Treatments and Study Updates: Highlights from ESMO 2023 

Contributing Authors: GO2 for Lung Cancer Associate Director, Clinical Research, Andrew Ciupek, PhD and Manager, Precision Medicine & Navigation, Matthew Reiss, MSE, PhD  

Each year, researchers, physicians, and industry partners gather at the European Society for Medical Oncology (ESMO) Congress to share the latest updates on new treatments and scientific breakthroughs in the world of cancer. GO2 for Lung Cancer team members attended and shared the following key takeaways: 

An investigational molecule to treat advanced small cell lung cancer 

Background 

Small cell lung cancer (SCLC) remains one of the most challenging and aggressive forms of cancer to treat. The DeLLphi-301 study aims to address that challenge by evaluating the use of a new targeted immunotherapy, tarlatamab, in people with advanced-stage SCLC who have progressed on two or more previous lines of therapy. 

Tarlatamab is an investigational bispecific T-cell engager (BiTE) molecule that helps encourage an individual’s immune system to attack the cancer. Tarlatamab’s unique ability to bind both the delta-like ligand 3 (DLL3) protein found on the surface of cancer cells and an individual’s native T-cells essentially allows the immune system to better identify and destroy cancer cells. DLL3 is an exciting therapeutic target for people with SCLC because 85-94% of SCLC cells express the DLL3 protein on their surface, with minimal expression in normal, healthy cells. 

Results from the phase two DeLLphi-301 study of 220 participants showed that 40% of individuals receiving tarlatamab had a measurable response to treatment with a meaningful impact on long-term survival and a manageable side effect profile. The SCLC community is eager for new therapeutic options and the reported outcomes are encouraging. The investigational molecule moves into various phase three studies to assess its viability versus current standards of care.

Key takeaway: A new investigational therapy, tarlatamab, could positively impact long-term survival for people with advanced-stage SCLC. 

ADC therapy after progression on immunotherapy 

Background 

Combination immunotherapy treatment, often with chemotherapy, is a standard first treatment for people without an actionable biomarker found in their NSCLC at diagnosis. However, there are few second-line treatments if progression on immunotherapy occurs. Chemotherapy is typically the main choice. The TROPION-Lung01 trial investigated whether or not a new type of treatment, called an antibody-drug conjugate (ADC), could be an option after progression on immunotherapy. 

The TROPION-Lung01 trial 

In TROPION-Lung01, people that had progression on immunotherapy. The initial data looks promising, but final results on how long people lived after receiving either treatment will be important to determine if Dato-DXd will become a new standard treatment after immunotherapy progression.  

Key takeaway: An antibody-drug conjugate (ADC) called datopotamab deruxtecan (Dato-DXd) could be a new standard treatment after immunotherapy progression for people with NSCLC.  

A selective RET-inhibitor for mutated non-small cell lung cancer 

Background 

Approximately 1-2% of individuals living with non-small cell lung cancer (NSCLC) have a RET-positive mutation. Currently, these individuals have access to a limited list of biomarker-directed targeted therapies as scientists continue to evaluate emerging therapies against the current standards of care. 

The LIBRETTO-431 study 

New results from the phase three LIBRETTO-431 study presented data for the use of the selective RET inhibitor Retevmo (selpercatinib) as a first-line therapy for RET-positive NSCLC versus the standard-of-care, combination chemotherapy-Keytruda (pembrolizumab). The highly anticipated data showed a significant improvement in progression-free survival and reduced instances of brain metastases for individuals treated with Retevmo (selpercatinib) compared to the current standard of care. Additionally, study participants reported a similar side effect profile to previously reported Retevmo (selpercatinib) data. 

The findings offer strong evidence to consider using Retevmo (selpercatinib) as an effective treatment in the first line setting with better outcomes for individuals living with RET-positive NSCLC. 

Key takeaway: A RET inhibitor, Retevmo (selpercatinib), could be an effective first-line treatment, with improved progression-free survival and reduced instances of brain metastases, for people with RET-positive NSCLC.  

Targeted therapy for EGFR exon 20-positive NSCLC 

Background 

Currently, chemotherapy is the standard first therapy for newly diagnosed NSCLC with an EGFR exon 20 insertion mutation. Targeted therapy, such as Rybrevant (amivantamab), has only been an option after progression on first-line treatment. The phase three PAPILLION trial was focused on seeing if targeted therapy could be effectively used as a first-line treatment for this type of lung cancer.  

The PAPILLION trial 

In PAPILLION, a combination treatment of Rybrevant (amivantamab) and chemotherapy was compared to chemotherapy alone as a first treatment. People in the trial had better outcomes when receiving the Rybrevant (amivantamab) combination, and this promising data may lead to the combination becoming a new first-line treatment for people with EGRF exon 20 NSCLC. Approximately 7% of people receiving the combination had to stop due to side effects, which may take a few days to resolve after ending treatment, so it is important to proactively discuss any side effects you may be experiencing with your care team. 

Key takeaway: A combination treatment of Rybrevant (amivantamab) and chemotherapy could be a future standard, first-line treatment for EGFR exon 20-positive NSCLC. 

Adjuvant targeted therapy for ALK-positive non-small cell lung cancer 

Background 

Previous evidence showed targeted therapies are generally superior to systemic chemotherapy in individuals living with metastatic non-small cell lung cancer (NSCLC). Drugs specifically targeting well-known and characterized NSCLC biomarkers, such as ALK (approximately 4% of NSCLC cases), are quickly becoming the standard first-line therapy given to individuals with laboratory-confirmed mutations. However, whether these therapies are superior across earlier disease stages is an active area of investigation.  

The ALINA trial 

Interim results from the international phase three ALINA trial examined the use of adjuvant Alecensa (alectinib) against the use of systemic chemotherapy following surgical resection for individuals diagnosed with stage 2-3A (II-IIIA) NSCLC. The data showed a potentially meaningful improvement in disease-free survival for individuals treated with Alecensa (alectinib) compared to chemotherapy. Additionally, interim results seem to show a meaningful benefit for its ability to prevent relapse of cancer in the brain, a common outcome for individuals with ALK-positive NSCLC. 

Full results of the study are still pending, but so far, we are seeing encouraging signs on the horizon for the use of adjuvant targeted therapy to treat ALK-positive NSCLC following resection in non-metastatic disease. 

Key takeaway: Alecensa (alectinib) could increase disease-free survival and prevent relapse of cancer in the brain for people living with ALK-positive NSCLC.  

First- and second- line treatments for EGFR-mutated non-small cell lung cancer  

Background 

One of the most common outcomes of prolonged use of targeted therapies is the cancer’s ability to become resistant to treatment. Some individuals, such as those with EGFR-mutated non-small cell lung cancer (NSCLC), eventually develop resistance to even some of the newest available treatment options. Therefore, scientists continue to develop more effective first-line therapies to better treat NSCLC and provide new therapeutic options for individuals following relapse. 

The MARIPOSA study 

A pair of highly anticipated phase three trials were presented that evaluated using combination Rybrevant (amivantamab)-Leclaza (lazertinib) to target EGFR mutations (exon 19 deletions or L858R mutations) in treatment-naïve individuals (those who have never received treatment for their condition) or individuals who have relapsed following treatment with a previous EGFR-targeted therapy. Results from the MARIPOSA study showed combination Rybrevant (amivantamab)-Leclaza (lazertinib) in treatment-naïve individuals led to a 30% reduction in disease progression or death compared to another third-generation EGFR-inhibitor. 

Additionally, results from the MARIPOSA-2 study showed combination Rybrevant (amivantamab)-chemotherapy and combination Rybrevant (amivantamab)-Leclaza (lazertinib)-chemotherapy significantly increased progression-free survival compared to chemotherapy alone in individuals who have relapsed following treatment with a previous EGFR-targeted therapy. 

For both studies, participants reported a range of treatment-related adverse events in response to the study combination treatments. Careful consideration must be given to the overall health and necessary companion treatments to mitigate side effects for individuals seeking treatment with the new lines of therapy. Overall, the two studies add to a growing body of evidence for better therapeutic options for people living with EGFR-mutated NSCLC. 

Key takeaway: New potential combination therapies, Rybrevant (amivantamab)-chemotherapy and Rybrevant (amivantamab)-Leclaza (lazertinib)-chemotherapy, could reduce disease progression for people living with EGFR-mutated non-small cell lung cancer.