When you are dying, every moment matters.
Even more so when it is from a disease like cancer, which can strike you when you think you still have many years of living left.
While cure rates for cancer have improved over the decades, they are invariably linked to the stage of the cancer at diagnosis.
The earlier the stage of the cancer, the better the chances of curing it – or at least, putting it into long remission.
Unfortunately, the majority of Malaysians tend to be diagnosed only at the later stages of their condition.
According to the latest National Cancer Registry Report in 2007, 57.6% of cancer patients were already at stages 3 and 4 when they were first diagnosed. (Editor’s note: Yes, the data that is available is almost a decade old, but there’s no indication that things have changed much in the last 10 years.)
While there are still a range of treatment options to be had at these late stages, most of them are aimed at buying more time for the patient (versus curing them) and giving them a better quality of life by alleviating their symptoms.
Said Sungkyunkwan University School of Medicine, Seoul, South Korea, Medicine Department’s Division of Haematology-Oncology professor Dr Park Keunchil: “Let me remind you first, none of these drugs will ever cure your patients.”
But they can give them extra time.
“During the first generation tyrosine kinase inhibitor (TKI) introduction, I had a patient who was suppose to die in a few days,” shared Prof Park.
“But with the drug, he recovered in three weeks and walked out the door on his own two feet.
“That, I felt, was a real miracle.
“But, in 10 months, he succumb- ed to the disease.”
Prof Park was speaking to reporters from around the region during a recent press conference announcing the results of the Lux-Lung 7 study in Seoul, South Korea.
The study is the first clinical trial to directly compare the second- generation TKI, afatinib, with first generation TKI, gefitinib.
Both drugs were developed to treat EGFR (epidermal growth factor receptor) mutations that cause cancer, specifically non-small cell lung cancer (although gefinitib has also been shown to treat other cancers with prominent EGFR mutations, like breast cancer).
Types of lung cancer
During the press conference, Sun Yat-Sen University, Guangzhou, China, Lung Cancer Research Centre deputy director Prof Dr Zhang Li said that lung cancer generally consists of two types: small cell and non-small cell.
Non-small cell lung cancer (NSCLC) forms the majority of lung cancer cases at 85%.
And while, it generally affects smokers, NSCLC is also the main type of lung cancer affecting non-smokers and females.
NCSLC can be divided into four types: adenocarcinoma (40-50%), squamous cell carcinoma (25-40%), large cell carcinoma (3-5%) and other less common types (less than 5%).
Prof Zhang also shared that more than half of lung cancer cases in the world (51.4%) occur in Asia, where it is the number one and number two cause of cancer death in Asian men and women respectively.
In addition, EGFR mutations are found in 40% of Asian NSCLC patients, compared to 10-15% of similar Caucasian patients.
This means that around one in three Asian lung cancer patients (34%) will have an EGFR mutation-positive NSCLC.
That is also the reason why half the participants for the Lux-Lung 7 trial were recruited from Asia.
Said Prof Zhang: “All the international guidelines recommend that we test for EGFR mutation at the diagnosis of advanced disease, especially for adenocarcinoma type.
“The test result should guide the treatment plan.
“If the patient has EGFR-mutant lung cancer, it should be treated with afatinib. If it is non-mutated, it should be treated with chemotherapy.”
Irreversible action
While there are a few different types of EGFR mutations, the two most common ones (del19 and L858R) account for 80-90% of lung cancer cases, and it is these mutations that gefitinib and afatinib treat.
Both drugs work by binding to the mutated EGFR, also known as ErbB1, which is part of a family of cell receptors called ErbB.
These receptors, once mutated, produce excessive amounts of protein that lead to uncontrolled cell reproduction.
However, there are two main differences between the two drugs.
According to Prof Park, gefitinib is a reversible TKI, which only binds to EGFR.
He explained: “If you give enough ATP (adenosine triphosphate) energy to the cell, then the ATP is competing with gefitinib to bind to the EGFR.
“Gefitinib has a very strong binding affinity to EGFR, but if you give enough ATP, ATP will kick off gefitinib from the binding sites.”
In contrast, afatinib is an irreversible TKI, which not only binds to EGFR, but also to the three other members of the ErbB receptor family.
“An irreversible TKI – for example, afatinib – binds to the receptor covalently, which is a really strong bond.
“So, even though you give enough ATP, afatinib will still remain there,” he said.
Gefitinib vs afatinib
This difference in action is likely what contributed to the results of the Lux-Lung 7 study.
This phase IIb clinical trial involved 316 patients across 13 countries.
These patients, who all had untreated advanced EGFR mutation-positive lung adenocarcinoma, were randomly selected to receive either gefitinib or afatinib.
The three main outcomes the study was designed to look at were progression-free survival rate, time to treatment failure and overall survival rate.
Explained Prof Park: “The key primary endpoint, progression-free survival (PFS), is the time from start of the treatment until the tumour starts to regrow, or the patient progresses while on treatment.”
The study found that afatinib significantly reduced the risk of lung cancer progression by 27%, compared to gefitinib.
While the median PFS time was similar at 11 months for afatinib and 10.9 months for gefitinib, those on afatinib showed a better PFS rate in the longer term.
At 18 months, 27% of patients on afatinib were still alive with their tumours in check, compared to 15% of patients on gefitinib.
And at 24 months, 18% of patients on afatinib were alive and progression-free, compared to 8% of patients on gefitinib.
In fact, 70% of the afatinib group saw a clinically meaningful shrinkage of their tumour during the trial, compared to 56% of the gefitinib group, with the median duration of the tumour shrinking in response to treatment lasting 10.1 months and 8.4 months respectively.
Prof Park explained that the second primary endpoint – time to treatment failure – is the period between the start and discontinua-tion of treatment for any reason.
These reasons, he said, were usually due to progression of the disease, unbearable drug side-effects or death.
The results showed that patients on afatinib tended to stay on their treatment much longer than those on gefitinib, with the risk of treatment failure significantly reduced by 27% for the afatinib group.
As this endpoint takes into account discontinuation of treatment due to the drug’s side effects, Prof Park opined that this indicates these side effects are acceptable and manageable by both patients and doctors.
This is important as nearly all the participants in the trial experienced side effects from both afatinib (98.8%) and gefitinib (100%), although only 6.3% of patients in each group stopped their treatment because of it, with one patient taking gefitinib dying from the drug’s toxicity.
Said Prof Park: “We know how to manage and take care of the toxicities. They are quite predictable.
“We have a well-established treatment scheme for the reported adverse events.”
He shared that he usually starts proactive management of side effects if he sees that his patient is likely to develop them once they start treatment.
According to him, the most common side effects of afatinib are diarrhoea, skin rash and mucositis (inflammation of the mucosal cells that line the digestive tract), while for gefitinib, they are elevation of liver enzymes, skin rash and diarrhoea.
While the collection of data for overall survival rate is not yet complete, Prof Park does not think that it will affect the results already shown by the trial.
“Even though overall survival is one of the three primary endpoints of the Lux-Lung 7 study, whether or not the overall survival result is positive, I don’t think that would affect the overall results of the study.
“The clinical relevance of the Lux-Lung 7 study is already met, I think,” he said.
Overall, the study was meant to provide both doctors and patients a better understanding of their treatment options when it comes to previously untreated advanced EGFR mutation-positive NSCLC.
Prof Park said that at the end of the day, it is up to doctors and patients to balance the benefits of their treatment options against their abilities to manage and tolerate the expected side effects.
