side effect resulting in death, 38% experiencing a serious side effect, and 48% experiencing a side effect leading to discontinuation. When broken up by treatment, 11%, 17%, and 43% of patients had a side effect leading to discontinuation related to Tagrisso, carboplatin or cisplatin or pemetrexed, respectively.
In the monotherapy arm, side effects of any cause occurred in 97% of patients, with 27% experiencing a grade 3 or higher side effect, 3% having a side effect resulting in death, 19% experiencing a serious side effect and 6% experiencing a side effect leading to discontinuation.
Side effects 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 Tagrisso, 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 side effects 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 side effectsin 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 side effects 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 side effects were reported in the monotherapy arm.
Of note, any-grade interstitial lung disease, which was used as a grouped term, was reported in eight patients (3%) in the Tagrisso/platinum/pemetrexed arm and 10 patients (4%) in the Tagrisso monotherapy arm.
Investigators noted that ongoing analyses include CNS response and progression, post progression endpoints, 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, Dr. Yi-Long Wu, 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 Tagrisso 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 two years and 15.5% answered greater than two years. For patients, 72% would opt for the combination if it delayed resistance for 10 months. Patients and family said they would expect delays of 12 months (18%), 18 months (10%), two years (15%), or more than two 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.
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