Bij patiënten die een volledige resectie hebben ondergaan van een niet-kleincellig longcarcinoom (stadium I-III) wordt in de MDO’s gesproken over welke adjuvante therapie relevant is. Daarbij is de huidige (anno 2023) standaard om bij patiënten met een stadium II-III adjuvant chemotherapie te geven. Inmiddels wordt er bij het uitgebreid of gemetastaseerd longcarcinoom gekeken naar moleculaire veranderingen, omdat die impact hebben op de keuze van palliatieve therapie. De vraag is in hoeverre het meten van zulke veranderingen relevant is voor de adjuvante setting en of dit behandelconsequenties heeft.
Hierbij is het van belang op te merken dat de studies over het algemeen zijn uitgevoerd onder 5^e-7^e TNM editie. Voor het advies zal gebruik worden gemaakt van de 8^e TNM editie.

Adjuvant osimertinib* compared with placebo in patients who underwent completely resected, early-stage (IB to IIIA) pathological confirmed EGFR+ NSCLC

* Currently, osimertinib is the only available treatment in the Netherlands within the adjuvant setting for patients with a completely resected, early-stage (I to III) pathological confirmed NSCLC harbouring a common EGFR-mutation

Other adjuvant treatments

Summary of literature

Description of studies

Ou (2023) – CORIN described a randomized, single-centre, open-label, phase II trial, with a median follow-up length of 39.9 months in China. They evaluated the efficacy and safety of adjuvant icotinib versus observation in patients with EGFR mutation-positive resected stage IB NSCLC (7th TNM classification). A total of 128 patients were randomized to receive icotinib (n=63) (125 mg, three times daily) for 12 months or to undergo observation (n=65) until disease progression or intolerable toxicity occurred. The median age (range) was 56 (35-75) in the icotinib group, compared with 57 (32-75) in the observation group. In the icotinib group 26/63 (41.3%) were males, compared with 27/65 (41.5%) in the observation group. The following relevant outcomes were reported; OS, DFS, AEs.

Tada (2021) - IMPACT described a randomized, open-label, phase III trial, which was conducted in 25 institutes in Japan with a median follow-up length of 70 months. They evaluated the efficacy and safety of adjuvant gefitinib versus chemotherapy as postoperative adjuvant therapy in patients with completely resected stage II-III NSCLC harbouring a common EGFR mutation (7^th TNM classification). A total of 232 patients were randomized to receive gefitinib (n=116) (250 mg once daily) for 24 months or cisplatin (80 mg/m2 on day 1) plus vinorelbine (25 mg/m2 on days 1 and 8; cis/vin) once every 3 weeks for four cycles (n=116). The median age (range) was 64 (35-74) in the gefitinib group, compared with 64 (34-74) in the chemotherapy group. In the gefitinib group 44/116 (37.9%) were males, compared with 45/116 (38.8%) in the chemotherapy group. The following relevant outcomes were reported; OS, DFS, AEs. 

He (2021) - EVIDENCE described a randomized, open-label, phase III trial, which was conducted in 29 institutes in China with a median follow-up length of 24.9 months. They evaluated the efficacy and safety of adjuvant icotinib versus chemotherapy in patients with completely resected stage II-IIIA NSCLC (7th TNM classification) harbouring an EGFR-mutation. A total of 322 patients were randomized to receive icotinib (n=151) (125 mg thrice daily) or four cycles (21 days per cycle) for 24 months of vinorelbine (25 mg/m2 IV on days 1 and 8 of each cycle) plus cisplatin (75 mg/m2 IV on day 1 of each cycle) for adenocarcinoma or squamous carcinoma; or intravenous pemetrexed 500 mg/m² plus cisplatin 75 mg/m² on day 1 every 3 weeks for non-squamous carcinoma (n=132). The median age (range) was 60 (52-64) in the icotinib group compared to 58 (51.5-63) in the chemotherapy group. In the icotinib group 77/151 (51%) were males, compared with 55/132 (42%) in the chemotherapy group. The following relevant outcomes were reported: OS, DFS, AEs.

Wu (2020) / Majem (2022) / Herbst (2023) / Tsuboi (2023) / John (2023) - ADAURA described a randomized, international, multi-centre double-blind, phase III trial, with a median follow-up length of 22.1 months (primary analysis Wu (2020)). This was followed by two years of further follow-up (updated analysis Herbst (2023), Tsuboi (2023) and John (2023)). They evaluated the efficacy and safety of adjuvant osimertinib versus placebo in patients with completely resected stage IB-IIIA (7th TNM classification) NSCLC harbouring an EGFR-mutation. A total of 682 patients were randomized to receive osimertinib (n=339) (80 mg once daily) or placebo (n=343) for 36 months. The median age (range) was 64 (30-86) in the osimertinib group compared to 62 (31-82) in the placebo group. In the osimertinib group 108/339 (32%) were males, compared with 96/343 (28%) in the placebo group. The planned treatment duration of 3 years was completed by 66% of the patients in the osimertinib group and 41% of the patients in the placebo group (Herbst, 2023). Cross-over was not allowed. The following relevant outcomes were reported: OS (secondary end point), DFS (primary end point), AEs, QoL. The trial was unblinded 2 years early because of evidence of an efficacy benefit (Wu, 2020).

Zhong (2018/2021) - ADJUVANT described a randomized, open-label, phase III trial, which was conducted in 27 institutes in China with a median follow-up length of 80 months. They evaluated the efficacy of adjuvant gefitinib versus cis/vin as postoperative adjuvant therapy in patients with completely resected stage II-IIIA (7^th TNM classification) NSCLC harbouring an EGFR mutation. A total of 222 patients were randomized to receive gefitinib (n=111) (250 mg once daily) for 24 months or cisplatin (75 mg/m2 on day 1) plus vinorelbine (25 mg/m² on days 1 and 8; cis/vin) once every 3 weeks for four cycles (n=116). The median age (range) was 58 (32-74) in the gefitinib group, compared with 60 (26-76) in the chemotherapy group. In the gefitinib group 46/111 (41.4%) were males, compared with 46/111(41.4%) in chemotherapy group. The following relevant outcomes were reported; OS, DFS.

Yue (2018) - EVAN described a randomized, open-label, phase II trial, which was conducted in 16 institutes in China with a median follow-up length of 33 months. They evaluated the efficacy and safety of adjuvant erlotinib versus cis/vin as postoperative adjuvant therapy in patients with completely resected stage IIIA (7^th TNM classification) NSCLC harbouring an EGFR mutation. A total of 102 patients were randomized to receive erlotinib (n=51) (150 mg once daily) for 24 months or cisplatin (75 mg/m² on day 1) plus vinorelbine (25 mg/m2 on days 1 and 8; cis/vin) once every 3 weeks for four cycles (n=51). The median age (range) was 59 (50-66) in the erlotinib group, compared with 57 (51-61) in the chemotherapy group. In the erlotinib group 17/51 (33%) were males, compared with 20/51 (39%) in chemotherapy group. The following relevant outcomes were reported; OS, DFS, AEs.

Kelly (2015) – RADIANT described a randomized, international, multi-centre, double-blind, phase III trial with a median follow-up length of 47 months. They evaluated the efficacy and safety of adjuvant erlotinib versus cis/vin as postoperative adjuvant therapy in patients with completely resected stage IB-IIIA (6^th TNM classification) NSCLC. A total of 973 patients were randomly assigned and of those 161 patients were EGFRm-positive. These patients were randomized to receive erlotinib (n=102) (150 mg once daily) for 24 months or placebo (n=59). The median (range) age was 62 (38-84) in the erlotinib group, compared with 60 (42-86) in the placebo group. In the erlotinib group 36/102 (35.3%) were males, compared with 20/59 (33.9%) in placebo group. The following relevant outcomes were reported; OS, DFS, AEs. 

Feng (2015) - described a randomized, single-centre, open-label, unknown phase trial, which was conducted in China with an unknown median follow-up time. They evaluated the efficacy and safety of adjuvant chemotherapy plus icotinib versus chemotherapy as postoperative adjuvant therapy in patients with completely resected stage IB-IIIA (edition TNM classification unclear) NSCLC harbouring an EGFR mutation. A total of 41 patients were randomized to receive chemotherapy plus icotinib (n=21) (125 mg, thrice daily; two weeks after finishing chemotherapy) for four to eight months, or until the occurrence of disease relapse, metastasis or unacceptable icotinib or chemotherapy toxicity or only chemotherapy (150 mg/m2 paclitaxel plus 80 mg/m2 nedaplatin or 30mg/m2 lobaplatin on day one of a three-week cycle) (n=20). The mean age (SD) was 57.3 (10.9) in the chemotherapy + icotinib group, compared with 55.5 (9.74) in the chemotherapy group. In the chemotherapy + icotinib group 16/21 (76.2%) were males, compared with 11/18 (61.1%) in chemotherapy group. The following relevant outcomes were reported; DFS, AEs. 

Li (2014) – described a randomized, single-centre, open-label, phase II trial, which was conducted in China with a median follow-up length of 30.7 months. They evaluated the efficacy and safety of adjuvant chemotherapy plus gefitinib versus chemotherapy as a postoperative adjuvant therapy in patients with completely resected stage III-N2 (5^th TNM classification) NSCLC harbouring an EGFR mutation. A total of 60 patients were randomized to receive chemotherapy plus gefitinib (n=30) (250 mg/day) for six months after chemotherapy, or chemotherapy (500 mg/m2 pemetrexed and carboplatin), administered every 21 days for 4 cycles. The median age (range) was 59.5 (32-78) in the chemotherapy + gefitinib group, compared with 54.6 (39-74) in the chemotherapy group. In the chemotherapy + gefitinib group 17/30 (56.7%) were males, compared with 18/30 (60%) in the chemotherapy group. The following relevant outcomes were reported; OS, DFS, AEs.

Results

Osimertinib for EGFR+ NSCLC

Currently, osimertinib is the only available treatment in the Netherlands within the adjuvant setting for patients with a completely resected, early-stage (I to III) pathological confirmed NSCLC harbouring a common EGFR-mutation. Therefore, the analysis of outcomes below is restricted to osimertinib.

Overall survival

Results from the ADAURA trial were immature at the time of the analysis of Wu 2022 and could therefore not be assessed in their systematic review. In June 2023, Tsuboi 2023 published the final analysis of OS data. The median duration of follow-up for OS in patients with stage II to IIIA disease was 59.9 months (range: 0 to 82) in the osimertinib group and 56.2 months (range 1 to 86) in the placebo group. The 5-year overall survival was 85% (95% CI: 79% to 89%) in the osimertinib group and 73% (95% CI: 66 to 78) in the placebo group (HR 0.49; 95.03% CI: 0.33 to 0.73). In the osimertinib treated group there was no significant OS difference between those who received adjuvant chemotherapy (HR 0.16 (95%CI 0.10-0.26)) and those who did not (HR 0.23 (95%CI 0.13-0.40)). However follow-up time could not be long enough and power was probably too low to find any differences in OS.

It should be noted that only 79 of 205 patients who had disease recurrence in the placebo group received osimertinib at relapse in the ADAURA trial.

Quality of life

Majem (2022) reported the outcome health-related quality of life from the ADAURA trial. HR-QOL was measured using the Short Form-36 (SF-36). Baseline physical/mental component summary (PCS/MCS) scores were comparable between osimertinib and placebo (range: 46-47) and maintained to week 96, with no clinically meaningful differences between arms; difference in adjusted least squares (LS) mean -1.18 (95% CI -2.02 to -0.34) and -1.34 (95% CI -2.40 to -0.28), for PCS and MCS, respectively. No differences exceeding 10 points were reported for any of the scales.

In-depth analyses showed a maintained HR-QOL over prolonged exposure of three years (John, 2023).

Disease-free survival

Wu (2020) reported the disease-free survival which was defined as the time from randomization to disease recurrence (determined by computer tomography or magnetic resonance imaging, pathological disease on biopsy, or both) or death from any cause. In the primary analysis, the median disease-free survival was not reached in the osimertinib group (95% CI 38.8 to could not be calculated) and 19.6 months (95% CI 16.6 to 24.5) in the placebo group. In the osimertinib group 37/339 (11%) patients had disease recurrence or died, compared with 159/343 (46%) patients in the placebo group. The percentage of patients who were alive and disease-free at 24 months was 89% (95% CI 85% to 92%) in the osimertinib group, compared with 52% (95% CI 46% to 92%) which resulted in an overall hazard ratio of disease recurrence or death of 0.20 (99.12% CI 0.14 to 0.30). This HR and the confidence interval exceed the minimal clinically (patient) important difference of HR<0.6. Moreover, a major difference in brain metastasis occurrence was found between osimertinib and placebo treated patients with a HR of 0.18 (95%CI 0.10-0.33).

Herbst (2023) reported an updated exploratory analysis of final DFS data. The median DFS was 65.8 months (95% CI 61.7 to could not be calculated) in the osimertinib group and 28.1 months (95% CI 22.1 to 35.0) in the placebo group. In the osimertinib group 94/339 (28%) patients had disease recurrence or died, compared with 211/343 (62%) patients in the placebo group. The percentage of patients who were alive and disease-free at 48 months was 73% (95% CI 67% to 78%) in the osimertinib group, compared with 38% (95% CI 32% to 43%). The overall DFS HR was 0.27 (95% CI 0.21 to 0.34). This HR and the confidence interval exceed the minimal clinically (patient) important difference of HR<0.6. These results are consistent with the primary reporting (Wu, 2020).

Toxicity

Wu (2020) reported the outcome adverse events grade 3 or higher and serious adverse events. In the primary analysis, 68/339 (20%) (95% CI 16% to 24%) patients in the osimertinib group reported adverse events of grade ≥3, compared with 46/343 (13%) (95% CI 10% to 17%) patients in the placebo group (RR 1.50; 95% CI 1.06 to 2.11). This result indicates that among patients who receive osimertinib an additional 7 (95% CI 1 to 12) patients per 100 treated patients experienced adverse events grade 3 or higher.

Serious adverse events were reported in 54/339 patients (16%) (95% CI, 12% to 20%) in the osimertinib group and in 42/343 patients (12%) (95%, 9% to 16%) in the placebo group. 

Herbst (2023) reported long-term safety. In the osimertinib group, 79/337 (23%) patients reported adverse events of grade ≥3, compared with 48/343 (14%) patients in the placebo group (RR 1.68; 95% CI 1.21 to 2.32). The most common were diarrhea (n = 9, 3%), stomatitis (n = 6, 2%), pneumonia (n = 4, 1%) and QTc prolongation (n = 4, 1%) in the osimertinib group, which were also reported in one (<1%), zero, four (1%), and one (<1%) patient in the placebo group (John, 2023).

Among patients who receive osimertinib an additional 9 (95% CI 1 to 12) patients per 100 treated patients experienced adverse events grade 3 or higher.

Serious adverse events were reported in 68/337 (20%) patients in the osimertinib group and in 47/343 (14%) patients in the placebo group. Most common was pneumonia, reported in five (1%) patients in the osimertinib group and in four (1%) patients in the placebo group (John, 2023).

Level of evidence of the literature

The evidence was derived from an RCT, therefore the level of evidence for all outcomes started at ‘high’.

The level of evidence regarding the outcome measure overall survival was downgraded by two levels because of serious study limitations (-1 level for risk of bias, because of incomplete information about random sequence generation and allocation concealment and loss to follow-up) and imprecision (confidence interval crosses the boundary of clinical decision making, i.e. HR 0.7). Therefore, the level of evidence was graded as low.

The level of evidence regarding the outcome measure quality of life was downgraded by two levels because of serious study limitations (-1 level for risk of bias because of incomplete information about random sequence generation and allocation concealment and loss to follow-up) and  imprecision (few events, optimal information size not met). Therefore, the level of evidence was graded as low.

The level of evidence regarding the outcome measure disease-free survival was downgraded by two levels because of serious study limitations (-1 level for risk of bias, because of incomplete information about random sequence generation and allocation concealment and loss to follow-up) and imprecision (few events, optimal information size not met). Therefore, the level of evidence was graded as low.

The level of evidence regarding the outcome measure toxicity was downgraded by two levels because of serious study limitations (-1 level for risk of bias, because of incomplete information about random sequence generation and allocation concealment and loss to follow-up) and imprecision (few events, optimal information size not met). Therefore, the level of evidence was graded as low.

Search and select

A systematic review of the literature was performed to answer the following question:

Following a complete resection, which adjuvant treatment should be given to patients with early-stage (stage I-III) lung cancer with a targetable gene alteration?

P:       patients with completely resected, early-stage (I to III) pathologically confirmed non-small cell lung cancer (NSCLC) with a targetable gene alteration;

I:       adjuvant treatment specific for EGFR, ALK, RET, ROS1, BRAF, MET alterations;

C:       chemotherapy or placebo;

O:      overall survival, disease-free survival, response rate, adverse events, quality of life.

Relevant outcome measures

The guideline development group considered overall survival and disease-free survival as critical outcome measures for decision making; and quality of life and toxicity as important outcome measures for decision making. A priori, the working group did not define the outcome measures listed above but used the definitions used in the studies. The working group defined the following minimal clinically (patient) important differences (using the PASKWIL criteria 2023 for adjuvant treatment (https://www.nvmo.org/over-de-adviezen/) where possible):

•       Overall survival (OS): >5% difference between the groups or >3% difference and HR <0.7, at least three years of median follow-up time

•       Disease-free survival (DFS): HR <0.6

•       Quality of life (QoL): A minimal clinically important difference of 10 points on the quality-of-life instrument EORTC QLQ-C30 or a difference of a similar magnitude on other quality of life instruments.

•       Toxicity (adverse events grade ≥3): statistically significant difference between the groups.

Search and select (Methods)

The systematic review published by Zhao (2022) was used as the basis for this literature summary. This systematic review included patients with completely resected, early-stage (stage I to III) pathological confirmed NSCLC; Phase 2/3 RCTs comparing adjuvant EGFR-TKIs with chemotherapy or placebo; primary endpoints such as OS or DSF were reported; safety and adverse events (AEs) of EGFR-TKI or chemotherapy were evaluated in these trials. No studies were found for other mutations.

Search and select (Methods)

Zhao (2022) searched PubMed, Embase and the Cochrane library with relevant search terms until February 16, 2022. The detailed search strategy is depicted in the article published by Zhao (2022). The systematic literature search performed by Zhao (2022) resulted in 3483 hits. Based on title and abstract screening, 32 studies were initially selected. After reading the full text and thorough assessment of the studies, 23 studies were excluded (no RCTs, no outcome of interest and insufficient information after reviewing the full text), and nine RCTs were included (Tada, 2021; He, 2021; Wu, 2020; Zhong, 2018, 2021; Yue, 2018; Kelly, 2015; Feng, 2015; Li, 2013; Goss, 2013). An overview of all the included RCTs in the systematic review can be found in table 1.

On the 27th of January 2023, we performed a systematic search for systematic reviews and RCTs about NSCLC and adjuvant therapy for patients with EGFR, ALK, RET, ROS1, BRAF, MET mutations in the databases Embase.com and Ovid/Medline. The search resulted in 1075 unique hits and we screened publications published after the search date of Zhao (2022). From this yield a recent publication of quality of life data from the ADAURA trial was found (Majem, 2022). No studies were found for other mutations.

On the 5th of June 2023, we performed an update of the systematic search for RCTs in the same databases. The search resulted in 28 additional unique hits. From this yield recent publications of OS, DFS and safety/QoL data from the ADAURA trial were found (Herbst, 2023; Tsuboi, 2023; John, 2023). Moreover, one additional RCT was included (Ou, 2023).

In this updated search, no studies were found for other mutations.

Results

A total of ten studies were included in the analysis of the literature for EGFR+ NSCLC in adjuvant setting. The study by Goss (2013) was not included in our summary since only 4% of the study population had an EGFR mutation-positive tumor and did not meet our criteria. Furthermore, not all described treatments were available in the Netherlands at the moment of developing this guideline module. The assessment of the risk of bias is summarized in the risk of bias tables. The important study characteristics and results are summarized in the evidence tables.