This article is a Clarivate Analytics Market Insight report, an ongoing series featuring expert reviews of hot topics in the pharma/biotech field, with analysis and discussion on the factors currently affecting the industry.
The presence of a targetable driver mutation in nearly 50% of non-small-cell lung cancer (NSCLC) patients led to a paradigm shift in the treatment of NSCLC last decade, through the development of targeted agents, most notably to EGF receptor (EGFR) mutations or rearrangements of the ALK or ROS1 gene, and genotype testing to determine appropriate treatment is now routine. It has been nearly 15 years since the first EGFR-targeted therapies were introduced, replacing chemotherapy in the first line, and while progress in the targeted therapy arena continues unabated there are now new modalities entering the space. Not least of these are the immune checkpoint inhibitors, with Merck’s Keytruda (pembrolizumab) the first to be approved in the first-line setting, in May 2017.
The pace of progress in the field was highlighted at the recent American Society of Clinical Oncology meeting in Chicago in June, where lung cancer was the leading indication among the numerous and diverse presentations, as targeted therapies continue to be explored in NSCLC in wider-ranging genetically defined subgroups, and optimal molecular subpopulations and/or combination regimens are sought for immunotherapies.
Many practice-changing data were presented this year that will influence the management of this disease. Here we take a look at some of the biggest impact data, which are expected to affect drug sales forecasts in the category going forward.
ALK-positive: Alecensa lowers risk of progression versus Xalkori in the first line (ALEX trial)
The second-generation ALK inhibitor Alecensa (alectinib) was approved for Xalkori (crizitonib)-refractory ALK-positive NSCLC in December 2015; however, recently reported data from the phase III ALEX trial in the first-line setting now indicate that the drug should be treatment of choice for this patient population as well. ALEX compared Alecensa with current standard of care ALK inhibitor Xalkori in 303 patients with Stage IIIB/IV ALK-positive NSCLC, and demonstrated a 15.3-month improvement in progression-free survival (PFS) for Alecensa (10.4 months vs. 25.7 months), for a 53% decreased risk of progression or death.
In addition, the drug was more effective in patients with CNS metastases; at 12 months, the incidence of brain metastases was 9.4% with Alecensa versus 41.4% with Xalkori, and the median duration of response in the CNS was 5.5 months versus 17.3 months. Severe side effects were also lower, and patients randomized to Alecensa were less likely to experience adverse events leading to discontinuation (13% vs. 11%), dose reduction (21% vs .16%) or interruption (25% vs. 19%).
ALK translocation only accounts for around 5% of NSCLC cases, but these results are dramatic. Treatment of CNS lesions also remains an unmet need in this setting, and the favorable data in these patients will drive additional sales. Roche filed Alecensa for approval in the first-line setting in March 2017, and with approval almost certainly guaranteed based on the ALEX data as well as supported by Breakthrough Designation. Cortellis forecasts sales are $898.8 million in 2022 (Thomson Reuters I/B/E/S).
EGFR-positive: dacomitinib tops Iressa in the first line (ARCHER 1050)
Pfizer’s dacomitinib was not previously expected to be a major player in the EGFR-mutant setting, having failed to prove superiority to Tarceva (erlotinib) in previously treated patients. However, promising data have now been reported from the ARCHER 1050 trial in the first-line setting which may indicate a more promising future.
In ARCHER 1050, the median PFS for previously untreated patients with advanced EGFR-positive NSCLC who received dacomitinib was 14.7 months (n = 227), compared with 9.2 months for Iressa (gefitinib; n = 225), for a 42% reduction in risk of progression. The PFS response was driven by responders among the Asian patients enrolled in the trial, as the difference was not significant among non-Asian patients. The median duration of response was 14.8 months versus 8.3 months. Dacomitinib’s efficacy was accompanied by an increase in skin and gastrointestinal toxicities (dermatitis 49% vs. 29%, diarrhea 87% vs. 56%), while hepatic toxicity was more common with Iressa (39% vs. 19%).
Although there are already three EGFR inhibitors approved for use in the first line (Iressa, Tarceva, Gilotrif (afatinib)), these data will mean the drug is a contender in the market should it be approved. Cortellis expects possible approval in 2018 and forecasts sales of $153 million in 2022.
EGFR T790M-positive: activity for Tagrisso in CNS metastases (AURA3)
EGFR T790 testing represents the first companion diagnostic in oncology that allows a new biopsy upon treatment resistance, and confirming that a patient’s EGFR resistance is mediated by the EGFR 790M mutation now allows for continued targeted therapy upon progression, through treatment options such as AstraZeneca’s Tagrisso (osimertinib). Tagrisso was launched in November 2015 for patients with tyrosine kinase inhibitor-refractory disease, and its market potential is undisputed: Sales were $419 million in its first full year of launch. However, an important characteristic for continued success will be control of CNS disease, a common cause of morbidity in progressing patients.
In a recent additional analysis of the phase III AURA3 trial, Tagrisso demonstrated a PFS of 11.7 months in patients with EGFR T790M mutation-positive NSCLC and CNS metastases, compared with 5.6 months for platinum-based doublet chemotherapy. The CNS objective response rate was 70% versus 31% with chemotherapy. Updated results from the BLOOM study also show an overall disease response of 43% in patients with leptomeningeal metastases, a particularly lethal form of CNS spread.
AstraZeneca is also seeking to move the drug into earlier-line settings ahead of resistance, through the phase III FLAURA trial, and is also conducting the ADAURA trial in the adjuvant setting. Cortellis forecasts sales of $2.782 billion in 2022.
Immuno-oncology changing the dynamic in the NSCLC space
The emergence of immuno-oncology has been transformative in cancer treatment, and lung cancer has been a major focus in the sector, with immuno-oncology-based treatments offering the potential to provide outcomes regardless of mutation status.
The PD-L1 inhibitor Tecentriq (atezolizumab) was approved for NSCLC patients progressing on platinum chemotherapy in October 2016, where it will compete with Merck’s Keytruda and Bristol-Myers Squibb’s Opdivo (nivolumab). Approval in this setting was based on the phase III OAK study, which demonstrated a 4.2-month survival benefit versus chemotherapy (13.8 months vs. 9.6 months), and further data from OAK presented recently demonstrated that patients treated beyond progression saw subsequent responses in target lesions. After progression, patients who continued on Tecentriq had overall survival of 12.7 months compared with 8.8 months for those who switched to other treatments, with no additional safety signals observed, indicating that retreatment is feasible.
Significantly, patients treated with Tecentriq do not have to be screened for PD-L1 expression, while patients taking Keytruda have to be tested, presenting a market advantage for Tecentriq. Competitor Opdivo also failed to improve PFS in the first line and BMS announced it would not be pursuing approval in this setting in January 2017, therefore success in Roche’s B-F1RST study for Tecentriq in the first-line setting could establish it as the front-runner in the NSCLC space among all three drugs. However, competition will be fierce, with data from Merck’s phase I/II KEYNOTE-021 trial in the first line reporting a spectacular hazard ratio of 0.53 for PFS, and the drug gaining a head start in the first line following approval in May 2017; recent survival data in June 2017 also indicated a 31% reduction in the risk of death.
Lung cancer is the biggest commercial market for immuno-oncology, and Cortellis forecast sales for Tecentriq top $1 billion in 2018, and reach $4.382 billion in 2022. This compares to 2022 forecast sales for Keytruda of $10.675 billion and $11.200 billion for Opdivo.