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InOncology.com

Dose modification

Afatinib dose adjustment in LUX-Lung 3, 6 and 7

Afatinib* dose adjustment may allow patients with non-small cell lung cancer (NSCLC) to remain on treatment longer, thereby maximising clinical benefit. Post-hoc analyses of the LUX-Lung 3, LUX-Lung 6 and LUX-Lung 7 studies were conducted to evaluate the effect of afatinib dose modifications on efficacy.1,2

Of the patients treated with afatinib, dose reductions occurred in 53% of patients in LUX-Lung 3 and in 28% of patients in LUX-Lung 6. Tolerability-guided dose adjustment of afatinib reduced the incidence and severity of treatment-related adverse events (AEs) without affecting efficacy.1 Median progression-free survival (PFS) in patients who had dose reductions in the first 6 months was found to be similar to that in patients who remained on afatinib 40 mg once daily.1

Similarly, in the Phase IIb LUX-Lung 7 trial of afatinib versus gefitinib, 42% of afatinib-treated patients had tolerability-guided dose reductions and experienced fewer treatment-related AEs without any loss in afatinib efficacy.2

PFS outcomes for patients with and without dose reductions in LUX-Lung 3 and 6

LUX-Lung 3: figure for PFS in patients with and without dose reductions

CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.

LUX-Lung 6: figure for PFS in patients with and without dose reductions

CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.

Treatment-related AEs requiring tolerability-guided dose modification in LUX-Lung 31

LUX-Lung 3: adverse events requiring dose modification

Treatment-related AEs requiring tolerability-guided dose modification in LUX-Lung 61

LUX-Lung 6: adverse events requiring dose modification

RealGiDo: a real-world study of afatinib dose adjustment

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Professor Angela Märten discusses the RealGiDo study of afatinib dose adjustment in a real-world setting

RealGiDo was a global, observational, non-interventional study of afatinib dose adjustment in a real-world clinical practice setting.3 The aim of RealGiDo was to determine whether afatinib dose modification in a real-world setting had a similar impact on afatinib safety and efficacy as observed in LUX-Lung 3. Patients (N=228) with advanced epidermal growth factor receptor (EGFR) mutation-positive, EGFR TKI-naïve NSCLC (Del19, L858R) were treated with afatinib according to the approved label.3 Analysis groups included patients with a dose reduction during treatment (<40 mg), and those with no dose reduction (≥40 mg).3 The primary outcome measures were the percentage of patients with adverse drug reactions (ADRs) by severity, time to treatment failure (TTF), and time to progression (TTP).3 The secondary outcome measure was the percentage of patients receiving a modified starting dose, and the reasons for modifying the starting dose.3

Afatinib starting dose in the RealGiDo study

Thirty-one percent of patients received a modified afatinib starting dose of <40 mg/day and the reasons for modifying the starting dose were broad but most commonly related to patient characteristics.3

Afatinib starting dose in the RealGiDo study

RealGiDo study: afatinib starting dose

Reasons for modifying the afatinib starting dose in the RealGiDo study

RealGiDo study: reasons for modifying starting dose

Dose reduction in the RealGiDo study

Overall, 177 (78%) patients in RealGiDo had a dose modification and 149 had a dose reduction.3 Among patients who received afatinib 40 mg/day as their starting dose, 86% of dose reductions occurred within the first 6 months of treatment.3

Safety profile of afatinib in the RealGiDo study

All-grade ADRs and Grade ≥3 ADRs occurred in 94% and 25% of patients participating in the RealGiDo study, respectively.3 Among patients who received a starting dose of afatinib 40 mg/day (n=155), 94% had an ADR, 28% had a Grade ≥3 ADR and 5% had a serious AE.3 There were fewer Grade ≥3 ADRs (28% vs 49%) and serious AEs (5% vs 14%) in patients treated with afatinib 40 mg/day in RealGiDo than in the LUX-Lung 3 trial.3,4

The most common ADRs in the overall population in RealGiDo were diarrhoea, rash/acne, paronychia/nail effect and stomatitis/mucositis.3 The incidences of these ADRs were lower in RealGiDo than in LUX-Lung 3 (diarrhoea, 75% vs 95%; rash/acne, 63% vs 89%; paronychia/nail effect, 49% vs 57%; stomatitis/mucositis, 34% vs 72%).3,4 Overall, no new safety signals were identified in RealGiDo.3

Among the 91 patients who had a dose reduction within the first 6 months after starting on afatinib 40 mg/day, 99% experienced an ADR of any grade prior to dose modification, compared with 71% after dose modification.3 The severity of ADRs was reduced following dose modification (see figure).In summary, dose reductions led to decreases in the incidence and severity of ADRs, including the most commonly reported ADRs.3

Overall safety profile in RealGiDo before and after dose reduction in patients who had a dose reduction within 6 months of starting afatinib at 40 mg/day3

RealGiDo study: Overall safety profile before and after dose reduction

Overall safety profile by starting dose in the RealGiDo study

The overall safety profile in patients who received a modified afatinib starting dose of ≤30 mg/day (n=71) is shown in the figure below.

Overall safety profile by starting dose in the RealGiDo study

RealGiDo study: ADRs by starting dose

TTF in RealGiDo

Median TTF was reasonably consistent across subgroups: 18.7 months (95% confidence interval [CI]: 15.1–21.5) in the overall population, 19.5 months (95% CI: 13.4–not evaluable [NE]) in patients who remained on afatinib ≥40 mg/day for the first 6 months (n=66), 17.7 months (95% CI: 14.5–21.5) in patients who had a dose reduction to <40 mg/day within the first 6 months (n=91), and 19.4 months (95% CI: 12.9–NE) in patients who started with afatinib ≤30 mg/day (n=71).3

The proportion of patients remaining on treatment at 12 months was estimated as 70% in the patients who remained on ≥40 mg/day for the first 6 months, 74% in patients who had a dose reduction to <40 mg/day within the first 6 months and 66% in patients who started with afatinib ≤30 mg/day.3 The corresponding rates at 18 months were 53%, 50% and 53%, respectively.3

TTF among patients in RealGiDo, by afatinib dose3

RealGiDo study: TTF by dose received

CI, confidence interval; NR, no response.

TTP in RealGiDo

Median TTP was 20.8 months (95% CI: 19.1–25.9) in the overall population, 29.0 months (95% CI: 17.9–NE) in patients who remained on afatinib ≥40 mg/day, 20.0 months (95% CI 14.7–23.0) in patients who had a dose reduction to <40 mg/day within the first 6 months, and 25.9 months (95% CI: 17.3–NE) in patients who started on afatinib  ≤30 mg/day.3

The proportion of patients without progressive disease or tumour-related death at 12 months was estimated as 79% in patients who remained on afatinib ≥40 mg/day for the first 6 months, 84% in patients who had a dose reduction to <40 mg/day within the first 6 months, and 86% in patients who started on afatinib ≤30 mg/day.3 The corresponding rates at 18 months were 65%, 60% and 64%, respectively.3

TTP among patients in RealGiDo, by afatinib dose3

RealGiDo study: TTP by dose received

CI, confidence interval; NR, no response.

Conclusions from the RealGiDo study

Tolerability-guided afatinib dose adjustment in real-world clinical practice reduced the frequency and intensity of ADRs, without impacting effectiveness.3 As seen in the LUX-Lung trials,4,5 the effectiveness of afatinib was consistent regardless of whether patients had a dose reduction or a modified starting dose.3 Overall, these results show that outcomes can be optimised by tailoring the afatinib dose according to individual patient characteristics and ADRs.

A low dose afatinib study in Japanese patients

In a single-arm, open-label, Phase II study of first-line afatinib in 46 Japanese patients with EGFR mutation-positive NSCLC, afatinib was initially prescribed at 20 mg/day and then, if tolerated, the dose was increased in 10 mg increments up to 50 mg/day.6 In patients with Grade ≥3 or selected prolonged Grade 2 drug-related AEs, the afatinib dose could be reduced 10 mg at a time to a minimum of 20 mg every other day.6 In the 44 patients with a target lesion, the objective response rate (ORR) was 82%.6 In the overall patient group, median PFS was 15.2 months (95% confidence interval [CI]: 13.2–not estimable) and median overall survival (OS) had not yet been reached at the data cut-off (median follow-up was 18.9 months).Low-dose afatinib treatment was well tolerated.6

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References

1

Yang JC, et al. Ann Oncol 2016;27(11):2103–10.

2

Hirsh V, et al. J Clin Oncol 2016;34(Suppl.):Abstract 9046.

3

Halmos B, et al. Lung Cancer 2018. doi: https://doi.org/10.1016/j.lungcan.2018.10.028 [Epub ahead of print].

4

Sequist LV, et al. J Clin Oncol 2013;31(27):3327–34.

5

Hirsch V, et al. Poster presented at ASCO 2016 (Poster 369).

6

Fujimoto D, et al. Poster presented at ESMO Asia 2017 (Poster 465P).

*Afatinib is approved in more than 80 markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF®, in the US under the brand name GILOTRIF® and in India under the brand name Xovoltib®; for the full list, please click here. Registration conditions differ internationally; please refer to locally approved prescribing information.

 

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Last updated: November 2018