Lung cancer remains the leading cause of cancer death in Australia and the fourth most commonly diagnosed cancer.¹ In May 2018, afatinib (Giotrif) became available on the PBS as monotherapy for the treatment of patients with advanced or metastatic non-squamous EGFR-mutation positive non-small cell lung cancer (NSCLC).^2,3 To better understand where this therapy fits within the current treatment paradigm in Australia, the limbic spoke with Professor Kenneth O’Byrne, Consultant Medical Oncologist at Princess Alexandra Hospital (PAH) and Queensland University of Technology in Brisbane.

While lung cancer remains one of the most challenging and complex cancers to treat, advances over the last few decades have led to major breakthroughs in its understanding, diagnosis and management.⁴ In particular, the EGFR pathway represented the emergence of personalised medicine in lung cancer for the first time with the introduction of the first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).⁴ Since then, the number of available therapies has continued to expand with the approval of second-generation EGFR TKIs, such as afatinib (Giotrif), ALK inhibitors and, more recently, immunotherapies.⁴

“In the early 2000s, the only therapies available to patients with advanced NSCLC were chemotherapy and palliative radiotherapy”, explained Professor O’Byrne. “The introduction of EGFR TKIs was a huge breakthrough in that we could now do precision medicine and actually target the right person with the right treatment for the first time in NSCLC.”

Professor O’Byrne continued, “When we are looking at our patients today as opposed to 10 years ago, what we can see is that instead of having an average survival of maybe 8 to 10 months, a significant proportion of patients can now expect to live for years – and that’s a massive change in a very short period of time.”

The LUX-Lung studies demonstrated the efficacy and safety profile of afatinib (Giotrif) in NSCLC

Afatinib (Giotrif) is an orally available, second-generation EGFR TKI that irreversibly binds to the ErbB family with the ability to block signaling from EGFR (ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), ErbB4, and all relevant ErbB family dimers.²

Professor O’Byrne, who was an investigator in the LUX-Lung studies, explained, “there are certain advantages that are emerging for the second-generation EGFR TKIs, including that these drugs are clearly superior to the first-generation drugs in terms of progression-free survival^,6 Afatinib (Giotrif) was also the first drug to show an overall survival benefit over chemotherapy in the subset of patients with EGFR exon 19 deletion mutations.”⁷

Indeed, the LUX-Lung 3 study investigating the efficacy of first-line afatinib (Giotrif) compared with chemotherapy (cisplatin plus pemetrexed) in patients with advanced or metastatic non-squamous EGFR-mutation positive NSCLC showed that for those with EGFR exon 19 deletions or L858R substitution mutations, there was a significant improvement in progression-free survival (PFS) with afatinib (Giotrif) versus chemotherapy (median 13.6 vs 6.9 months, respectively; hazard ratio [HR] 0.47; 95% confidence interval [CI], 0.34 to 0.65; p=0.001).⁵

Similarly, in the LUX-Lung 7 study, first-line afatinib (Giotrif) was associated with significantly increased PFS compared with the first-generation EGFR TKI gefitinib (median 11.0 vs 10.9 months, respectively; HR 0.73; 95% CI 0.57–0.95; p=0.017). Furthermore, afatinib (Giotrif) was associated with a significant increase in time to treatment failure versus gefitinib (median 13.7 vs 11.5 months, respectively; HR 0.73; 95% CI 0.58–0.92; p=0.0073).⁶

Professor O’Byrne highlighted that a preplanned analysis of the subset of patients with EGFR exon 19 deletions in LUX-Lung 3 did show that afatinib (Giotrif) significantly improved OS compared with chemotherapy (median 33.3 vs 21.1 months, respectively; HR 0.54; 95% CI 0.36–0.79; p=0.0015).⁷ However, median OS for the entire intention to treat population was not statistically significant (28.2 months vs 28.2 months, respectively; HR 0.88, 95% CI 0.66–1.17, p=0.39).

The role of afatinib (Giotrif) within the current treatment paradigm in Australia

Professor O’Byrne advised that, “at the present time in Australia… afatinib (Giotrif) is a very reasonable first choice treatment for patients with EGFR exon 19 deletions or L858R substitution mutations.”

“For people who have used the drug a lot, the toxicity is relatively straightforward to manage and it is just a matter of gaining the experience and then managing those toxicities to ensure that you get the benefit in terms of progression-free survival, time to treatment failure and potentially a benefit in overall survival compared with chemotherapy.”

Afatinib (Giotrif) is generally well tolerated²

The safety profile of afatinib (Giotrif) has been assessed in more than 3800 patients, including more than 1638 NSCLC patients treated with a daily dose of afatinib (Giotrif) 50 mg monotherapy and more than 497 NSCLC patients who received afatinib (Giotrif) 40 mg monotherapy once daily.² The most common side effects were diarrhoea, rash and stomatitis.² Overall in the LUX-Lung 3 trial, Grade 3 diarrhoea occurred in 15% of patients (0% for Grade 4), 14% experienced Grade 3 rash (0% for Grade 4), and 8% experienced Grade 3 stomatitis (0% for Grade 4).² These adverse events rarely led to discontinuation.²

Implementing an active adverse event management approach

Professor O’Byrne highlighted that, “It is really important to work closely with a nurse coordinator that the patients can contact, because sometimes the patients feel more relaxed and comfortable being able to contact the nurse rather than disturbing the doctor. So we establish that straight away.”

“The second thing is to ensure that patients are started on doxycycline to treat skin rash and they have a very active skin rash management program… We give patients a pack with various skin creams and advice leaflets and I think that really helps. We make sure that the patient has a good moisturising cream, as you don’t want the skin to get dry. People often think that the rash they get is a bit like acne so they think about drying it out, but that is the exact opposite of how to manage this rash. The skin should be kept moist.”

“The third issue is that occasionally patients can get significant diarrhoea. We tell them… to contact us straight away. The patients should have loperamide available to start treatment straight away… as we have loperamide available and can start treatment… often we also have to stop afatinib (Giotrif) temporarily and then restart at a reduced dose.”

Symptomatic adverse drug reactions, such as severe/persistent diarrhoea or skin-related adverse reactions, may be managed by treatment interruption and dose reduction.² Indeed, a post hoc analysis of the LUX-Lung 3 and 6 studies suggested that tolerability guided dose adjustment of afatinib (Giotrif) is an effective measure to reduce treatment-related adverse events, in addition to reducing interpatient variability of afatinib (Giotrif) exposure, without negatively impacting treatment efficacy.⁹

The recommended dose of afatinib (Giotrif) is 40 mg orally once daily for first-line treatment or for patients not previously treated with an EGFR TKI. A dose escalation to a maximum of 50 mg/day may be considered in EGFR TKI-naïve patients who tolerate a 40 mg/day dose (i.e. absence of diarrhoea, skin rash, stomatitis and other drug related events of Grade >1) in the first 3 weeks. The dose should not be escalated in patients with a prior dose reduction and the maximum daily dose is 50 mg.²

According to Professor O’Byrne, “We are very active in the care of patients during the first month, but once patients get through that first month or even first few weeks, in general, the treatment is pretty well tolerated.”

“The other nice thing about afatinib (Giotrif) is that you can dose reduce the drug. So if people are getting toxicities we can drop the dose down to a lower level and often just doing that alone will resolve the toxicities or make them more tolerable.”

Conclusions

Afatinib (Giotrif) has been shown to significantly prolong PFS compared with chemotherapy and gefitinib, is generally well tolerated and provides a useful addition to the treatment armamentarium for patients with advanced or metastatic non-squamous EGFR-mutation positive NSCLC.^5,6

Professor O’Byrne concluded, “There is no doubt in my mind that afatinib (Giotrif) is better than the first generation EGFR TKIs… and the good news is that it is available for our patients in the first line setting, giving us another choice of treatment.”

This article was sponsored by Boehringer Ingelheim, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Boehringer Ingelheim.

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References:

1. Australian Institute of Health and Welfare 2017. Cancer in Australia 2017. Cancer series no.101. Cat. no. CAN 100. Canberra: AIHW
2. Giotrif^® (afatinib) Product Information.
3. Pharmaceutical Benefits Scheme. Available at: www.pbs.gov.au. Accessed November 2018.
4. Cortinovis D et al. Ecancermedicalscience 2016;10:648.
5. Sequist LV et al. J Clin Oncol 2013;31:3327–34.
6. Park K et al. Lancet Oncol 2016;17:577–89.
7. Yang JC et al. Lancet Oncol 2015;16:141–51.
8. Paz-Ares L et al. Ann Oncol 2017;28:270–7.
9. Yang YC et al. Ann Oncol 2016;27:2103–10.