Dr. Shaw Meetup, January 24, 2026

Name: Dr. Shaw Meetup, January 24, 2026
Uploaded: 2026-02-04T18:48:23.000Z
Duration: 1 h 58 min 46 s

Introduction to the Ross Wonders Meetup

Welcome and Introduction

The meetup begins with a welcome message, introducing Dr. Alice Shaw from Dana Farber as the guest speaker.

Dr. Shaw prepares to present her slides, expressing excitement about the number of registrants attending.

Overview of Zitasanib and ROSS1 Targeted Therapy

Latest Data on Zitasanib

Dr. Shaw discusses the focus of her presentation: the latest data on zitasanib (also known as NVL520), derived from the Aeros one trial.

She emphasizes that zitasanib represents a significant advancement in ROSS1 targeted therapies.

Background on ROSS1 Positive Lung Cancer

A brief background is provided on ROSS1 positive lung cancer, highlighting its rarity (1-2% of lung adenocarcinomas).

Dr. Shaw explains "oncogenic drivers," which are genes activated by mutations leading to cancer growth; blocking these can induce cell death.

Development of ROSS1 Inhibitors

Historical Context and First Generation Inhibitors

The importance of identifying ROSS1 in patients is discussed due to effective targeted therapies available.

Crizotinib is introduced as the first-generation ROSS1 inhibitor, noted for launching research in this field.

Efficacy and Limitations

Crizotinib's effectiveness is highlighted through patient case studies showing dramatic improvements after treatment.

Following crizotinib, entrectinib was developed for better potency and brain penetration but still faced challenges with patient relapses.

Resistance Mechanisms and Next Generation Therapies

Understanding Resistance Mutations

Research identified resistance mutations within ROSS1 that cancers develop to evade treatments, notably G2032R mutation.

Advancements in Treatment Options

New generation inhibitors like repotrectinib and talotractinib were created to overcome previous limitations while also penetrating CNS effectively.

Efficacy Comparison Among Treatments

Summary of Treatment Efficacy

A summary slide compares efficacy between earlier ROSS1 inhibitors (crizotinib, entrectinib), emphasizing their performance against standard chemotherapy options.

Efficacy and Safety of ROSS1 Targeted Therapies in Lung Cancer

Overview of Clinical Trials and Comparisons

The effectiveness of targeted therapies compared to chemotherapy is highlighted, showing that targeted therapies have significantly better response rates and progression-free survival.

Response rates for ROSS1 TKIs range from 70% to 90%, indicating a substantial reduction in tumor burden among patients treated with these therapies.

Progression-Free Survival Insights

Newer ROSS1 targeted therapies like repotractib and talotractib demonstrate longer progression-free survival than earlier generation TKIs such as crizotinib and entrectinib. This suggests improvements in potency and resistance mutation coverage.

In newly diagnosed TKI-naive patients, the efficacy of repotractib and talotractib is notably higher; however, prior treatment with ROSS1 TKIs results in reduced efficacy (40-50% response rate).

Relapse and Resistance Challenges

Despite durable responses from first-line treatments, patients eventually relapse due to resistance, necessitating new treatment options for those who have previously received repotractib or talotractib.

There is potential for improved outcomes similar to those seen with third-generation ALK inhibitors like lorlatinib, which show prolonged responses beyond seven years in ALK-positive lung cancer cases.

Side Effects of Current ROSS1 TKIs

The side effects associated with current ROSS1 TKIs are significant limitations impacting patient quality of life and dosing adherence over time. Common severe side effects include dizziness, dysgeusia (taste changes), and neuropathy.

Approximately 50% of patients experience grade three or higher side effects during treatment, leading to dose reductions in about 37%-38% of cases; however, only a small percentage need to discontinue therapy entirely due to side effects.

Specific Side Effects Analysis

Repotractib's common troublesome side effects include dizziness, dysgeusia, and paresthesia (pins/needles sensation), likely due to its off-target inhibition affecting TRK-B pathways alongside ROS1 inhibition.

Talotractib presents different safety concerns primarily related to gastrointestinal toxicity (nausea, vomiting) rather than neurological issues; these GI side effects tend to be mild and manageable overall.

Introduction of Zitasanib as a Potential Solution

Zitasanib was developed considering the limitations observed with existing ROSS1 inhibitors; it aims for enhanced selectivity towards ROS1 while minimizing off-target effects that contribute to adverse reactions.

Preclinical data indicates zitasanib's superior potency against both wild-type ROS1 and known resistance mutations compared to other available ROSS1 TKIs like repotractib and talotractib.

Zyotanib: Potency and Selectivity in ROS1 Inhibition

Potency Against ROS1 Fusions and Mutations

Zyotanib demonstrates high potency against various ROS1 fusions, indicated by green on the heat map, while red signifies no potency and yellow indicates intermediate levels.

It maintains effectiveness even with the presence of ROS1 resistance mutations, unlike other inhibitors that lose efficacy, particularly against the G2032R mutation.

Enhanced Selectivity for ROS1

Zyotanib's design emphasizes enhanced selectivity for ROS1, depicted through a kynome selectivity tree showing its inhibition profile across different kinases.

The inhibitor shows potent activity against ROS1 and ALK but only modest inhibition (10 to 50-fold less) on other kinases like TRKB.

Compared to other ROS1 TKIs, zyotanib exhibits greater selectivity over TRKB, which is crucial for minimizing side effects related to off-target activities.

CNS Penetration Capabilities

A significant feature of zyotanib is its ability to penetrate the brain effectively, essential for treating existing brain metastases and preventing new ones.

Pre-clinical models show that zyotaninib penetrates the brain similarly to lorlatinib, both demonstrating superior CNS penetration compared to other inhibitors like repotrectinib.

In vivo studies indicate that zyotaninib induces deeper and more durable anti-tumor responses in intracranial settings than repotrectinib or talotractinib.

Aeros One Clinical Trial Overview

Study Design and Patient Enrollment

The Aeros One trial is an ongoing global phase 1/2 study assessing zyotanib in patients with ROS1-positive lung cancer and tumors.

Phase 1 involved dose escalation from 25 mg to 150 mg daily among over 50 patients previously treated with ROS1 TKIs; the recommended phase 2 dose was established at 100 mg daily.

Patient Characteristics in Efficacy Population

The phase 2 portion includes specific cohorts based on prior TKI exposure; enrollment continues for TKI-naive patients as well as those who have received one or two prior treatments.

A total of 514 patients were enrolled by March 2025 across both phases; safety data focuses on a population of 432 patients receiving standard doses of zyotanib.

Demographics and Treatment History

Among the pivotal efficacy population (117 pre-treated patients), average age was noted at 57 years old; nearly 70% were never smokers—consistent with known characteristics of non-smoking-related lung cancers.

Approximately half had brain metastases; over one-third exhibited documented resistance mutations after previous TKI treatments.

Efficacy of Zytosanitib in ROS1 Positive Lung Cancer

Overview of Patient Treatment Background

The study discusses patients who received one prior ROS1 TKI, with a notable split between crizotinib and entrectinib. Approximately 75% had prior lorlatinib, while 25% had repotrectinib, and fewer had talotractib.

Efficacy Results of Zytosanitib

In previously treated ROS1 positive lung cancer patients, the objective response rate for zytosanitib was reported at 44%. For those with only one prior ROS1 TKI, the response rate increased to 51%.

Comparatively, other TKIs like repotrectinib and talotractib also show activity after one prior TKI but primarily involved crizotinib as the previous treatment.

Tumor Regression Insights

A waterfall plot indicates that most patients experienced some tumor regression even if they did not meet formal response criteria. Patients with prior ROS1 TKI and chemotherapy showed significant responses.

Efficacy After Multiple Prior TKIs

Zytosanitib demonstrated efficacy even after two or more prior ROS1 TKIs, achieving a response rate of 38%. Notably, nearly 50% responded after previous treatment with repotrectinib.

Upcoming Data Presentation

An upcoming presentation at the AACR meeting will provide larger datasets on patients previously treated with repotrectinib or talotractinib, indicating promising efficacy results.

Durability of Responses to Zytosanitib

Duration of Response Analysis

The data shows that 93% of patients remained in response after 18 months when treated with zytosanitib following one prior ROS1 TKI.

Comparison to Other Treatments

The 12-month duration of response (DR) for zytosanitib is significantly higher than that for repotrectinib and talotractinib, which stands around 60%.

Progression-Free Survival Metrics

Impressive Progression-Free Survival Rates

About 70% of patients remained progression-free after 18 months on zytosanitib treatment. This contrasts sharply with median progression-free survival rates for other treatments being only about 9 to 10 months.

Efficacy Against Resistance Mutations and CNS Metastases

Effectiveness in G2032R Mutation Cases

Zytosanitib can induce responses in a significant fraction of patients harboring documented G2032R resistance mutations.

CNS Metastases Response Rates

Among patients with measurable brain metastases who received any prior ROS1 TKIs, the intracranial response rate was recorded at 48%, increasing to an impressive 85% among those previously treated with crizotinib.

Safety Profile and Emerging Data

Safety Data Overview

Safety data from a cohort of 432 patients receiving standard doses indicate that zytosanitib has differentiated itself from other ROS1 inhibitors regarding its safety profile.

This structured summary provides insights into the efficacy and safety profile of zytosanitib in treating ROS1 positive lung cancer based on patient history and treatment outcomes discussed within the transcript.

Overview of Zitasanib's Efficacy and Safety Profile

Common Side Effects of Zitasanib

The most frequently reported treatment-emergent adverse events (TE AEs) in 15% or more of patients include peripheral edema, constipation, increased blood levels of CPK, fatigue, and shortness of breath.

Notably, these side effects are generally mild rather than severe, with a low incidence of dizziness or paresthesia that can complicate treatment tolerance.

Other gastrointestinal side effects such as nausea, vomiting, diarrhea, and liver toxicity are not prevalent compared to other treatments like talatrinib.

Dose Reduction and Discontinuation Rates

Only 10% of patients treated with zitasanib required a dose reduction due to side effects; this is significantly lower than the over one-third rate seen with repotrectinib or talatrinib.

The discontinuation rate due to side effects for zitasanib stands at just 2%, indicating a favorable safety profile.

Efficacy Insights from Aeros One Data

Durable Activity in Resistant Patients

Zitasanib demonstrates durable activity even in patients who have previously received ROS1 TKIs like repotrectinib and talatrinib.

It shows particular effectiveness against the G2032R resistance mutation and other mutations consistent with its design.

Intracranial Activity

Zitasanib exhibits potent intracranial activity in patients who have undergone prior CNS penetrant TKIs such as entrectinib and repotrectinib. This feature is crucial for treating CNS metastases effectively.

Therapeutic Landscape for ROS1 Positive Lung Cancer

Positioning within Treatment Paradigms

In the current landscape for advanced ROS1 positive lung cancer treatment, zitasanib is positioned as an option after prior ROS1 inhibitors but may eventually be used as a first-line therapy due to its improved potency and ability to prevent resistance.

Future Treatment Strategies

Beyond improving efficacy and safety profiles, zitasanib opens avenues for combination therapies aimed at eradicating disease rather than merely controlling it over time.

Challenges in Current Treatment Approaches

Addressing Resistance Mechanisms

Sequential use of ROS1 targeted therapies faces challenges from evolving heterogeneous resistance mechanisms that complicate effective treatment.

Proposed Combination Approach

A proposed strategy involves starting with the most effective targeted therapy as an anchor while employing local therapies like radiation or surgery to eliminate residual disease before maintenance therapy begins.

Conclusion & Q&A Session

Closing Remarks

Dr. Shaw concludes by emphasizing the potential future impact of zitasanib on treatment paradigms for advanced lung cancer. He invites questions from the audience regarding his presentation.

Audience Engagement

The moderator encourages audience participation through Q&A about specific cases involving brain metastasis management alongside TKI treatments.

Understanding Brain Metastases in ROS1 Positive Lung Cancer

Prevalence and Detection of Brain Metastases

Approximately 20-30% of patients with ROS1 positive lung cancer present with brain metastases, indicating that this is a common occurrence.

Often, brain metastases are discovered incidentally during staging MRIs when patients show no symptoms, revealing small or multiple lesions.

Treatment Approaches for Asymptomatic Brain Metastases

In cases where brain metastases are found incidentally and the patient is asymptomatic, radiation therapy may not be immediately necessary.

Instead, starting a CNS penetrant ROS1 TKI (Tyrosine Kinase Inhibitor) is often preferred due to their effectiveness in treating and preventing further brain metastasis.

Considerations for Symptomatic Patients

For patients with large symptomatic brain metastases causing acute neurological issues, neurosurgery may be required before considering other treatments.

Future Availability of Zitasanib

Expected Approval Timeline

The anticipated approval date for Zitasanib in the US is September 2026; however, this timeline remains uncertain.

Accessing Zitasanib Before Approval

Until formal approval occurs, an expanded access program (EAP) allows some patients to access Zitasanib at various sites.

Managing Resistance to Targeted Therapies

Understanding Resistance Mechanisms

When targeted therapies like Zitasanib stop working, it’s crucial to identify the underlying resistance mechanisms through liquid biopsies or tumor biopsies.

Importance of Biopsies

Liquid biopsies can provide insights into circulating tumor DNA changes but have limitations regarding sensitivity and detection capabilities.

Potential Resistance Mechanisms

Non-targetable resistance mechanisms may arise; MET amplification is a known issue that can occur across various targeted therapies.

Next Steps After Therapy Failure

Exploring New Treatment Options

If resistance mechanisms are identified (e.g., MET amplification), adding a MET-targeted therapy could potentially reinduce responses in previously treated patients.

Liquid Biopsy and Immunotherapy Challenges

Difficulties in Liquid Biopsies

Finding MET amplification or gene loss (e.g., MTAP) in liquid biopsies is challenging, making them less reliable for certain genetic assessments.

Liquid biopsies are useful as an initial step in patient evaluation but often require follow-up with a biopsy of the resistant tumor.

Immunotherapy Efficacy Concerns

A recurring question is why immunotherapy fails for many patients; it’s crucial to exhaust all treatment options before considering it.

Data indicates that patients with rearrangements like ALK and ROS1 respond poorly to immunotherapy, with some studies showing 0% response rates among ROS1 patients.

Reasons for Poor Response to Immunotherapy

ROS1-positive lung cancer is typically found in non-smokers, leading to a low overall tumor mutation burden and fewer neoantigens that can trigger immune responses.

The lack of T cells infiltrating these tumors contributes to their classification as "immune deserts," further diminishing the effectiveness of immunotherapies.

Considerations for Treatment Options

In cases where ROS1 patients have exhausted other therapies, immunotherapy may be considered but generally as a later-line option.

Combining TKIs with immunotherapy is usually avoided due to increased side effects; if switching to immunotherapy, stopping the TKI is necessary.

Switching Treatments: Case-by-case Basis

The decision to switch from one TKI (like crizotinib) to another (like zitasanib), which is not yet approved, should be made cautiously based on individual patient circumstances.

For stable patients developing brain metastases, the approach may involve either switching therapies or continuing current treatment while addressing brain lesions through radiation.

Brain Metastases and Targeted Therapy

Patient Preferences in Treatment Decisions

The choice of treatment for brain metastases often depends on patient preferences, indicating a personalized approach to care.

In cases of small brain metastases (2-3 mm), radiation may be used while closely monitoring the patient's condition and maintaining targeted therapy.

Switching Targeted Therapies

There is a lower threshold for switching to more CNS-penetrant therapies when patients develop brain metastases, especially if they are on less effective treatments like certain ROS1 TKIs.

Discussions about switching therapies arise particularly when patients show signs of developing brain metastases, emphasizing proactive management.

Efficacy of Zitanid in Specific Conditions

Pleural Effusions

Managing pleural effusions can be challenging regardless of the ROS1 TKI being used; over time, the pleural space may become scarred, complicating drainage.

Zitanid has shown activity in improving pleural disease but does not lose efficacy due to the presence of pleural effusions.

Bone Metastasis

Zitanid demonstrates significant activity against bone metastases, similar to its effectiveness in other disease sites.

Managing Side Effects of TKIs

Dose Reduction vs. Switching

The decision between dose reduction or switching TKIs depends on the specific drug and side effects experienced by the patient.

For early-generation ROS1 TKIs with severe side effects, switching to a more effective option is often preferred if accessible.

Challenges with Specific Drugs

Patients struggling with dizziness from repotrectinib may continue to experience issues even after dose reductions; thus, switching might be necessary for better safety profiles.

Drug Approval Process Overview

Steps Following Clinical Trials

After clinical trials, preclinical data forms the basis for further evaluation; phase one and two data are crucial for assessing safety and efficacy.

Data Compilation for FDA Submission

Sponsors compile extensive data packages that include preclinical findings and clinical trial results before submitting them to the FDA for review.

Review Process by FDA

The FDA collaborates closely with sponsors during their review process, which includes setting timelines for decisions based on comprehensive data analysis.

Clinical Trial Eligibility Concerns

Impact of Secondary Cancers on Trial Participation

Discussion around whether having multiple cancer types disqualifies patients from participating in clinical trials highlights complexities in eligibility criteria.

Understanding Clinical Trials and Advances in ROS1 Positive Cancer

Challenges in Clinical Trials for Cancer Patients

Many clinical trials exclude patients with active second malignancies, although exceptions exist for early-stage cancers that are completely resected.

A new cancer diagnosis requiring active treatment generally complicates participation in clinical trials.

Progress Towards a Cure for Stage 4 ROS1 Positive Cancer

The speaker expresses optimism about advancements in treating stage 4 ROS1 positive cancer, noting significant progress over the past two decades.

Understanding the biology of specific cancers like ROS1 has led to the development of effective targeted therapies, which are crucial for treatment.

Targeted therapies alone may not cure advanced disease; combining them with other treatments (e.g., chemotherapy) is essential for better outcomes.

Strategies to Combat Residual Disease

There is a focus on eliminating residual cancer cells that survive despite effective targeted therapy, as these cells can lead to resistance.

Potential strategies include using radiation on residual disease sites or surgical resection to target persistent cancer cells biologically.

Future Directions and Research Opportunities

The speaker emphasizes the need for multimodal regimens that combine various therapeutic approaches to enhance treatment efficacy and potentially achieve cures.

Current research aims to identify molecular features that could predict patient responses to targeted therapies, which would help tailor treatments more effectively.

Closing Thoughts on Community Involvement and Research Impact

Gratitude is expressed towards the community's involvement in clinical trials and funding research, highlighting its importance in advancing treatment options for patients with advanced ROS1 positive lung cancer.

The speaker remains hopeful about achieving a real cure through ongoing research efforts and collaboration within the community.