On June 24, 2025 Syndax Pharmaceuticals (Nasdaq: SNDX), a commercial-stage biopharmaceutical company advancing innovative cancer therapies, reported that the U.S. Food and Drug Administration (FDA) has granted Priority Review for its supplemental New Drug Application (sNDA) for Revuforj (revumenib) for the treatment of relapsed or refractory (R/R) mutant NPM1 (mNPM1) acute myeloid leukemia (AML) (Press release, Syndax, JUN 24, 2025, View Source [SID1234654092]). The sNDA is being reviewed under the FDA’s Real-Time Oncology Review (RTOR) program and has been assigned a Prescription Drug User Fee Act (PDUFA) target action date of October 25, 2025. RTOR allows for a more efficient review and close engagement between the sponsor and the FDA throughout the submission process.

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"We are pleased that the FDA has granted Priority Review to our sNDA in R/R mNPM1 AML, a filing which builds on the initial approval of Revuforj for R/R acute leukemia with a KMT2A translocation in 2024," said Michael A. Metzger, Chief Executive Officer. "Syndax is uniquely positioned to continue leading this exciting new therapeutic class with a first- and best-in-class menin inhibitor supported by compelling pivotal data across the broadest population of patients and a strong foundation already established among clinicians, payers, and other key stakeholders."

Revuforj is an oral, first-in-class menin inhibitor that was FDA approved in 2024 for the treatment of R/R acute leukemia with a KMT2A translocation in adult and pediatric patients one year and older. The sNDA, if approved, would expand the indication for Revuforj to include patients with R/R AML who have an NPM1 mutation, the most common genetic alteration in AML. The sNDA is supported by positive pivotal data from the AUGMENT-101 trial of revumenib in patients with R/R mNPM1 AML. Results from this population were published in the journal Blood in May 2025 and presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress Meeting in June 2025.

About Mutant NPM1 (mNPM1) Acute Myeloid Leukemia (AML)

Mutations in the NPM1 gene are the most common genetic alteration observed in adults with AML, occurring in approximately 30% of cases. Mutations in this gene play a critical role in the development of mutant NPM1 (mNPM1) AML, an aggressive blood cancer associated with high rates of relapse. Patients with relapsed or refractory mNPM1 AML have a poor prognosis and critical unmet need. Similar to KMT2A-rearranged acute leukemia, mNPM1 AML is highly dependent on the menin-KMT2A interaction and disruption of this interaction has been shown to lead to downregulation of certain leukemogenic genes. mNPM1 AML is routinely diagnosed through currently available screening techniques. There are currently no approved therapies that selectively target the underlying disease mechanisms driving mNPM1 AML.

About Revuforj (revumenib)

Revuforj (revumenib) is an oral, first-in-class, selective menin inhibitor that is FDA approved for the treatment of relapsed or refractory (R/R) acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients one year and older.

The FDA has granted Priority Review to Syndax’s supplemental New Drug Application (sNDA) seeking the approval of revumenib for the treatment of R/R mNPM1 AML. The sNDA is being reviewed under the FDA’s Real-Time Oncology Review (RTOR) program, which allows for a more efficient review and close engagement between the sponsor and FDA. The sNDA is supported by positive pivotal data from the AUGMENT-101 trial of revumenib in patients with R/R mNPM1 AML. Results from this population were published in the journal Blood and presented at the 2025 European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress Meeting.

Additionally, multiple trials of revumenib in combination with standard-of-care agents in mNPM1 AML or KMT2A-rearranged acute leukemia are ongoing or planned across the treatment landscape, including in newly diagnosed patients.

Revumenib was previously granted Orphan Drug Designation for the treatment of AML, ALL and acute leukemias of ambiguous lineage (ALAL) by the U.S. FDA and for the treatment of AML by the European Commission. The U.S. FDA also granted Fast Track designation to revumenib for the treatment of adult and pediatric patients with R/R acute leukemias harboring a KMT2A rearrangement or NPM1 mutation and Breakthrough Therapy Designation for the treatment of adult and pediatric patients with R/R acute leukemia harboring a KMT2A rearrangement.

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME

Differentiation syndrome, which can be fatal, has occurred with Revuforj. Signs and symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and renal dysfunction. If differentiation syndrome is suspected, immediately initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS

Differentiation syndrome: Revuforj can cause fatal or life-threatening differentiation syndrome (DS). Symptoms of DS, including those seen in patients treated with Revuforj, include fever, dyspnea, hypoxia, peripheral edema, pleuropericardial effusion, acute renal failure, and/or hypotension. In clinical trials, DS occurred in 39 (29%) of 135 patients treated with Revuforj. DS was Grade 3 or 4 in 13% of patients and fatal in one. The median time to onset was 10 days (range 3-41 days). Some patients experienced more than 1 DS event. Treatment interruption was required for 7% of patients, and treatment was withdrawn for 1%.

Reduce the white blood cell count to less than 25 Gi/L prior to starting Revuforj. If DS is suspected, immediately initiate treatment with systemic corticosteroids (e.g., dexamethasone 10-mg IV every 12 hours in adults or dexamethasone 0.25-mg/kg/dose IV every 12 hours in pediatric patients weighing less than 40 kg) for a minimum of 3 days and until resolution of signs and symptoms. Institute supportive measures and hemodynamic monitoring until improvement. Interrupt Revuforj if severe signs and/or symptoms persist for more than 48 hours after initiation of systemic corticosteroids, or earlier if life-threatening symptoms occur such as pulmonary symptoms requiring ventilator support. Restart steroids promptly if DS recurs after tapering corticosteroids.

QTc interval prolongation: In the clinical trials, QTc interval prolongation was reported as an adverse reaction in 39 (29%) of 135 patients treated with Revuforj. QTc interval prolongation was Grade 3 in 12% of patients. The heart-rate corrected QT interval (using Fridericia’s method) (QTcF) was greater than 500 msec in 8%, and the increase from baseline QTcF was greater than 60 msec in 18%. Revuforj dose reduction was required for 5% of patients due to QTc interval prolongation. QTc prolongation occurred in 16% of the 31 patients less than 17 years old, 33% of the 88 patients 17 years to less than 65 years old, and in 50% of the 16 patients 65 years or older.

Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to treatment with Revuforj. Perform an electrocardiogram (ECG) prior to initiation of Revuforj, and do not initiate Revuforj in patients with QTcF >450 msec. Perform an ECG at least once weekly for the first 4 weeks and at least monthly thereafter. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring may be necessary. Concomitant use with drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation.

Interrupt Revuforj if QTcF increases >480 msec and <500 msec, and restart Revuforj at the same dose twice daily after the QTcF interval returns to ≤480 msec
Interrupt Revuforj if QTcF increases >500 msec or by >60 msec from baseline, and restart Revuforj twice daily at the lower-dose level after the QTcF interval returns to ≤480 msec
Permanently discontinue Revuforj in patients with ventricular arrhythmias and in those who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.
Embryo-fetal toxicity: Revuforj can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with Revuforj and for 4 months after the last dose of Revuforj.

ADVERSE REACTIONS
Fatal adverse reactions occurred in 4 (3%) patients who received Revuforj, including 2 with differentiation syndrome, 1 with hemorrhage, and 1 with sudden death.

Serious adverse reactions were reported in 99 (73%) patients. The most frequent serious adverse reactions (≥5%) were infection (24%), febrile neutropenia (19%), bacterial infection (17%), differentiation syndrome (12%), hemorrhage (9%), and thrombosis (5%).

The most common adverse reactions (≥20%) including laboratory abnormalities, were hemorrhage (53%), nausea (51%), phosphate increased (50%), musculoskeletal pain (42%), infection (41%), aspartate aminotransferase increased (37%), febrile neutropenia (35%), alanine aminotransferase increased (33%), parathyroid hormone intact increased (33%), bacterial infection (31%), diarrhea (30%), differentiation syndrome (29%), electrocardiogram QT prolonged (29%), phosphate decreased (25%), triglycerides increased (25%), potassium decreased (24%), decreased appetite (24%), constipation (23%), edema (23%), viral infection (23%), fatigue (22%), and alkaline phosphatase increased (21%).

DRUG INTERACTIONS
Drug interactions can occur when Revuforj is concomitantly used with:

Strong CYP3A4 inhibitors: reduce Revuforj dose
Strong or moderate CYP3A4 inducers: avoid concomitant use with Revuforj
QTc-prolonging drugs: avoid concomitant use with Revuforj. If concomitant use is unavoidable, obtain ECGs when initiating, during concomitant use, and as clinically indicated. Withhold Revuforj if the QTc interval is >480 msec. Restart Revuforj after the QTc interval returns to ≤480 msec.
SPECIFIC POPULATIONS
Lactation: advise lactating women not to breastfeed during treatment with Revuforj and for 1 week after the last dose.

Pregnancy and testing: Revuforj can cause fetal harm when administered to a pregnant woman. Verify pregnancy status in females of reproductive potential within 7 days prior to initiating Revuforj.

Pediatric: monitor bone growth and development in pediatric patients.

Geriatric: compared to younger patients, the incidences of QTc prolongation and edema were higher in patients 65 years and older.

Infertility: based on findings in animals, Revuforj may impair fertility. The effects on fertility were reversible.

To report SUSPECTED ADVERSE REACTIONS, contact Syndax Pharmaceuticals at 1-888-539-3REV or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see Full Prescribing Information, including BOXED WARNING.

About the Real-Time Oncology Review (RTOR) Program

RTOR provides a more efficient review process for oncology drugs to ensure that safe and effective treatments are available to patients as early as possible, while improving review quality and engaging in early iterative communication with the applicant. Specifically, it allows for close engagement between the sponsor and the FDA throughout the submission process and it enables the FDA to review individual sections of modules of a drug application rather than requiring the submission of complete modules or a complete application prior to initiating review. Additional information about RTOR can be found at: View Source

On June 24, 2025 Revolution Medicines, Inc. (Nasdaq: RVMD), a late-stage clinical oncology company developing targeted therapies for patients with RAS-addicted cancers, reported that it has partnered with Royalty Pharma on $2 billion in flexible funding to support Revolution Medicines’ independent global development and commercialization strategy and operations (Press release, Revolution Medicines, JUN 24, 2025, View Source [SID1234654091]). Revolution Medicines retains full strategic and executional control of product development and commercialization for its portfolio of RAS(ON) inhibitors in the US and internationally, enabling the company to leverage its assets, capabilities and momentum toward establishing new global standards of care and creating value for shareholders.

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"Today’s announcement represents a major boost to our bold vision on behalf of patients with RAS-addicted cancers," said Mark A. Goldsmith M.D., Ph.D., chief executive officer and chairman of Revolution Medicines. "This funding agreement significantly increases the financial resources we can deploy while preserving optionality as we scale our operations to create the industry-leading global targeted medicines franchise for patients with RAS-addicted cancers based on our highly differentiated RAS(ON) inhibitor portfolio."

"We are excited to announce today a groundbreaking partnership that provides Revolution Medicines with up to $2 billion of long-term capital through a customized funding solution that facilitates the expansive development and global commercialization of its leading RAS(ON) inhibitor portfolio," said Pablo Legorreta, founder and chief executive officer of Royalty Pharma. "This partnership exemplifies a new funding paradigm for highly innovative biotech companies. In contrast to a conventional pharma partnership, this large scale and flexible funding agreement enables Revolution Medicines to retain control of the clinical development of daraxonrasib, as well as the ability to capture significant value creation that would result from the successful clinical development and commercialization of its pipeline."

Transaction overview

The funding agreement provides for $2 billion in committed capital comprised of up to $1.25 billion in synthetic royalty monetization on sales of daraxonrasib, the company’s RAS(ON) multi-selective inhibitor, and up to $750 million in corporate debt. The agreement provides significant flexibility to Revolution Medicines with $1.25 billion of the total funding reserved as optional to the company at its discretion, subject to the achievement of specific milestones.

Synthetic royalty details

Royalty Pharma will provide up to $1.25 billion in exchange for tiered royalties for a term of 15 years on worldwide annual net sales of daraxonrasib; the royalties decrease based on sales and for sales above $8 billion the royalty rate is zero.
The $1.25 billion synthetic royalty funding is divided into five tranches of $250 million.
The first two $250 million tranches, totaling $500 million, are payable prior to daraxonrasib’s approval by the FDA and royalty obligations begin only after daraxonrasib approval. Revolution Medicines received the first $250 million tranche at closing and the second $250 million tranche is due to the company upon a positive data readout from the company’s RASolute 302 study, a global Phase 3 trial in patients with previously treated pancreatic ductal adenocarcinoma (PDAC).
The royalty rates on annual net sales for these two tranches are 4.55% on the first $2 billion, 2.50% on $2 billion to $4 billion, 1.00% on $4 billion to $8 billion and zero above $8 billion.
At annual net sales of $8 billion, the effective blended royalty rate for these tranches would be 2.26% and this rate progressively decreases as net sales increase above $8 billion.
The subsequent three equal tranches, totaling $750 million, are post-approval tranches that can be drawn at the company’s discretion after certain milestones are achieved.
In a scenario where the company draws the entire $1.25 billion:
The royalty rates for all five tranches on annual net sales are 7.80% on the first $2 billion, 4.55% on $2 billion to $4 billion, 2.40% on $4 billion to $8 billion and zero above $8 billion.
At annual net sales of $8 billion, the effective blended royalty rate would be 4.29% and this rate progressively decreases as net sales increase above $8 billion.
The potential exists for overlapping indication labels across certain assets within the company’s pipeline. If zoldonrasib, the company’s RAS(ON) G12D-selective inhibitor, were approved in the same indication as daraxonrasib, zoldonrasib sales would be included in the calculation of total net sales that are subject to the royalty schedule noted above. If zoldonrasib is approved solely for indications outside of daraxonrasib indications, zoldonrasib sales would not be subject to any royalties under the royalty agreement.
Debt details

The debt facility is an up to $750 million senior secured term loan consisting of three $250 million tranches linked to commercialization of daraxonrasib.
The company would receive the first debt tranche of $250 million following first FDA approval of daraxonrasib for the treatment of metastatic PDAC, if this occurs by January 1, 2028. Debt tranches two and three are optional at the company’s discretion and will be available to the company based on achievement of annual net sales milestones for daraxonrasib.
The term loan is an interest-only facility, with principal due at the earlier of (i) 6 years after the first tranche is funded and (ii) December 31, 2032. The interest rate is calculated based on the 3-month Standard Overnight Financing Rate (SOFR) plus 5.75%, with a SOFR floor of 3.50%.
Further details on this transaction can be found in the Current Report on Form 8-K filed by the company today with the Securities and Exchange Commission.

Cash runway update

As a result of entering into this funding agreement with Royalty Pharma, the company is removing its cash runway end date guidance.

Investor webcast

Revolution Medicines management will host an investor webcast today, June 24, at 8:00 a.m. ET (5:00 a.m. PT) to discuss this transaction. To participate in the live webcast, participants may register at View Source A live webcast of the call will be available on the Investors section of Revolution Medicines’ website at View Source Following the live webcast, a replay will be available on the company’s website for at least 14 days.

Advisors
TD Securities acted as financial advisor and Latham & Watkins acted as legal advisor to Revolution Medicines. Goodwin Procter and Maiwald acted as legal advisors to Royalty Pharma.

On June 24, 2025 Priothera, a late-stage biopharma company pioneering the development of mocravimod, a novel oral sphingosine 1 phosphate (S1P) receptor modulator, to treat hematologic malignancies, reported that it has been awarded nearly €1.7 million in non-dilutive funding through the i-Nov innovation competition (Press release, Priothera, JUN 24, 2025, View Source [SID1234654090]). Part of the France 2030 initiative, i-Nov is a flagship French government program operated by Bpifrance to support breakthrough innovation from high-potential French companies across strategic sectors. The funding will support Priothera’s clinical programme to evaluate whether adding mocravimod to commercial CAR-T cell therapies could improve patient outcomes.

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CAR-T cell therapies represent a novel and promising modality for the treatment of hematological malignancies. They have demonstrated the potential for remarkable clinical responses and durable disease control in patients with acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma and multiple myeloma. However, their use is still associated with significant challenges, as 40-60% of patients treated with CAR-T cells experience high-grade toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), a form of severe neurological toxicity.

Mocravimod is a novel, oral S1P receptor modulator with a unique dual mechanism of action that has the potential to enhance the effectiveness of CAR-T cell therapy by:

Reducing the incidence and severity of CRS and ICANS, and
Improving response rates and durability of treatment

"We are honoured to receive this i-Nov funding from Bpifrance, which underscores the innovation and therapeutic potential of mocravimod beyond allo-HCT," said Florent Gros, Co-Founder and CEO of Priothera. "With its unique immunomodulatory properties, mocravimod is well-positioned to become a key component in the next generation of cell therapy regimens. The MOCART trial represents an exciting expansion of our clinical development into CAR-T therapy, building on our deep expertise in allo-HCT and momentum from our ongoing global Phase 3 MO-TRANS trial in acute myeloid leukemia."
Priothera continues to advance mocravimod in the MO-TRANS global Phase 3 study for patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (allo-HCT). The company remains focused on unlocking the full therapeutic potential of S1P receptor modulation across multiple settings in blood cancers.

About mocravimod
Mocravimod (KRP203) is a synthetic S1P receptor modulator being developed for the adjunctive and maintenance treatment of AML to enhance the curative potential of allo-HCT. Mocravimod’s dual mechanism of action preserves the graft-versus-leukemia (GvL) effect, critical for eliminating cancer cells while reducing the risk of graft-versus-host disease (GvHD), a major complication following allo-HCT. This novel treatment approach – mocravimod being the only S1P receptor modulator in development to treat blood cancers – tackles a high unmet medical need and aims to improve treatment outcomes and patients’ quality of life.

On June 24, 2025 Philogen S.p.A (BIT: PHIL) ("Philogen") reported the decision to voluntarily withdraw the application for marketing authorization to the European Medicines Agency (EMA) for Nidlegy, a biological investigational medicinal product which is intended to be used for the neoadjuvant treatment of adult patients with locally advanced fully resectable melanoma (Press release, Philogen, JUN 24, 2025, View Source [SID1234654089]).

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The Marketing Authorization Application (MAA) for Nidlegy submitted in June 2024 was supported by data from PIVOTAL (NCT02938299), a randomized Phase 3 study in 256 patients with locally advanced fully resectable melanoma, in which Nidlegy reduced the risk of relapse or death by 41% compared to the control arm (Hauschild et al. Journal of Clinical Oncology 2024, 43; Kähler et al Annals of Oncology, 2025, manuscript accepted). The safety profile of Nidlegy was characterized mostly by low-grade, local adverse events.

The company’s decision to withdraw the MAA was due to the timing of the availability of Chemistry Manufacturing and Controls (CMC) and additional clinical data to better characterize the benefit:risk profile in patients with locally advanced resectable melanoma. Provision of the CMC and clinical data were unlikely to be completed within the current allowed timeframe.

Philogen remains confident in the favorable benefit-risk profile of Nidlegy, underscored by its clinically meaningful efficacy and tolerable safety profile in both melanoma (Hauschild et al. Journal of Clinical Oncology 2024, 43, Kähler et al. Annals of Oncology, 2025, manuscript accepted) and in non-melanoma skin cancers (Flatz et al. JEADV 2025, 39, e147). Until now, Nidlegy has been given to more than 450 patients with different types of skin cancer.

The company continues to closely interact with the EMA and with the medical community, with the goal of making Nidlegy available to both melanoma and non-melanoma skin cancer patients as soon as possible.

Prof. Dr. Dario Neri, CEO and CSO of Philogen, commented: "After careful consideration of the feedback and ongoing dialogue with EMA, we have decided to withdraw the MAA for Nidlegy and resubmit an updated application, in view of the potential of the product in melanoma and beyond. We are working closely together with EMA to address their requests in preparation of the forthcoming resubmission of the MAA."

On June 24, 2025 Nuvalent, Inc. (the "Company") reported positive pivotal data for zidesamtinib, a novel ROS1-selective inhibitor, in tyrosine kinase inhibitor ("TKI") pre-treated patients with advanced ROS1-positive non-small cell lung cancer ("NSCLC") from the global ARROS-1 Phase 1/2 clinical trial (Press release, Nuvalent, JUN 24, 2025, View Source [SID1234654087]).

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In addition, Nuvalent announced progress on the front-line development strategies for its parallel lead programs in ROS1-positive and ALK-positive NSCLC, including:

•
The first report of preliminary data from the Phase 2 TKI-naïve cohort in its ARROS-1 clinical trial, in which global enrollment is ongoing; and,
•
The advancement of clinical startup activities to support the global initiation of the ALKAZAR Phase 3, randomized, controlled trial. The trial is designed to evaluate neladalkib, a novel ALK-selective inhibitor, versus alectinib, a front-line standard of care, for the treatment of patients with TKI-naïve ALK-positive NSCLC, and the Company expects to begin enrollment early in the second half of 2025.
The Company completed a pre-New Drug Application ("NDA") meeting with the U.S. Food and Drug Administration ("FDA") and aligned on its plans to move forward with an NDA submission seeking an indication for the treatment of zidesamtinib for TKI pre-treated patients with locally advanced or metastatic ROS1-positive NSCLC. The FDA agreed to accept the NDA for participation in the Real-Time Oncology Review ("RTOR") pilot program, which facilitates earlier submission of topline data to support an earlier start to the FDA’s evaluation of the application. The Company plans to initiate a rolling NDA submission in July 2025 with completion targeted for the third quarter of 2025, and continues to engage with the FDA on potential opportunities for line-agnostic expansion.

Summary of Pivotal Data

Zidesamtinib is being evaluated in ARROS-1, a first-in-human Phase 1/2 clinical trial for patients with advanced ROS1-positive NSCLC and other solid tumors. The recommended phase 2 dose ("RP2D") for zidesamtinib of 100 mg once daily ("QD") was determined during the Phase 1 dose-escalation portion of the trial. The ongoing global, single arm, multi-cohort, open label Phase 2 portion is designed to evaluate zidesamtinib at the RP2D with registrational intent for both TKI-naïve and TKI pre-treated patients with advanced ROS1-positive NSCLC.

In this pivotal dataset for the TKI pre-treated ROS1-positive NSCLC population, data are pooled across Phase 1 and 2 and reported for the primary objective of objective response rate ("ORR", RECIST 1.1) by blinded independent central review ("BICR"). Key secondary objectives include duration of response ("DOR"), intracranial ORR ("IC-ORR"), and safety.

As of the data cut-off date of March 21, 2025, 514 patients with ROS1-positive solid tumors had received zidesamtinib at any starting dose across the Phase 1 and Phase 2 portions of the ARROS-1 clinical trial. Of these, 432 patients with advanced ROS1-positive NSCLC were treated with zidesamtinib at the RP2D.

Efficacy Analysis in TKI Pre-treated Advanced ROS1-positive NSCLC

The primary analysis population consisted of 117 TKI pre-treated patients with advanced ROS1-positive NSCLC with measurable disease who received zidesamtinib at the RP2D by May 31, 2024 with DOR follow-up of at least 6 months available for nearly all responders.

The primary analysis population was distinct from the ROS1 TKI pre-treated populations that have been reported for the current available and investigational ROS1 TKIs:

Patients received a median of 2 prior lines of therapy (range, 1 – 11) and 53% had received prior chemotherapy.

•
47% of patients received crizotinib or entrectinib, the most commonly used front-line TKIs, as their only ROS1 TKI ± prior chemotherapy. Within this subset, 51% of patients received prior crizotinib and 49% of patients received prior entrectinib; 47% of patients received prior chemotherapy.
•
50% of patients had received 2 or more prior ROS1 TKIs ± prior chemotherapy, of which 93% had received prior lorlatinib, repotrectinib, or taletrectinib.
•
36% of patients had a secondary ROS1 resistance mutation, a key driver of disease progression.
•
49% of patients had active CNS disease by BICR, including cases of disease progression following treatment with the brain-penetrant TKIs lorlatinib, repotrectinib, and/or taletrectinib.
Activity was observed across subsets of TKI pre-treated patients, and durability of response was assessed as the probability of patients remaining in response for at least 6, 12 and 18 months by Kaplan-Meier estimate (Table 1). Median duration of response ("mDOR") continues to mature.

Table 1.

All TKI Pre-treated a

1 prior ROS1 TKI

(crizotinib or entrectinib)

± chemotherapy b

n

117

55

ORR, % (n/N)

(95% CI)

44% (51/117) c

(34, 53)

51% (28/55) d

(37, 65)

% DOR ≥ 6 months e

(95% CI)

84%

(71, 92)

93%

(74, 98)

% DOR ≥ 12 months e

(95% CI)

78%

(62, 88)

93%

(74, 98)

% DOR ≥ 18 months e

(95% CI)

62%

(28, 84)

93%

(74, 98)

G2032R mutation f

n

26

6

ORR, % (n/N)

(95% CI)

54% (14/26)

(33, 73)

83% (5/6)

(36, 100)

% DOR ≥ 6 months e

(95% CI)

79%

(47, 93)

80%

(20, 97)

% DOR ≥ 12 months e

(95% CI)

60%

(28, 81)

80%

(20, 97)

NE = not estimable.

a The median duration of follow-up was 11.1 months (range 0.2 – 25.6) and mDOR continue to mature. For responders, the emerging mDOR was 22.0 months (95% CI: 17.2, NE) overall and 17.2 months (95% CI: 3.7, NE) for the subset with G2032R.

b The median duration of follow-up was 11.8 months (range 1.2 – 25.6) and mDOR continue to mature. For responders, the emerging mDOR was 22.0 months (95% CI: 22.0, NE) overall and NE (95% CI: 1.9, NE) for the subset with G2032R.

c Includes responses observed in patients previously treated with at least 2 prior ROS1 TKIs ± chemotherapy (22/58, ORR = 38%), and in patients previously treated with repotrectinib (8/17, ORR = 47%) or taletrectinib (3/7, ORR = 43%).

d For patients receiving crizotinib only ± chemotherapy, ORR was 68% (19/28) with no progression events among responders. For patients receiving entrectinib only ± chemotherapy, ORR was 33% (9/27) with three progression events among responders.

e Estimated for responders by Kaplan-Meier analysis.

f ROS1 G2032R mutation identified in local or central testing of blood ("ctDNA") or tissue.

In patients that had measurable CNS lesions by BICR at baseline (n = 56), the IC-ORR was 48% with 20% (11/56) intracranial complete responses ("CR") and 2 unconfirmed partial responses ("PR"), and IC-DOR ≥ 12 months of 71% (95% CI: 46, 87).

•
In patients that had only received prior crizotinib, which has limited brain penetrance, ± chemotherapy (n = 13), the IC-ORR was 85% with 54% (7/13) intracranial CRs. There was only one CNS progression event among CNS responders.
•
Intracranial responses were also observed in patients previously treated with the brain-penetrant TKIs entrectinib, lorlatinib, repotrectinib or taletrectinib.
Safety Analyses in Advanced ROS1-positive NSCLC

Zidesamtinib demonstrated a well-tolerated safety profile consistent with its ROS1-selective, TRK-sparing design.

In the 432 patients with advanced ROS1-positive NSCLC treated at RP2D as of the data cut-off date, the median duration of exposure was 5 months (range, 0, 32). The most frequent treatment-emergent adverse events ("TEAEs") occurring in ≥ 15% of patients were peripheral edema (36%), constipation (17%), blood CPK increase (16%), fatigue (16%), and dyspnea (15%).

Dose reductions due to TEAEs occurred in 10% of patients and 2% of patients discontinued treatment due to TEAEs.

Preliminary Data for TKI-Naïve Patients with Advanced ROS1-positive NSCLC

Encouraging preliminary data were available for 35 TKI-naïve patients with advanced ROS1-positive NSCLC treated with zidesamtinib at RP2D as of August 31, 2024. Patients may have received up to one prior line of chemotherapy.

The preliminary ORR was 89% (31/35) and DOR ranged from 1.9+ to 13.9+ months with DOR ≥ 6 months and 12 months of 96% (95% CI: 76, 99). In 6 patients with measurable intracranial lesions, the IC-ORR was 83% (5/6) and the intracranial CR rate was 67% (4/6). The IC-DOR ranged from 4.6+ to 11.1+ months with no CNS progression among responders.

As of June 16, 2025, a total of 104 patients had been enrolled in the ongoing TKI-naïve cohort of the ARROS-1 trial.