Non-Small Cell Lung Cancer (NSCLC) accounts for 80–85% of all lung cancer diagnoses and poses challenges in early detection due to symptoms often resembling common illnesses or long-term smoking effects. In 2023, NSCLC incident cases in the 7MM totaled approximately 532K with projections indicating further increases by 2034. Treatment options vary based on cancer type, stage, side effects, patient preferences, and health status. Common approaches include surgery, radiotherapy, chemotherapy, chemoradiotherapy, and immunotherapy.
The existing NSCLC treatment landscape is mainly dominated by checkpoint inhibitors such as KEYTRUDA (pembrolizumab), and OPDIVO (nivolumab), as well as targeted therapies like TAGRISSO (osimertinib), ALECENSA (alectinib), and others. PD-(L)-1 therapies are mainly utilized in patients without genetic drivers. Merck’s KEYTRUDA is generally considered the “gold standard” of care in first-line NSCLC when combined with platinum chemotherapy, regardless of PD-L1 status.
These therapies significantly shape the NSCLC treatment landscape. According to the analysis, the metastatic NSCLC market reached ~USD 21 billion across the 7MM in 2023, with ~USD 12 billion attributed to the US market alone. Therapies targeting PDL1, EGFR, ALK, and KRAS play pivotal roles in this market. Amid ongoing research and innovation, promising new drugs are poised to revolutionize NSCLC treatment, offering renewed hope to patients.
In this article, we will explore four groundbreaking NSCLC medications that promise to redefine treatment options and inspire optimism among patients.
1. Eftilagimod Alpha (Efti)
Company: Immutep
Phase: II (Phase III planned)
Mechanism of Action (MoA): APC (Antigen-presenting cell) activator, MHC II agonist
Route of Administration (RoA): Subcutaneous
Expected Launch Year: 2027
Market Potential: USD 1.4 billion by 2032
Immutep’s Eftilagimod alpha, also known as Efti, represents a significant advancement in cancer immunotherapy, particularly in NSCLC and other solid tumors. By activating Antigen-presenting cells (APCs) and agonizing MHC II, Efti enhances the immune system’s ability to recognize and attack cancer cells. What sets Efti apart is its potential to synergize with existing therapies, particularly PD-1 inhibitors like pembrolizumab, offering a chemo-free treatment option with superior safety and efficacy profiles.
The ongoing Phase III trials for NSCLC are a testament to Efti’s promising results, positioning it as a frontrunner in the next generation of cancer treatments.
Eftilagimod Alpha (Efti) vs. Checkpoint Inhibitors (KEYTRUDA, OPDIVO, TECENTRIQ):
- Advantages: In 1L NSCLC, efti-pembro combination outperforms SoC therapies. Efti offers a chemo-free option and synergizes with PD-1 inhibitors like pembrolizumab, potentially enhancing efficacy without adding toxicity.
- Impact: Competes by providing a novel immunotherapy approach that may attract patients seeking alternatives to traditional checkpoint inhibitors.
Why is it a drug to watch?
Efti has the potential to be a leader in cancer immunotherapy, especially in NSCLC, due to its targeting of LAG-3. Notably, Efti has shown remarkable synergy with existing ICIs like pembrolizumab, offering a chemo-free treatment option. Promising Phase IIb data from TACTI-002 demonstrate significant improvements in overall survival compared to the standard of care in first-line NSCLC, earning Fast Track designation from the US Food and Drug Administration (FDA). The drug is now moving towards late-stage registrational directed study in NSCLC. In July 2024, Immutep received positive feedback from the US FDA regarding the planned registrational TACTI-004 Phase III trial of efti in combination with pembrolizumab and platinum doublet chemotherapy for the treatment of first-line NSCLC, regardless of PD-L1 expression. The Spanish Agency for Medicines and Health Products (AEMPS) in April 2024 and the Paul-Ehrlich-Institut in Germany in December 2023 both gave this study positive feedback.
Favorable efficacy and safety profile underscore Efti’s potential to reshape NSCLC treatment paradigms, making it a candidate to watch in oncological advancements. Efti offers a novel type of immunotherapy with remarkable and long-lasting responses in NSCLC, in addition to many presently approved therapies.
2. Lifileucel (LN-145)
Company: IOVANCE Biotherapeutics
Phase: II
Mechanism of Action (MoA): Tumor-infiltrating lymphocyte (TIL) therapy
Route of Administration (RoA): Intravenous
Expected Launch Year: 2027
Market Potential: USD 1.2 billion by 2032
IOVANCE Biotherapeutics is pioneering Tumor-Infiltrating Lymphocyte (TIL) therapy with Lifileucel (LN-145), offering a personalized approach to treating advanced NSCLC. Lifileucel harnesses the patient’s immune cells, re-engineered to recognize and destroy cancer cells, thus presenting a promising alternative for patients who have relapsed after anti-PD-1 therapy. At present, the drug is being investigated in registration-directed second-line post-chemo and anti-PD-1 advanced NSCLC in the IOV-LUN-202 study (Cohorts 1 and 2). Key cohort enrollment in IOVANCE’s IOV-LUN-202 lifileucel study won’t be completed until 2025. Apart from this, the drug is being investigated in 2-4L including post-anti-PD-1 advanced NSCLC in Cohorts 3A, 3B, 3C of IOV-COM-202 study.
LN-145’s potential for accelerated approval is highlighted by the ongoing IOV-LUN-202 clinical study, which represents a major advancement in personalized therapy in cancer. The FDA provided positive regulatory feedback on the proposed potency matrix for lifileucel in NSCLC, at a recent Type D meeting. The FDA previously provided positive regulatory feedback that the design of the single-arm IOV-LUN-202 trial may be acceptable for approval of lifileucel in post-anti-PD-1 NSCLC.
Lifileucel (LN-145) vs. Chemotherapy, Immunotherapy
- Advantages: LN-145’s personalized TIL therapy targets advanced NSCLC post anti-PD-1 treatment, offering a tailored approach for patients resistant to current therapies.
- Impact: Challenges conventional treatments by addressing specific patient populations with innovative cellular therapies.
Why is it a drug to watch?
For metastatic NSCLC, TIL cell therapy represents a feasible, and personalized treatment approach. LN-145 is a drug to watch due to its demonstrated promising responses in advanced NSCLC patients who have relapsed post anti-PD-1 treatment. The registrational Phase II IOV-LUN-202 clinical trial (NCT04614103) has shown significant potential for accelerated approval in patients with advanced NSCLC lacking genomic mutations in EGFR, ROS, or ALK, whose disease progressed despite prior chemotherapy and anti-PD-1 therapy. The trial’s design focuses on a specific patient population, enhancing LN-145’s prospects for regulatory success. Despite a temporary clinical hold in December 2023 affecting new patient enrollment, ongoing monitoring and treatment continuation for existing trial participants underscore IOVANCE’s commitment to advancing TIL therapies. With over 700 patients treated across multiple solid tumors, including 100+ in NSCLC, LN-145’s robust clinical data and targeted approach position it as a pivotal therapy in the evolving landscape of advanced NSCLC treatment.
As the industry leader in TIL cell therapy space, IOVANCE is at the forefront of next-generation strategies that might potentially address unmet needs for NSCLC. IOVANCE recently initiated a phase I/II first in human IOV-GM1-201 trial to investigate genetically modified PD-1 inactivated TIL therapy (IOV-4001) in previously treated NSCLC.
3. Datopotamab Deruxtecan (Dato-DXd)
Company: Daiichi Sankyo/AstraZeneca
Phase: III
Mechanism of Action (MoA): TROP2-directed ADC
Route of Administration (RoA): IV Infusion
Expected Launch Year: 2024
Market Potential: USD 2 billion by 2032
Daiichi Sankyo and AstraZeneca’s collaboration on Datopotamab Deruxtecan (Dato-DXd) represents a novel approach in NSCLC treatment with its targeted ADC therapy. Utilizing Daiichi Sankyo’s exclusive DXd ADC Technology, Dato-DXd represents one of six ADCs in Daiichi Sankyo’s oncology pipeline and is among the most advanced programs within AstraZeneca’s ADC scientific platform. By directing a potent payload to TROP2 receptors on cancer cells, Dato-DXd offers a promising strategy for patients with advanced NSCLC who have progressed after prior therapies. The recent TROPION-Lung02 and TROPION-Lung04 (in first-line advanced NSCLC) trials have demonstrated encouraging response rates when Dato-DXd is combined with pembrolizumab or durvalumab, setting the stage for potential regulatory approval. Daiichi Sankyo/AstraZeneca’s strategic focus on advancing ADC therapies underscores its commitment to addressing unmet needs in NSCLC treatment, promising new avenues for patient care.
Datopotamab Deruxtecan (Dato-DXd) vs. Immunotherapy and Targeted Therapies
- Advantages: This drug may have broader use in NSCLC, as it is currently being evaluated in patients with and without actionable genomic alterations. At present, the drug appears to be a potentially helpful novel treatment for advanced non-squamous NSCLC qualified for second-line chemotherapy.
- Impact: Dato-DXd is expected to have first-mover advantage and is expected to compete with Gilead Sciences’ TROP2 ADC TRODELVY. In addition to this, the expected approval in the 2nd-line and above setting could underscore the confidence in ongoing trials evaluating Dato-DXd in first-line NSCLC
Why is it a drug to watch?
The competition in the TROP2 ADC in NSCLC is getting more fierce. At present Gilead, and Daiichi Sankyo/AstraZeneca are at the forefront of the competition. In advanced NSCLC that had received prior treatment, Dato-DXd exhibited an improvement in overall survival that was clinically meaningful but not statistically significant. Gilead’s TRODELVY also failed in phase III EVOKE-01 lung cancer study (not able to show a statistically meaningful OS benefit). At present, there is no clarity when the company is planning to file for approval in second-line setting. The company has not disclosed any timelines for filing. On the other hand, based on data (PFS readout—5.6 months versus 3.7 months [Dato-DXd versus chemo]) from the phase III TROPION-Lung01 study (NCT04656652) presented at ESMO 2023 supported the Biologics License Applications (BLA) of Dato-DXd, and a Prescription Drug User Fee Act (PDUFA) target action date is expected in the fourth quarter of 2024. Even though the PDUFA is set for the fourth quarter of 2024, the launch could be delayed. Dato-DXd is a better tolerated medication, despite some apparent differences in its toxicity profile. For patients with advanced non-squamous NSCLC eligible for second-line chemotherapy, it seems to be a potentially useful new treatment.
Looking at the current scenario, it can be expected that Dato-DXd is likely to become the first TROP2 ADC to enter the NSCLC market. Tapping into the broader NSCLC market, both with or without actionable genomic alterations, is Daiichi Sankyo/AstraZeneca’s ambition. At present, Dato-DXd with or without Osimertinib is also being explored in TROPION-Lung14 (NCT06350097), and TROPION-Lung15 (NCT06417814) studies for the treatment of EGFRm locally advanced or metastatic NSCLC. Growth potential for Dato-DXd in NSCLC may be further accelerated by expansion in EGFR NSCLC.
With these advancements, Dato-DXd stands out as a therapy that every other pharma company should keep an eye on.
4. TRODELVY
Company: Gilead Sciences
Phase: III
Mechanism of Action (MoA): TROP2-directed ADC
Route of Administration (RoA): IV Infusion
Expected Launch Year: 2025
Market Potential: USD 1 billion by 2032
Gilead Sciences’ TRODELVY, while facing challenges in recent NSCLC trials (phase III EVOKE-01 Study), shows promise in first-Line metastatic NSCLC. The EVOKE-02 trial, in combination with KEYTRUDA, has demonstrated robust progression-free survival rates, highlighting TRODELVY’s potential as a frontline treatment option in specific patient subsets. Despite recent setbacks, Gilead remains optimistic about TRODELVY’s efficacy in NSCLC, particularly in PD-1 refractory patients. The ongoing research and development efforts underscore Gilead’s commitment to advancing cancer care through innovative ADC therapies.
Why is it a drug to watch?
The opportunity for any drug is greater in Lung Cancer, especially NSCLC. And second line NSCLC space is really difficult to tackle. That’s why even after the failure to achieve significant OS benefit, Gilead is likely to try to file for approval in a second-line setting. The company may go for approval in a subset of NSCLC where there is evidence of efficacy and tolerability. The company may provide updates around TRODELVY’s filing sometime this year (information from recent global healthcare conference). However, with the current dataset in second-line NSCLC, Gilead could face a tough time convincing regulators to extend the label of TRODELVY.
In addition to this, Gliead is hoping to tap into the first-line NSCLC segment as well (EVOKE-03 Phase III trial). The data readouts are pointed to 2025 plus for EVOKE-03 study, however it all depends on enrollment. Opportunity in the first-line segment is backed by clear activity observed in the EVOKE-02 study (although a small dataset). The EVOKE-02 trial’s promising results, with a median progression-free survival of 13.1 months, indicate its effectiveness when combined with KEYTRUDA.
Despite the EVOKE-01 trial’s mixed results, TRODELVY showed a more than three-month difference in median overall survival in a subgroup of patients, motivating further research. Analysts suggest that if Gilead can file for NSCLC in the second line based on subgroup analysis, it would drive a significant upside. It will be intriguing to watch how Gilead’s future plans for TRODELVY play out.
Conclusion
The future of NSCLC treatment is brimming with promise, driven by groundbreaking advancements and relentless research. The existing NSCLC treatment is mainly dominated by Checkpoint-inhibitors such as KEYTRUDA, and OPDIVO. Acquired resistance to these anti-PD-1/L1 therapies is a key issue. Acquired resistance renders these therapies effectively useless in half of the patient population after this period where they fall back to chemotherapy approaches which are often ineffective and/or toxic. Given the high unmet need in this area, many companies are exploring novel molecules and combinations in second-line NSCLC post-IO.
As we witness the dawn of new therapies like Eftilagimod Alpha, Lifileucel, Datopotamab Deruxtecan, and TRODELVY, it’s clear that innovation is at the heart of these developments. These drugs represent the cutting edge of cancer treatment and herald a new era where personalized medicine and targeted therapies pave the way for better patient outcomes.
For the pharmaceutical industry, this is a call to action—a reminder of the power of scientific discovery and the potential it holds to transform lives. The upcoming years will be pivotal, with these drugs expected to make significant impacts, setting new benchmarks in oncology care. As these therapies advance through clinical trials and inch closer to regulatory approvals, they symbolize hope and progress in the battle against NSCLC. The journey ahead is exciting, and the pharma world must stay vigilant, ready to embrace and integrate these innovations, shaping a brighter future for cancer patients globally.
Non-Small Cell Lung Cancer Market Research
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