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Clinical

TAK-21-TTD0548 - /clinical/lung

In season 4, episode 13 of Targeted Talks, Benny Weskler, MBA, MD, FACS, FACCP, professor of cardiothoracic surgery, Drexel University College of Medicine, as well as the system chief of thoracic surgery, Allegheny Health Network, and chief of the Division of Thoracic Surgery at the Department of Cardiothoracic Surgery at Allegheny General Hospital, discusses neoadjuvant therapy for patients with non–small cell lung cancer.

According to Wexler, there is a role for all modalities in the treatment of NSCLC. However, timing of treatment plays an important role in patient outcomes. He explains that neoadjuvant systemic therapy is intended to give patients the best chance before their blood supply is impacted by surgery. Whether patients receive preoperative chemotherapy, radiation, or chemoradiation is dependent upon their disease stage and other factors. But, at AHN, use of radiation neoadjuvantly is reserved for special cases.

Research published in recent years has shown that there is no difference in outcomes between patients with NSCLC treated with neoadjuvant chemotherapy followed by surgery or neoadjuvant chemoradiation plus surgery, according to Weskler. Further, results from the PACIFIC study (NCT02125461), showed improvement in disease-free and overall survival when immunotherapy followed by chemoradiation. He says, this provided proof-of-concept for the use of immunotherapy in the neoadjuvant setting.

“I think the PACIFIC trial opened the door for the immunotherapy in the neoadjuvant setting. Truly after many years of not a lot of evolution in that space we started seeing small trials with preoperative immunotherapy in patients with stage 3 disease, says Weskler. “So, those small trials showed that we could operate patients after immunotherapy, but some of them show that there was a little slightly higher conversion rate to open surgery after immunotherapy.”

After neoadjuvant immune checkpoint inhibitors with chemotherapy or chemoradiation, the next best strategy for improving patient outcomes is the use of minimally invasive surgery. Further, some experts are now taking a trimodal approach to NSCLC treatment, which has been hypothesized to improve outcomes further.

In season 4, episode 13 of Targeted Talks, Benny Weskler, MBA, MD, FACS, FACCP, discusses neoadjuvant therapy for patients with non–small cell lung cancer. 

Strategies for Neoadjuvant NSCLC Treatment

In season 1, episode 1 of Targeted Talks, community physician Jason R. Williams, MD, DABR, interventional radiologist, Williams Cancer Institute, leads a discussion with George R. Simon, MD, FACP, FCCP, medical oncologist, The University of Texas MD Anderson Cancer Center, about the use of immunotherapy in patients with non–small cell lung cancer (NSCLC), whether treated in an academic or community setting, and how this could be challenged with the discovery of a genetic driver alteration.

During the discussion, the 2 experts cover the pros and cons of immunotherapy use and how they differ in the community setting versus the academic setting, the available tools for profiling patients, promising immune checkpoint inhibitors for the treatment of NSCLC, key genetic drivers in NSCLC, and choosing the optimal subsequent therapy for patients with NSCLC.

Community physician Jason Williams, MD, DABR, talks to academic oncologist George R. Simon, MD, FACO, FCCP, for an episode of Targeted Talks.

Individualizing Immunotherapy in Non–Small Cell Lung Cancer

In the non–small cell lung cancer space, identifying the appropriate candidate to receive perioperative approaches, such as neoadjuvant or adjuvant therapy, remains the clinical objective.

Defining Earlier Use of Immunotherapy in Patients With NSCLC

Topline results from MARIPOSA reveal a survival advantage with amivantamab plus lazertinib vs osimertinib in patients with EGFR-mutant non–small cell lung cancer. Additional follow-up is planned.

Amivantamab Plus Lazertinib Improves PFS Over Osimertinib in EGFRm NSCLC

Treatment with CAN-2409 produced promising survival data and continues to show a favorable safety and tolerability profile for the treatment of non-resectable, stage III/IV non–small cell lung cancer.

CAN-2409 Combination Elicits Encouraging Survival Results in NSCLC

During a Targeted Oncology™ Case-Based Roundtable™ event, Timothy F. Burns, MD, PhD, discussed the use of sotorasib and adagrasib for patients with KRAS-mutated non–small cell lung cancer including those with brain metastases. 

Identifying the Role of Targeted Therapy in KRAS-Mutated NSCLC

In the phase 3 CheckMate-77T trial, a neoadjuvant and adjuvant treatment strategy including nivolumab and chemotherapy improved survival in resectable stage IIA to IIIB non–small cell lung cancer.

CheckMate-77T Update: Nivolumab-Based Regimen Improves EFS in NSCLC

Se-Hoon Lee, MD, an oncologist at the Samsung Medical Center in Seoul, Korea, discusses his focus of research in the lung cancer space, including the phase 1 CHRYSALIS study (NCT02609776) of amivantamab (Rybrevant) and lazertinib (Leclaza) in patients with 

-mutated non–small cell lung cancer (NSCLC).

In the first-in-human, open-label, dose-escalation, phase 1 CHRYSALIS study, 20 treatment-naive patients with NSCLC harboring an 

 mutation were evaluated to assess the safety, pharmacokinetics, and preliminary efficacy of the combination of amivantamab and lazertinib. Patients were required to be aged 18 years and older and have an ECOG performance status of 0-1.

According to long-term follow-up data from the CHRYSALIS study, patients treated with 1050 mg (1400 mg if ≥ 80 kg) of amivantamab and 240 mg of lazertinib had an overall response rate (ORR) of 100%. Additionally, all patients acheived a partial response on the combination therapy. However, any discussion on long-term results was limited due to the shorter follow-up.

 This is the era of targeted therapy and immuno-oncology. I'm conducting translational research for [patients with] lung cancer, especially focused on immuno-oncology or targeted therapy such as [targeting the] 

 mutations have very high prevalence [among patients with] lung cancer.

 For the introduction of the CHRSYALIS trial, we looked at the first-line treatment for treatment naive patients with amivantamab and lazertinib for patients with 

-NSCLC. [This research was] reported in a previous academic meeting, [which showed an] objective response rate of 100%. [It was a smaller patient population, but] a 100% response rate was fascinating. [However], for every clinician their concern is about the long-term follow-up of the research. After nearly 3 years [of follow up] the ORR was still 100%, and half of the patients remain disease-free and alive. This is also happy news for patients with 

Videos

Se-Hoon Lee, MD, an oncologist at the Samsung Medical Center in Seoul, Korea, discusses his focus of research in the lung cancer space, including the phase 1 CHRYSALIS study of amivantamab and lazertinib in patients with EGFR-mutated non–small cell lung cancer.

News

CHRYSALIS Study Shows Potential of Amivantamab/Lazertinib in EGFRm NSCLC

Dr. Florez and Dr. Sabari delve into areas of progress, unmet needs, and future research in NSCLC, encompassing novel biomarkers and targeted therapies such as CEACAM5.

Recent Progress and Unmet Needs in NSCLC

Important findings from the CARMEN-LC05 study evaluating tusa in combination with pembrolizumab and chemotherapy in NSCLC are discussed, highlighting their implications for clinical practice.

Efficacy and Safety of Tusa with Pembrolizumab and Chemotherapy in NSCLC: CARMEN-LC05 Study

An overview of the CARMEN-LC03 and CARMEN-LC04 trials investigating tusa in different treatment settings for NSCLC and their impact on treatment approaches is provided.

CARMEN-LC03 and CARMEN-LC04 Trials: Study Design and Anticipated Findings

The transformative potential of antibody drug conjugates in NSCLC treatment is discussed, encompassing their design, bystander effect, biomarkers, and impact on the treatment landscape.

Transforming the NSCLC Treatment Landscape with Antibody Drug Conjugates

Dr. Florez and Dr. Sabari discuss standards of care for different patient populations in NSCLC.

Clinical Pearls: Treating Different Patient Populations in NSCLC

David S. Hong, MD, deputy chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses which disease subgroups may benefit from treatment with larotrectinib (Vitrakvi).

Previously in 2018, the FDA granted an accelerated approval to larotrectinib for the treatment of adult and pediatric patients with solid tumors that have an 

 gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. The other FDA approved TRK inhibitor is entrectinib (Rozlytrek).

Results from multiple studies, including the phase 2 NAVIGATE (NCT02576431), phase 1 LOXO-TRK-14001 trial (NCT02122913), and phase 1/2 SCOUT trial (NCT02637687), sought to evaluate larotrectinib as an NTRK inhibitor and have confirmed the long-term response and efficacy of larotrectinib in patients with lung cancer who harbor 

Here, Hong notes that patients who have either primary central nervous system (CNS) or brain are benefiting from larotrectinib, and highlights other subgroups that may as well.

 The CNS is a component of it. We didn't present the data at ASCO [last] year, but there are clearly patients who have either primary CNS, or who also have brain metastases who are benefiting from larotrectinib. A highlight of entrectinib is that it seems to be brain penetrating, but we know that both molecules can penetrate the brain.

Some of these patients, particularly the pediatric patients with infantile fibrosarcoma, who got the drug had significant tumor shrinkage and they were able to go in and resect the tumor out in a way, NGS [next generation sequencing] like in a neoadjuvant setting. Primarily, as more patients are becoming or getting NGS earlier in the staging, I think we will identify these patients that may benefit from these drugs earlier, as soon as they're identified within transfusion.

David S. Hong, MD, discusses which disease subgroups may benefit from treatment with larotrectinib.


Hong Discusses Patients Who Benefit From Larotrectinib

Liza C. Villaruz, MD, associate professor of medicine and co-leader of the Immunotherapy and Drug Development Center at UPMC Hillman Cancer Center, discusses the most promising biomarkers in the non–small cell lung cancer (NSCLC) space.

She says that the known driver mutations in oncogenes have been most successful, such as 

. There are approved targeted therapies for these alterations that are effective enough to be used as frontline therapy for patients with NSCLC, making broad genetic testing important for patients with advanced disease.

PD-L1 is also an important biomarker since PD-L1 expression level is predictive of benefit in patients who receive immune checkpoint inhibitors alone or in combination with other therapies. This includes pembrolizumab (Keytruda) monotherapy and combination nivolumab (Opdivo) plus ipilimumab (Yervoy), which targets both PD-1 and CTLA-4.

In terms of upcoming therapy targets, Villaruz says research will show whether TROP expression is predictive of response to TROP2 inhibitors such as the antibody-drug conjugate (ADC) datopotamab deruxtecan; if so, this will be another valuable biomarker. The adhesion molecule CEACAM5 is another biomarker with a novel therapy tusamitamab ravtansine (SAR408701) under investigation in the phase 2 CARMEN-LC05 trial (NCT04524689). Additionally, 

 may become a more significant biomarker, as research into c-MET ADCs including telisotuzumab vedotin has shown potential for patients with 

 We have our oncogene driven disease, and they are the gold standard in terms of predictive biomarkers of therapeutic benefit with regard to 

. We have PD-L1, which is the gold standard for predicting therapeutic benefits to immunotherapy, either by itself, chemoimmunotherapy combinations, or immunotherapy/immunotherapy combinations—combined PD-1 and CTLA-4 therapies.

I think as we go forward, [it will] be interesting to see how TROP…is predictive of benefit to TROP2 inhibitors, and also CEACAM5, because there are novel therapies aimed toward that as well. I think it'll be interesting to see how all of these different biomarkers could potentially predict the benefit of their targeted agents. There is still a fair amount of work with 

, and several different MET ADCs, which are also within development.

Liza C. Villaruz, MD, discusses the most promising biomarkers in the non–small cell lung cancer space.

Top Targets and Novel Biomarkers Attract Interest in NSCLC

David S. Hong, MD, deputy chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses updated findings from an analysis of 3 trials which ultimately led to the approval of larotrectinib (Vitrakvi) for patients with solid tumors that harbor an 

These studies include the phase 2 NAVIGATE (NCT02576431), phase 1 LOXO-TRK-14001 (NCT02122913), and phase 1/2 SCOUT (NCT02637687) trials which each evaluated larotrectinib as an NTRK inhibitor.

Looking at each trial, SCOUT, NAVIGATE, and LOXO-TRK-14001, Hong notes that larotrectinib continues to show robust and durable objective responses when used to treat patients with 

 fusions. The agent also demonstrated to have a favorable long-term safety profile in the analysis.

In this most recent analysis, we looked at close to 244 patients. In those 244 patients, we looked at response rates, progression-free survival, duration of response, and overall survival. It's always amazing to me when I see this updated data, how durable and how beneficial this drug is in these patients. The overall response rate remained very high, close to 70%, 69%, with complete response rates of over 21%. The median duration of response was 32.9 months, with median progression-free survival at 29.4 months, and the overall survival had yet to be reached across all different pathologies.

 The overall safety signal, including in the phase 1 trial and all the other studies of about 269 patients, the vast majority of adverse events had only been grades 1 and 2. About 20% of the patients had grade 3 treatment related adverse events, mostly related to elevated liver function tests, which were usually reversible once the drugs were held, and dose reduced. This was pretty much the same thing that we saw with larotrectinib with the initial approval at 55 patients.

In this expanded analysis, larotrectinib continued to show robust and durable objective responses in patients with 

 fusions and a favorable long-term safety profile. It speaks to the fact that with next generation sequencing [NGS] being a common test that we can get in our patients, it behooves every oncologist to try to find these patients through NGS testing.

David S. Hong, MD, discusses updated findings from an analysis of 3 trials which ultimately led to the approval of larotrectinib for patients with solid tumors who harbor an NTRK fusion.


Evaluating Larotrectinib for TRK Fusion-Positive Lung Cancer Across 3 Trials

Cary Gross, MD, professor of medicine and of epidemiology, and founder and director, the Cancer Outcomes, Public Policy and Effectiveness Research Center, Yale School of Medicine; director, Adult Primary Care Center, Quality Improvement; chair, National Clinician Scholars Program; and director, National Clinician Scholars Program, discusses the findings from a retrospective study which revealed there to be an association between Medicaid insurance, rates of biomarker testing, and patient outcomes among patients with advanced non–small cell lung cancer (NSCLC).

The study was published in the Journal of the National Comprehensive Cancer Network and assessed 6,145 commercially insured patients and 865 Medicaid beneficiaries with advanced NSCLC. Data was collected from electronic medical records of patients with advanced NSCLC who were between the ages of 18 and 64. The recommended biomarker tests for advanced NSCLC include 

 gene alterations, as well as PD-L1 expression, and the recommended biomarker-driven therapies for advanced NSCLC were immunotherapy or tyrosine kinase inhibitor treatment.

Findings revealed that Medicaid beneficiaries were less likely to have gotten biomarker testing (HR, 0.81; 

Cary Gross, MD, discusses the findings from a retrospective study which revealed there to be an association between Medicaid insurance, rates of biomarker testing, and patient outcomes among patients with advanced non–small cell lung cancer.


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