Assistant Professor of Medical Oncology
National Cancer Institute (NCI-AIIMS), Jhajjar, Haryana, India
Lung cancer management is advancing day by day. The most transformed sub-group is the EGFR mutated advanced non-small cell lung (NSCLC). This current snapshot focuses on the major studies published in the last year, i.e 2020 which has changed or may potentially change the way we treat lung cancer in future. The snapshot highlights a summary of various strategies, the role of tyrosine kinase inhibitors (TKI) in early-stage cancers, and combinations in advanced stages. It also encompasses the updated result of previous published important trials.
This phase III, double-blind, multi-center trial evaluated osimertinib (80 mg) once daily or placebo for three years among patients with resected EGFR mutated (del19/L858R) stage IB – IIIA NSCLC. The primary and secondary endpoints were disease-free survival (stage II-IIIA) and overall survival (IB-IIIA), overall survival, and safety. The reported analysis was an unplanned interim analysis after independent data monitoring committee recommendations. The trial randomized 682 patients (stage IB: 26%) and reported outcome after follow up of 22.1 months. The trial met its primary endpoint and at two years, the patients who were disease-free in osimertinib and placebo arm were 90% and 44% (HR 0.17, CI 0.11-0.26, p <0.001). The central nervous system disease-free survival was 98% and 85% (HR 0.18, CI 0.10-0.33). The benefit was seen irrespective of chemotherapy administration. Osimertinib reduced local, distant, and CNS recurrences. The trial was immature for overall survival (OS), with a total of 29 deaths. There were no new toxicities identified. Long-term data are needed before consideration of a change of current practice.
Ramalingam et al. published the long-term OS data of osimertinib versus erlotinib or gefitinib in EGFR mutated advanced lung cancer patients. The OS was the secondary outcome. With a median follow-up of three years, this analysis reported median OS of 38.6 months versus 31.8 months (HR 0.8, 0.64-1.0, p 0.046) among osimertinib and first-generation TKI arms, respectively. The grade ≥ 3 adverse events were 42% and 47%. It establishes the osimertinib as the current standard of care in EGFR mutated advanced NSCLC.
This updated trial data reported the role of osimertinib over platinum-pemetrexed among T790M advanced NSCLC who progressed on the first-generation tyrosine kinase inhibitors. Cross over to osimertinib was allowed. Overall survival was the secondary endpoint. The median overall survival was 26.8 months and 22.5 months (HR 0.87, CI 0.67-1.12, p 0.277). Time to next therapy was favoring osimertinib, HR 0.21. The high cross over rate among platinum-pemetrexed arm (99/136, 73%), have possibly prevented the overall benefit.
Zhong et al. reported the final overall analysis of two years of gefitinib versus four cycles of chemotherapy in EGFR activating mutated NSCLC after complete resection, stage II-IIIA (N1-N2). The primary endpoint was disease-free survival (DFS). The analysis was reported with median follow-up of 80 months. The median OS was 75.5 months and 63 months in gefitinib versus chemotherapy arm. The rate of subsequent therapy administration was 68% versus 74%. The activity of rechallenge of EGFR TKI in gefitinib arm (N 15) who progressed after two years of therapy was modest with median PFS and OS of 14 months and 19.6 months. The DFS benefit (28.7 months versus 18 months; HR 0.6, p 0.005) did not translate into OS benefit. In both arms, the OS data were far better than historic data. The data do not support use in routine care.
This phase II study randomized 72 Chinese patients to erlotinib (42 days as neoadjuvant -> surgery -> 12 months of adjuvant) versus gemcitabine and cisplatin (two cycles as neoadjuvant -> surgery -> two cycles). The primary endpoint was overall response rate (ORR) after 42 days of erlotinib. The trial failed for the primary endpoint. The ORR for erlotinib and chemotherapy was 54% versus 34% (OR, 2.26; CI 0.9-5.8, p 0.92). The rate of major pathologic response was 10% versus none. No pCR was observed in either arm. The median progression-free survival (PFS) was 21.5 and 11.4 months in erlotinib and chemotherapy arm. The strategy remains exploratory.
The study enrolled a total of 40 patients with EGFR mutated (19del/L858R), pretreated patients with CSF positive for malignant cells. For part B of the study, the dose of osimertinib was 160 mg per day. The study showed an impressive rate of LM ORR (62%) and duration of response (15.2 months) by a blinded independent review. The median PFS and OS were 8.6 months and 11 months. The 160 mg dose provided reasonable activity in this cohort.
RELAY study was a phase III, multi-center trial studying erlotinib with or without ramucirumab (10 mg/kg/2 weeks) till progression, among EGFR (del19/L858R) mutated stage IV lung cancer. The trial excluded patients with T790M mutation and CNS metastasis. The primary endpoint was PFS. At a median follow-up of 20.7 months, PFS in erlotinib and ramucirumab arm was 19.4 months versus 12.4 months, respectively (HR 0.59, p <0.001). The rate of response was similar to the increased duration of response in the experimental arm. The rate of CNS events was low in two arms to make any reasonable conclusion. There were more grade ≥ 3 treatment-emergent adverse events in the ramucirumab arm (72% vs 54%), the most common being hypertension (24%) and dermatitis acneiform (15%). The rate of dose reduction was 10% vs 2%, with proteinuria being the most common reason in the experimental arm. It may be useful where osimertinib is not available.
This phase II/III study studied the role of cetuximab (400 mg/m2/biweekly) over Afatinib (40 mg) in treatment naïve, EGFR-mutant (19del/L858R) advanced NSCLC with or without brain metastasis. PFS was the primary endpoint. The addition of cetuximab to afatinib arm resulted in neither the improvement of PFS (11.9 versus 13.4 months, HR 1.01) nor the response rate (67% versus 74%, HR 0.82). There was higher grade three or more adverse events (72% versus 40%) with most common being rash (40% versus 2%). Dose reduction was more in the cetuximab arm with cetuximab discontinuation rate of 30%. The dose reduction to 30 mg was more frequent in the combination arm (57% versus 26%), a similar frequency to 20 mg reduction. The further enrollment for the phase III part was stopped due to insufficient evidence of activity.
In this phase II study, patients who progressed on prior EGFR TKI, other than third-generation TKI, and had acquired T790M were randomized to osimertinib (80 mg/day) with or without bevacizumab (15 mg/kg, every 3 weeks) till progression. The primary endpoint was PFS. This trial failed to show PFS benefit (osimertinib alone, 13.5 months versus combination arm, 9.4 months; HR 1.44, p 0.20) and overall survival benefit (22.1 months versus not reached, p 0.26). The response rate was better in the combination arm (68% versus 54%) but the time to treatment failure was shorter (8.4 months versus 11.2 months, p 0.12). The combination approach was not promising.
Eighty patients were enrolled in a two-stage design who were classified as frail based on age, Charlson Comorbidity index, and ECOG performance status. The primary endpoint was the ORR. The ORR - was 60% and the disease control rate was 90%. The median age was 80 years, with median PFS and OS of 9.3 months and 26.2 months. The rate of discontinuation and dose reduction was 2.5% and 6% for low dose erlotinib. The low dose remains a potential option for the frail patient who can’t afford next-generation TKI.
Multicenter, single-arm study in advanced EGFR mutated NSCLC patients carrying non-T790M, del19, L858R, and exon 20 insertion mutation. Osimertinib was given as first, second, and third-line in 61%, 31%, and 8% of the study cohort. The common mutations were G719X (53%) followed by L861Q (25%) and S768I (22%). The rest (four cases) included L747S, S720A, exon 18 deletion, and exon 20 insertion H773_V774insH. The median PFS and OS was 8.2 months and not reached with an ORR of 50%. The ORR and median PFS in the three most common mutation types were G719X (53%, 8.2 months), L861Q (78%, 15.2 months), and S768I (38%, 12.3 months). This study suggested reasonable activity of osimertinib in these uncommon mutated patients.
The first study randomized 345 patients carrying EGFR mutations (del18, L858R, G719A, G719C, G719S, L861Q)) to gefitinib with or without chemotherapy (pemetrexed, carboplatin, AUC 5, up-to six cycles with maintenance). Patients with stable and or treated brain metastasis were allowed. The primary endpoint was PFS, PFS-2 and OS tested via a sequential hierarchical method. The median follow-up in this trial was 45 months. The combination showed better ORR and PFS (ORR, 84% versus 67%; PFS, 20.9 versus 11.9 months) with similar PFS-2 (20.9 versus 18 months). The median OS was numerically higher (50.9 versus 38.8 months, p 0.722), but not significant. The QOL was similar but with a higher grade of 3 or more treatment-related adverse events, (TRAE, 65% versus 31%). The second study was done in an Indian cohort with the inclusion of ECOG PS - 2 patients. The primary endpoint was PFS. About 20% patients had brain metastasis. The study showed a doubling of PFS (16 versus 8 months, HR 0.5, p <0.001) with improved ORR (75% versus 63%). The estimated median OS was better in combination (not reached versus 17 months, HR 0.45, p <0.001) with higher grade ≥ 3 toxicity (51% versus 25%, p <0.001). Both studies suggest that combination therapy is one of the valid options for patients not affording for osimertinib.
Courtesy - Indian Journal of Medical and Paediatric Oncology (IJMPO)
Editor-in-Chief - Dr. Padmaj Kulkarni