NSCLC Treatment Paradigm: Where Do We Stand?
NSCLC treatment paradigm: where do we stand?
Lung cancer is, by a large margin, the leading cause of cancer death in both men and women. The survival rate for lung cancer is less than 18% within a five-year period. The survival rate for advanced lung cancer is dire – a median survival of only one year. About 80-85% of all lung cancers are non-small cell lung cancer (NSCLC).
How do biomarkers affect the clinical decision-making for treating individuals with NSCLC?
Biomarker testing is now essential for the treatment of NSCLC, as there is strong evidence that individuals respond to both generalized and targeted treatments differently based on the presence of specific tumor biomarkers in their bodies. The numbers of targeted therapies for NSCLC are clearly on the rise and the current treatments for NSCLC display a very fragmented market of many lines.
The faster the doctor receives the biomarker profiles, the better the clinical outcome. Physicians routinely check for the following biomarkers when making a decision on therapy for NSCLC.
1. Epidermal growth factor receptor (EGFR) mutations
2. Programmed death ligand-1 (PD-L1)
3. EGFR T790M resistance mutation
4. Anaplastic lymphoma receptor tyrosine kinase (ALK) status
5. ROS1 status
6. EGFR expression
7. PD-L1 expression
8. KRAS mutation
In order to decide what diagnostic tests to perform first, clinicians use a strategy known as the “reflex strategy.” The reflex strategy combines various diagnostics, including tissue histology, genetic/genomic tests, and proteomic tests.
For a newly diagnosed patient, clinicians typically start with a tissue histology and blood biopsy, which may be performed on the same day. Tissue histology is routinely performed to confirm the initial diagnosis of NSCLC. However, if there is drug resistance, it becomes increasingly difficult to perform a re-biopsy due to patients performing poorly and the challenge of accessing tumors. In these secondary cases, liquid biopsies are preferred as they are minimally invasive.
Recent results from Medimix Real World Evidence LiveTracker™ offer an interesting perspective on differences in Biomarker testing across world regions.
As seen in figure 1, Europe tends to lag behind US and Japan in terms of testing, with oncologists performing biomarker testing to only 79% of their patients, quite behind Japan (90%) and the US (97%).
Figure 1. LiveTracker™ real-world evidence – compared rate of biomarker test – April – June 2018
Differences exist across European countries with testing rates being higher in Germany and France than Italy, as well as across Latin American countries with Chile testing at a higher rate than Brazil or Colombia, but altogether, the main difference resides in the type of biomarker tested.
As seen in Figure 2, if EGFR (the only biomarker available for targeted therapy 10 years ago) is still among the most frequently tested biomarker across countries, it is much more tested in the US than elsewhere, and in every region, it is now less often tested than PD-L1.
This has profound implications on the way oncologists and pathologists decide to treat their patients, as PD-L1 and EGFR are not exclusive and immuno-oncology therapies can be prescribed independently for squamous and non-squamous patients.
Figure 2. LiveTracker™ real-world evidence – compared rate of biomarker test – April – June 2018
Why is PD-L1 biomarker testing on the rise?
Since higher PD-L1 biomarker levels are associated with advanced NSCLC, researchers are actively searching for a “companion diagnostic testing” for tumors with PD-L1 expression. However, PD-L1 biomarker testing is mostly prognostic, as the test does not identify patients who do not benefit from it.
In the KEYNOTE-024 clinical trial for pembrolizumab, the trial design included patients with PD-L1 expression higher than 50%, and the trial was successful. The Checkmate-026 clinical trial for nivolumab included patients with PD-L1 expression higher than just 5%, and the trial was a failure. The differences in outcomes between both trials have sparked a curiosity among researchers as to the importance of PD-L1 biomarkers.
Subsequently, pembrolizumab got an approval for first line usage in patient overexpressing PD-L1, which explains the rapid increase of PD-L1 testing.
Clinical-decision making from first-line treatment of NSCLC and beyond
As we write, the standard-of-care for advanced NSCLC is still platinum-based doublet chemotherapy. Even with advancements in targeted medicine, research shows that chemotherapy increases the outcome and quality of life of patients with NSCLC. However, the prognosis is no longer than 10 months of survival.
Targeted therapy for mutations in NSCLC cases is on the rise due to success in clinical trials, and routine molecular testing is now the standard-of-care. Approximately 25% of people with NSCLC have EGFR, ALK, or ROS1 mutations or rearrangements at the initial diagnosis. The FDA has approved several first-line targeted drugs for these mutations as studies demonstrate that targeted therapy improves survival rates more than chemotherapy for this sub-group of patients.
In cases where the patient needs immediate treatment, doctors may start with chemo and switch to targeted therapy later once biomarker testing confirms that there is a mutation. Real-world evidence by LiveTracker™ in Figure 3 below shows the percentages of patients receiving each NSCLC treatment regimens, as well as the treatment sequencing (from first-line to third-line therapy) for both non-squamous and squamous tumor types.
Figure 3. NSCLC treatment sequencing by LiveTracker™ for both non-squamous and squamous tumor types – TOP 3 EU.
Patients with EGFR mutation-positive NSCLC typically receive EGFR tyrosine kinase inhibitors (EGFR-TKIs) as a first-line treatment. The current first-line therapies for NSCLC patients with EGFR mutations include erlotinib, gefitinib, and afatinib. The choice of EGFR-TKI is decided on an individual basis, as doctors have to put various factors into consideration. If the EGFR mutation is an exon 19 deletion or an L858R point mutation, then this predicts that the patient will respond well to erlotinib or gefitinib. However, if the mutation is a T790M or exon 20 insertion, then the patient may be resistant to these drugs.
At some point during treatment, all EGFR-mutant advanced NSCLC patients acquire resistance to EGFR-TKIs and the doctor will need to change the therapy. To switch to a new drug, the oncologist will perform another genetic profiling to detect the resistant EGFR mutations, for example, T790 M resistance—the most common resistance occurring in 50-70% of tumors. So far, the drug with the best second-line efficacy for EGFR T790M resistance mutation is osimertinib. Note that sometimes osimertinib is offered as a first-line treatment as well. If a wild-type EGFR or unknown EGFR is found, then proteomic profiling can be used to find out how aggressive the tumor is growing. If the prognosis is “good,” the physician may use a platinum-based therapy, single-agent chemo, or EGFR-TKI-based therapies. If the prognosis is “poor,” then EGFR-TKI-based therapies may not work at all.
Another mutation oncologists watch out for in NSCLC is the KRAS mutation. The KRAS protein helps in the activation of the EGFR pathway. KRAS mutations do not respond to EGFR-TKI therapies such as erlotinib and gefitinib mentioned above. Studies show improved progression-free survival in NSCLC patients with KRAS-mutant mutations when treated with selumetinib in conjunction with chemo. However, in patients with previously treated advanced KRAS-mutant NSCLC, there are no benefits of selumetinib over chemo.
Patients with NSCLC may have ALK mutations. These mutations are often associated with younger people, with the most common ALK mutation being the EML4-ALK rearrangement. If biomarker test results show that a patient has an ALK mutation, it means that they would be resistant to EGFR TKI inhibitors and alternative therapies need to be considered. The first FDA-approved therapy for ALK mutations is crizotinib, which had a response of 50-60% in single-arm clinical studies.
In addition, patients with advanced NSCLC who express ? 50% of PD-L1 may benefit from pembrolizumab as a first-line therapy. The choice of therapy for PD-L1 expression is dependent on the levels of PD-L1 in the patient. Of important note is the coexpression of PD-L1 and EGFR mutations. There is evidence that the expression of PD-L1 is higher in patients with EGFR-mutated NSCLC tumors than in those with EGFR-wild-type NSCLC tumors. The reason for this could be that PD-L1 may increase resistance to EGFR-TKIs. Therefore, the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of NSCLC now include routine testing for PD-L1 expression.
Data from LiveTracker™ shows that in Europe, physicians still prefer EGFR and ALK-targeted therapies as a first-line of treatment, as can be seen in Figure 4 below, with the highest percentage (80%) of physicians opting for gefitinib as first-line treatment. (Similar data is available for the US market).
Figure 4. LiveTracker™ real-world evidence – Drug preference for 1st line, 2nd line, and 3rd line therapies
However, as depicted in Figure 5 below, LiveTracker™ shows that between October 2016 and November 2017, pembrolizumab climbed up rapidly to the top of preferred first-line treatment by HCPs for advanced NSCLC, (even with its restriction for PD-L1 expression greater than 50%).
It will be interesting to see what the next few months bring with Keytruda + Chemo and Opdivo + Yervoy in first line.
Figure 5. LiveTracker™ real-world evidence – Increase in drug preference for Keytruda as first-line treatment
In patients with ALK mutations, the first-line treatment is typically crizotinib. Unfortunately, these patients develop resistance within the first 12 months. Various second-generation ALK inhibitors, for example, ceritinib, have been developed to improve treatment of NSCLC patients with ALK mutations. Ceritinib has up to 20 times more selectivity for ALK than crizotinib. Real World Evidence data from the LiveTracker™ also shows that oncologists often switch to an immunotherapy after a first line ALK treatment which represents a challenge for the now numerous manufacturers of ALK targeted therapies.
Finally, for patients with ROS1 mutations, a single phase I clinical trial found a 72% response rate and median progression-free survival of 19.2 months when treated with crizotinib, which is also used to treat patients with ALK mutations as seen above.
Will testing strategies change with the rise of immunotherapy in cancer treatments?
Traditionally, patients have always been tested using histology first. However, with the rise of immunotherapy for first-line treatment of NSCLC, will the paradigm of testing shift from histology testing to biomarker testing?
From a pathologist’s perspective, although PD-L1 expression is directly correlated with drug efficacy, the PD-L1 tests are not yet standardized, especially because of the complex biology of PD-L1 expression, which is variable. It is important to note that different PD-L1 assays were used in the different PD-1/PD-L1 inhibitor clinical trials. Moreover, some therapies do not require patients to be PD-L1 positive to begin therapy.
One major reason for a rise in PD-L1 testing is simply its prognostic value and just to have the entire patient’s information at hand. With this value in patients’ records, physicians can counsel patients about the most appropriate therapies to meet their needs. PD-L1 testing is now being introduced as a standard part of the workup for patients in line to receive treatment for advanced NSCLC. However, histology testing is still very necessary.
One big challenge oncologists face is the coexistence of PD-L1 expression and ALK mutations. The relationship between PD-L1 expression and the ALK gene is a controversial topic among researchers. One study showed that PD-L1 expression was upregulated with the fusion of the echinoderm microtubule-associated protein-like 4 (EML4) and ALK genes to form EML4-ALK. In patients that are ALK+ and PDL1 >1%, the best treatments are ALK inhibitors such as crizotinib, ceritinib, or alectinib. Physicians typically start with first-generation crizotinib, and if there is resistance, they switch the therapy to ceritinib or alectinib.
LiveTracker™ can help researchers and pharmaceutical executives understand changes in the NSCLC pharma landscape that can affect clinical decision-making either for first-line therapy or for switching therapy after resistance.
Background on Information Presented
The Market insights and Real World Evidence information presented in this article are derived from data obtained from 2016 to 2018 in the US, European, Japanese and Latin American LiveTracker™ developed by Medimix International. Medimix’s LiveTracker™ provides physician AND patient real-time level data aggregated monthly, quarterly, or annually which helps forecast trends and understand evolution of treatment patterns.
LiveTracker™ is available in 50 countries and across 22 Oncology and Hematology indications.
Please do not hesitate to ask us for more information on how LiveTracker™ can improve your understanding of global specialty markets with the goal of increased product usage and better patient outcomes.
© Medimix International – Real World Evidence consulting – July 2018