Disease Overview
Lung cancer is generally categorized as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Of these, NSCLC is the most common type of lung cancer, accounting for roughly 85% of all cases. NSCLC can be further divided into non-squamous and squamous NSCLC histologies. Squamous NSCLC refers to patients with squamous cell carcinoma, whereas non-squamous NSCLC includes patients with adenocarcinoma, large cell carcinoma, and other less common subtypes. Incidence of adenocarcinoma and squamous cell carcinoma varies greatly by both geographic region and gender. In general, adenocarcinoma comprises approximately 30-50% of all lung cancer cases, while squamous cell carcinoma accounts for roughly 25-35%.
Latest Key Takeaways
Lung cancer is generally categorized as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Of these, NSCLC is the most common type of lung cancer, accounting for roughly 85% of all cases. NSCLC can be further divided into non-squamous and squamous NSCLC histologies. Squamous NSCLC refers to patients with squamous cell carcinoma, whereas non-squamous NSCLC includes patients with adenocarcinoma, large cell carcinoma, and other less common subtypes. Incidence of adenocarcinoma and squamous cell carcinoma varies greatly by both geographic region and gender. In general, adenocarcinoma comprises approximately 30-50% of all lung cancer cases, while squamous cell carcinoma accounts for roughly 25-35%.
Latest Key Takeaways
- The publisher estimates that in 2018, there were 1.8 million incident cases of non-small cell lung cancer (NSCLC) worldwide, and expects that number to increase to 1.9 million incident cases by 2027. The majority of NSCLC diagnoses (65.4%) worldwide are in males, ranging from 52.9% to 72.1% across regions.
- In the last three years, the number of therapies targeting specific sensitizing mutations in metastatic NSCLC has drastically increased, permanently altering the treatment landscape. Many of the new drugs have shown dramatically increased response rates over the previous standard-of-care therapies. However, given the relatively small percentage of metastatic NSCLC patients presenting with each oncogenic driver, competition is fierce and first-to-market advantage is critical.
- Programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1)-targeted monoclonal antibodies for NSCLC are forecast to remain the best-selling class of drugs for this indication. Keytruda was the first PD-1/PD-L1 inhibitor to gain regulatory approval for first-line NSCLC patients without an oncogenic driver and has risen to dominance in this market as label expansions have broadened its target patient population and as late-phase trials have revealed consistently positive data. Furthermore, the commercial potential of this class of drugs will increase over the forecast period as the use of checkpoint inhibitors will likely soon extend beyond the metastatic patient population. Label expansions into the earlier treatment settings may provide an opportunity for the other checkpoint inhibitors to differentiate themselves from Keytruda and carve out a niche in this lucrative market.
- PD-L1 inhibitor Imfinzi’s approval for sequential therapy of locally advanced patients following chemoradiation minimizes direct competition with established immunotherapies and has allowed the drug to secure a modest market share.
- Third-generation EGFR inhibitor Tagrisso is now the first-line standard-of-care treatment for NSCLC patients whose tumors harbor activating EGFR mutations (exon 19 deletion or L858R point mutation). Despite competition from Tarceva, Iressa, Gilotrif, Vizimpro, and Alunbrig, Tagrisso will continue to dominate the EGFR inhibitor market due to continued uptake and a recent label expansion into the adjuvant setting. However, Janssen’s recently initiated Phase III MARIPOSA study of amivantamab in combination with lazertinib is the first head-to-head trial against Tagrisso, and the combination could eventually threaten Tagrisso’s position in the first-line setting.
- Amivantamab and mobocertinib are currently in late-stage development for metastatic NSCLC patients whose tumors harbor an exon 20 insertion mutation in EGFR, a population of patients where currently approved therapies are not effective. Competition will be fierce between these two drugs, and the first therapy to market will likely dominate. However, the relative rarity of this mutation limits the commercial potential of an approval in this patient population, and both therapies are also in development for the treatment of other actionable mutations.
- Alecensa has become the new first-line standard of care for ALK rearrangement-positive NSCLC. The Phase III ALEX study demonstrated superior progression-free survival when treated with Alecensa compared with previous standard of care Xalkori. Alecensa will likely remain the class leader even though it will face competition in the first-line setting from other ALK inhibitors such as Zykadia, Alunbrig, and Lorbrena. Dual ALK/ROS1 inhibitor Lorbrena is also approved in both the first- and second-line settings, but has experienced only modest uptake thus far.
- The ALK inhibitors Rozlytrek and Xalkori are both approved for the treatment of metastatic NSCLC patients whose tumors have a ROS1 rearrangement or fusion. Rozlytrek is also approved as a monotherapy for patients with NTRK+ gene fusions. The combined data from Rozlytrek’s development program compare favorably to the data for Xalkori, particularly in patients with CNS metastases at baseline. ROS1 gene rearrangements are present in 1-2% of NSCLC patients, while NTRK fusions are present in approximately 0.2% of cases.
- The combination of BRAF inhibitor Tafinlar and MEK inhibitor Mekinist has become the standard of care for advanced or metastatic NSCLC with BRAF V600E mutations. However, only 1-2% of NSCLC patients have a BRAF V600E mutation, which limits the combination’s commercial potential.
- Two MET inhibitors, Tabrecta and Tepmetko, have been approved for NSCLC patients with a MET exon 14 skipping mutation in the US and Japan. Both drugs are also in development for MET-amplified NSCLC and for patients with EGFR-mutated, c-MET-amplified NSCLC who have progressed after EGFR inhibitor treatment. Potential label expansions into these treatment settings represent a noteworthy market opportunity. Approximately 1-4% of NSCLC patients have a MET exon 14 skipping mutation.
- Retevmo is the first drug approved for the treatment of patients with RET fusion-positive NSCLC. In the pivotal Phase I/II trial, Retevmo demonstrated efficacy in RET fusion-positive patients and in a subgroup of patients with brain metastases. The confirmatory Phase III LIBRETTO-431 trial is ongoing, and approvals in both Europe and Japan are expected based on the Phase I/II data. However, Retevmo will face competition from RET inhibitor Gavreto, which was recently approved in the US.
- As therapies targeting specific oncogenic drivers have established themselves in metastatic NSCLC, attention has shifted toward mutations that do not yet have targeted therapies. Two notable pipeline examples are KRAS inhibitors sotorasib and adagrasib. Both KRAS inhibitors are being investigated as second-line or later treatments for patients with KRAS G12C-mutant NSCLC, a patient population that was previously thought to be undruggable. This is a significant market opportunity given that approximately 13% of NSCLC patients have KRAS p.G12C mutations.
- As checkpoint inhibitor regimens dominate in the first-line setting for patients without sensitizing mutations, effective treatments for the post-immunotherapy setting remain the largest unmet need within the indication. Treatment for these patients is largely palliative, and patients currently have very limited treatment options. A number of therapies, including Cabometyx, Lenvima, sitravatinib, and tusamitamab ravtansine, are in development for this treatment setting.
- The overall likelihood of approval of a Phase I NSCLC asset is 8.1%, and the average probability a drug advances from Phase III is 37.2%. NSCLC drugs, on average, take 9.1 years from Phase I to approval, compared to 9.6 years in the overall oncology space.
- Key upcoming catalysts for 2021 include top-line results for the Phase III SAPPHIRE study of sitravatinib and Opdivo and the Phase III JAVELIN Lung 100 study of Bavencio, as well as PDUFA dates for amivantamab and adagrasib.
Table of Contents
OVERVIEW
DISEASE BACKGROUND
TREATMENT
EPIDEMIOLOGY
KEY REGULATORY EVENTS
LICENSING AND ASSET ACQUISITION DEALS
CLINICAL TRIAL LANDSCAPE
FUTURE TRENDS
RECENT EVENTS AND ANALYST OPINION
BIBLIOGRAPHY
LIST OF FIGURES
LIST OF TABLES
