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The lung cancer treatment landscape has substantially evolved over the past decade. However, a systematic analysis of the current global drug development landscape has not been conducted.
We curated and analyzed a comprehensive list of therapeutic entities (TEs) in preclinical development and clinical trials for lung cancer.
On the basis of our analysis of 707 TEs, we found a consistent forward trajectory in the development pipeline for both NSCLC and SCLC. Most of the TEs were in the advanced stages of clinical trials. Targeted therapies continue to dominate in the non–immuno-oncology space. Immuno-oncology targets are expanding beyond inhibitors of the programmed death-ligand 1 axis.
Our analysis highlights a robust portfolio of both preclinical and clinical TEs and suggests that lung cancer treatment is going to become even more biomarker-driven.
We have made significant advances in screening and early detection, diagnosis, and treatment of lung cancer. The traditional classification of lung cancer into the two histologic subtypes, NSCLC and SCLC, was on the basis of pathologic features and treatment outcomes. This has, however, changed with large-scale genomic sequencing efforts such as The Cancer Genome Atlas.
The two main subsets of lung cancer are further divided into different subtypes on the basis of their distinct molecular underpinnings. It is now well-established that certain subsets of adenocarcinoma are oncogene-addicted and, hence, susceptible to targeted therapies. Furthermore, the early successes of immunotherapy, some of which were biomarker-driven, seen in solid tumors such as melanoma, have been rapidly translated into lung cancer. Indeed, as of July 2021, the U.S. Food and Drug Administration has approved 20 biomarker-driven therapies, including targeted therapies and immunotherapies.
In this short report, we provide a landscape of current lung cancer drug development, including therapeutic entities (TEs) in preclinical development and clinical trials.
Materials and Methods
All the information collected for these analyses comes from publicly available sources, including press releases, quarterly reports, web-based company pipelines, news alerts, and analyses conducted by Informa (New York). TEs already approved by the U.S. Food and Drug Administration for lung cancer were not included, whereas those approved for other indications (e.g., PARP inhibitors in ovarian cancer) were included in our analysis. A detailed flow diagram indicating the process of analysis is included in Supplementary Figure 1. Non–immuno-oncology TEs for NSCLC and SCLC were recoded into categories on the basis of the hallmarks of cancer each TE targeted.
For scenarios in which each target is known to have multiple biological functions, the primary function is considered for the TE’s classification. TEs that were applicable to both SCLC and NSCLC were counted each time for each individual histologic subtype. Similarly, TEs that target multiple oncogenes were separately counted for each oncogene. In addition, when TEs were at multiple stages of clinical development, the highest stage of development was used in the analysis. For example, if a TE was being studied in both phase 1 and phase 3 trials, the TE was categorized as being in a phase 3 trial. For a subset of TEs, the number of active, recruiting, and completed clinical trials, their locations, and the number of enrolled patients were extracted from the ClinicalTrials.gov database (National Institutes of Health). All data were manually curated and analyzed using Microsoft Excel and Statistical Package for the Social Sciences. For the location of the manufacturer, the headquarters of the company was considered as opposed to the location of IND filing. Hong Kong was considered a separate autonomous region from the People’s Republic of China while counting TEs for each country. Data is current as of April 2021 and a curated spreadsheet is available on request.
Results and Discussion
Here, we report on 707 TEs, 590 of which are being developed for the treatment of NSCLC and 117 for SCLC. Within NSCLC, 214 TEs are immunotherapies, whereas 376 TEs are in the non–immuno-oncology space. The SCLC landscape includes 36 immuno-oncology TEs and 81 non–immuno-oncology TEs (Fig. 1A).
Most TEs Identified in the Analysis Are in Clinical Trials
Within the NSCLC immuno-oncology landscape, 57% TEs are in either phase 2 or phase 3 clinical trials (Fig 1B). Within the NSCLC non–immuno-oncology landscape, 55% TEs are in either phase 2 or phase 3 clinical trials. The largest fraction within the NSCLC non–immuno-oncology landscape consists of 309 targeted therapies, of which 183 (59%) are in phase 2 and 3 clinical trials. Of the 309 targeted therapy TEs, proliferative signaling inhibitors account for the largest fraction with 166 compounds, of which 87 (52%) are in phase 2 and 3 clinical trials.
This trend of a larger number of TEs in the late phases of clinical trials is more prominent within the SCLC landscape. Within the SCLC immuno-oncology landscape, checkpoint blockade compounds continue to dominate, with 11 out of 15 TEs in phase 2 and 3 clinical trials (73%). When all 36 SCLC immuno-oncology compounds are considered, 18 TEs are in phase 2 and 3 clinical trials (50%). Similarly, within the SCLC non–immuno-oncology landscape, targeted therapies represent the largest fraction with 54 TEs and 43 of them in phase 2 and 3 clinical trials (80%). When all 81 SCLC non–immuno-oncology compounds are considered, 57 TEs are in phase 2 and 3 clinical trials (70%).
The United States Dominates the Global Landscape in Terms of the Number of TEs in both NSCLC and SCLC
The United States has developed 301 out of a total of 707 clinically-staged TEs (Supplementary Table 1 and Supplementary Fig. 2). Out of 590 TEs for NSCLC, the United States developed 246 compounds. Of the 117 TEs for SCLC, the United States developed 55 compounds. The second largest developer is the People’s Republic of China, with a development portfolio of 123 TEs, which includes 107 of the 590 TEs for NSCLC and 16 of the 117 TEs for SCLC. Immuno-oncology TEs for SCLC was developed in only six countries: the United States, the People's Republic of China, Switzerland, Australia, United Kingdom, and Hong Kong. The 376 non–immuno-oncology TEs for NSCLC were developed in 26 countries.
Targeted Therapy Dominates the Non–Immuno-Oncology Therapeutic Space
The NSCLC non–immuno-oncology space includes 376 TEs (Fig. 2A), most of which are targeted therapies (320 TEs when counted as separate entities for each of the multiple targets or 309 when counted as one entity with multiple targets, accounting for 82% to 85% of the portfolio).
With 166 TEs, proliferative signaling inhibitors makeup the major fraction of the targeted therapies portfolio. There is continuous activity in the oncogene-driven lung cancer space, as evidenced by the development of proliferative signaling inhibitors for major oncogenic driver targets, such as ALK, BRAF, the EGFR/HER2/ERBB2 family, KRAS, MET, NTRK, RET, and ROS1. This activity is important for several reasons. For EGFR+ and ALK+ tumors with multiple lines of therapies, these new TEs are being developed to address on-target mechanisms of acquired resistance, including solvent front and gatekeeper mutations in ALK and triple mutations (exon 19 deletions, C797S, and T790M) in EGFR. In addition, these new TEs are valuable for rare oncogene drivers such as RET, ROS1, and NTRK, which have fewer treatment options. Several of these rare oncogene-driven lung cancers also exhibit a high frequency of on-target mutations (e.g., a third of ROS1 tumors exhibit on-target mutations).
Several inhibitors of this pathway are being studied.
It is important to note that this proliferation in clinical development will have to take into account how recruitment for trials for these new TEs will proceed. Taking the example of TEs targeting ALK-positive tumors, a search through ClinicalTrials.gov reports a total of 19 trials that are active or recruiting or completed (Supplementary Table 2). Out of seven ALK-targeting TEs, only one is being studied at a single site. The total patient enrollment for all seven TEs is reported as 3676, whereas the number of enrollments across the individual TEs varies from 60 to 1654, depending on the trial. This ALK-specific analysis highlights the importance of both patient identification and enrollment. An analysis of novel TEs targeting EGFR mutations revealed that the sheer number of novel TEs will continue to face the issue of trial recruitment (Supplementary Table 3). On the contrary, the number of TEs targeting the KRAS pathway was not that many (Supplementary Table 4) given that the first KRAS G12C inhibitor was only recently approved. This analysis suggests that market saturation will be a huge determinant of how such trials recruit.
In addition to tyrosine kinase inhibitors (TKIs), small molecule inhibitors targeting genome instability and metabolism are being studied with specific targets, such as histone deacetylases (HDAC1 and HDAC6), HSP90, MDM2/4, PARP/tankyrase, pegargiminase, glutaminase, and fatty acid synthase.
Similar to NSCLC, the non–immuno-oncology landscape for SCLC (Fig. 2A and B) is dominated by 54 targeted therapies out of a total of 81 (67%). A traditional chemotherapy backbone has been the cornerstone of both limited-stage and extensive-stage SCLC.
DNA modification inhibitors targeting histone demethylase and deacetylase, BRD4, EZH1/2, and MDM2/4 makeup the largest fraction (30%) within this category. There were 8 TEs targeting apoptosis inhibitors such as Bcl2 (cell death stimulants) and those targeting Aurora Kinase A (cell division inhibitors) for SCLC. In addition, specific targets such as HSP90, PARP1/2, arginase, and pyruvate dehydrogenase are being studied in SCLC as well. Whereas these new agents are being currently tested in treatment-refractory patients with SCLC, on the basis of the success of these trials, we expect to see more of these new TEs being tested in patients with treatment-naive SCLC.
Taken together, our analysis suggests that targets from several hallmarks of cancer are being exploited within the space of targeted therapies.
New Targets and Mechanisms Are Being Exploited in Immunotherapies for Both NSCLC and SCLC
We are continuing to see advances in immuno-oncology (Fig. 3). Out of 217 NSCLC immunotherapies (214 when counted as one entity with multiple targets), 70 TEs are checkpoint blockers (brake lifters), 72 TEs are immunostimulants (accelerators) of both the innate and adaptive immune response, and the remaining 75 immunotherapies (miscellaneous) target other unique aspects of the tumor-immune microenvironment. Within checkpoint blockers, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cluster of differentiation antigens (CD3 agonists), and bispecific antibodies with T-cell–engaging capacity dominate. Some of these bispecifics are unique as they target both the oncogenic and the immune component, such as PD-L1/TBFβ1 or EGFR/CD3. Other bispecifics (such as the recently approved amivantamab developed in Denmark and GB-263 developed in the People’s Republic of China) target two oncogenic pathways—EGFR and MET. The other large fraction of checkpoint blockers targets CTLA-4.
Within immunostimulant TEs, the largest fraction targets cellular signaling pathways. Within this group, the largest fraction targets cellular signaling pathways for angiogenesis, cancer-associated microbiome, novel targets (such as M1/M2 macrophages), or other signaling molecules (such as CSFR1, MAGE, MUC1, and semaphorin). Immunovaccines and viruses were classified within this category as well. The second largest fraction includes cell-based therapies, such as tumor-infiltrating lymphocytes, T-cell receptors, chimeric antigen receptors, natural killer cells, and dendritic cells. With the recent success seen with tumor-infiltrating lymphocytes in treatment-refractory NSCLC,
Out of the 36 SCLC immuno-oncology compounds, 15 TEs are checkpoint blockers and 12 TEs are immunostimulants. As expected, PD-1, PD-L1, and CTLA4 are the major checkpoint blocker targets. However, LXR, CD47, TIGIT, and LAG3 inhibitors are noted as well. Some of the novel targets for immunotherapies in SCLC include CSF2, ANTXR, cadherin, and macrophages.
Similar to our analysis of ALK-targeting TE, we also analyzed targeting the PD-1(-L1) checkpoint pathway. ClinicalTrials.gov reports a total of 217 trials that are active/recruiting/completed (Supplementary Table 5). Out of 20 TEs in this category, we found only five TEs with single study sites. Trials for the remaining 15 TEs are global multisite trials, ranging from two to 15 sites. For these TEs, total patient enrollment is reported as 20,927, whereas the number of enrollments across the individual TEs varies from 22 to 8803. Spartalizumab was reported to have the maximum number of trials, a total of 17, including combination treatments with 13 types of TEs. Nivolumab-biosimilar TE, named CMAB-819, is reported to have the maximum number of patient enrollment, a total of 8803, and in combination with six types of treatments. Our analysis of the PD-(L)1 pathway inhibitors reinforces the issue of clinical trial enrollment.
Whereas this analysis reveals movement in several anticipated and some new directions, some central themes emerge.
In the immuno-oncology-space for both NSCLC and SCLC, TEs targeting the PD-(L)1 axis is saturated. It will be interesting to see how these TEs receive approval in this already-crowded market. This crowding is being exacerbated by the development of biosimilars for three already-approved immunotherapies—biosimilars for nivolumab, pembrolizumab, and atezolizumab. As indicated in Supplementary Table 3, this saturation will have major implications on clinical trial design and patient enrollment.
In addition to other checkpoint inhibitors such as CTLA4 and LAG3, we also note a proliferation of immuno-oncology agents targeting the innate immune response. Furthermore, new avenues such as vaccines and cell therapies will continue to emerge in the immuno-oncology space, especially as the population of patients refractory to checkpoint treatment increases. We anticipate these innate immune system targeting agents and cell-based immunotherapies playing a pivotal role in traditionally cold tumors such as oncogene-driven lung cancers.
It is interesting to see that non–immuno-oncology TEs are expanding beyond TKIs. This is especially reassuring for patients who may be looking for additional options after progression on multiple lines of TKIs.
Finally, given the molecular complexity of lung cancer and the wide range of targets being developed, we anticipate lung cancer treatment to become increasingly biomarker-driven—both for patient selection at the time before starting treatment and prognostic biomarkers to determine which patients will need to be monitored proactively for recurrence or progression. This will become especially true for drugs that target pathways such as the DNA damage response pathway and the new immuno-oncology agents, in which a biomarker signature will need to be characterized to determine which patients will benefit from starting treatment and which patients may need a combination approach. Access to high-quality biomarker testing will be a key determinant of how patients can be matched to these newer agents.
A limitation of our study is that we have not accounted for combination trials. Whereas the goal of our analysis is to provide a landscape of individual TEs, we appreciate that some of these TEs may be approved only in combination regimens. Despite this limitation, to our knowledge, this is the first comprehensive analysis of the therapeutic development landscape of lung cancer.
CRediT Authorship Contribution Statement
Upal Basu Roy, Amy Moore: Conceptualization.
Dhruba Deb, Upal Basu Roy: Data curation, Analysis, Writing - original draft, Writing - review & editing.
Disclosure: Dr. Roy reports receiving institutional research funding from AstraZeneca , Eli Lilly, Merck , Blueprint Medicine, Genentech , G1 Therapeutics, Takeda, Bristol Myers Squibb, and Janssen not related to the current project and is on the board of directors of the ROS1ders organization. Dr. Moore reports serving on an advisory panel for Merck and Bayer and is on the board of directors of the NTRKers nonprofit organization. The remaining author declares no conflict of interest.