Sitravatinib (MGCD516): A Comprehensive Monograph on a Spectrum-Selective Kinase Inhibitor for Immuno-Oncology

Executive Summary

Sitravatinib, also known by its code designation MGCD516, is an orally bioavailable, small molecule investigational drug developed as a spectrum-selective receptor tyrosine kinase (RTK) inhibitor.[1] Its core scientific rationale was centered on its potential as an immuno-oncology agent. The primary mechanism of action involves the potent and selective inhibition of a specific constellation of RTKs, most notably the TAM family (TYRO3, AXL, MerTK) and the split-kinase domain family (including VEGFR and KIT).[3] This targeted inhibition was designed to reverse the immunosuppressive tumor microenvironment (TME), thereby overcoming resistance to immune checkpoint inhibitors (CPIs) such as nivolumab, and augmenting anti-tumor immune responses.

The clinical development program for sitravatinib progressed through multiple phases, showing initial promise. Early Phase I/Ib studies established a manageable safety profile and a recommended Phase 2 dose, with modest signals of clinical activity in heavily pretreated patients with solid tumors.[6] Subsequent Phase II investigations, particularly the MRTX-500 study in non-small cell lung cancer (NSCLC), generated significant interest. While the study did not meet its primary endpoint of objective response rate, an exploratory analysis revealed an encouraging median overall survival of 14.9 months in the target population of CPI-experienced patients, providing the justification for advancing to a pivotal trial.[8]

The definitive outcome of the sitravatinib program was determined by the Phase III SAPPHIRE trial (NCT03906071). This large, randomized study was designed to confirm the survival benefit observed in Phase II by comparing the combination of sitravatinib and nivolumab against the standard-of-care chemotherapy, docetaxel, in patients with advanced non-squamous NSCLC who had progressed on prior CPI therapy.[10] The trial failed to meet its primary endpoint of overall survival, demonstrating no statistically significant benefit for the sitravatinib combination over docetaxel.[11]

Following this pivotal failure, the primary developer, Mirati Therapeutics, announced the discontinuation of the sitravatinib development program in May 2023.[12] Sitravatinib remains an unapproved, investigational agent with a terminated primary development path, serving as an important case study in the complexities of translating preclinical TME modulation and non-randomized Phase II survival data into successful Phase III outcomes in immuno-oncology.

Drug Profile and Chemical Properties

This section provides a comprehensive overview of the chemical and physical characteristics of sitravatinib, establishing its fundamental identity for scientific and regulatory reference.

Identification and Nomenclature

Sitravatinib is a well-characterized small molecule with multiple identifiers used across chemical, pharmacological, and clinical databases.

• Generic Name: Sitravatinib is the United States Adopted Name (USAN) and International Nonproprietary Name (INN).[14]
• Code Designations: During its development, it was primarily known by the code MGCD516. Other variations include MG-516 and MGCD-516.[2]
• DrugBank ID: The official DrugBank Accession Number is DB15036.[1]
• CAS Number: The Chemical Abstracts Service (CAS) Registry Number for the active free base form is 1123837-84-2.[1]
• Other Identifiers: For comprehensive cross-referencing, other key identifiers include its Unique Ingredient Identifier (UNII) CWG62Q1VTB, Anatomical Therapeutic Chemical (ATC) Classification System code L01EX26, Kyoto Encyclopedia of Genes and Genomes (KEGG) ID D11140, and ChEMBL ID CHEMBL3989926.[1]

Physicochemical Characteristics

Sitravatinib possesses distinct physicochemical properties that define its behavior as a pharmaceutical agent.

• Drug Type: It is classified as a small molecule drug.[1]
• Molecular Formula: The chemical formula for the free base is C33​H29​F2​N5​O4​S.[1]
• Molecular Weight: The calculated molar mass is 629.68 g/mol (often reported as 629.7 g/mol).[1]
• IUPAC Name: The systematic International Union of Pure and Applied Chemistry (IUPAC) name is 1-N'-[3-fluoro-4-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.[1]
• Structural Identifiers: Definitive structural representations are provided by its International Chemical Identifier (InChI), InChIKey (WLAVZAAODLTUSW-UHFFFAOYSA-N), and Simplified Molecular Input Line Entry System (SMILES) string.[1]
• Physical Properties: Sitravatinib is an off-white solid.[21] It is characterized by very low aqueous solubility (0.000527 mg/mL) and is soluble in organic solvents such as dimethyl sulfoxide (DMSO) and ethanol.[14] Its calculated partition coefficient ( logP) is between 4.5 and 5.3, indicating high lipophilicity, which influences its absorption and distribution properties.[1]

Formulations and Related Substances

The active pharmaceutical ingredient (API) has been formulated in different forms for research and clinical use.

• Sitravatinib Free Base: This is the primary active compound, identified by CAS number 1123837-84-2.[16]
• Sitravatinib Malate: To improve its pharmaceutical properties for clinical development, sitravatinib was formulated as a malate salt.[19] This form has its own distinct identifiers:
• CAS Number: 2244864-88-6.[16]
• Molecular Formula: C37​H35​F2​N5​O9​S (a 1:1 compound of sitravatinib and L-malic acid, C33​H29​F2​N5​O4​S⋅C4​H6​O5​).[22]
• Molecular Weight: 763.8 g/mol.[22]
• UNII: ZR2110H6XE.[22]

Table 1: Chemical and Physical Identifiers of Sitravatinib

Property	Value	Source(s)
Generic Name	Sitravatinib	14
DrugBank ID	DB15036	1
Drug Type	Small Molecule	1
Code Designation	MGCD516	16
CAS Number (Free Base)	1123837-84-2	1
Molecular Formula	C33​H29​F2​N5​O4​S	1
Molecular Weight	629.68 g/mol	15
IUPAC Name	1-N'-[3-fluoro-4-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	1
InChIKey	WLAVZAAODLTUSW-UHFFFAOYSA-N	1
ATC Code	L01EX26	1
Water Solubility	0.000527 mg/mL	14
logP	~5.2	1

Preclinical Pharmacology and Mechanism of Action

The therapeutic rationale for sitravatinib is rooted in its specific and potent activity against a select group of receptor tyrosine kinases that are critically involved in tumor progression and immune evasion. Its mechanism of action is multifaceted, combining direct anti-tumor effects with a primary focus on modulating the tumor microenvironment to enhance anti-tumor immunity.

Kinase Inhibition Profile and Target Selectivity

Sitravatinib is not a pan-kinase inhibitor but rather a "spectrum-selective" inhibitor, designed to target a specific profile of RTKs with high potency.[3] In a broad kinase panel, it was shown to inhibit 35 of 55 RTKs tested, with half-maximal inhibitory concentrations (

IC50​) spanning a wide range from 0.5 nM to 5,550 nM, indicating selectivity for certain kinases over others.[16]

The primary molecular targets, which are inhibited at low nanomolar concentrations, fall into several key families:

• TAM Family: Sitravatinib potently inhibits all three TAM family receptors: TYRO3, AXL (IC50​ = 1.5 nM), and MerTK (IC50​ = 2 nM). This is central to its immunomodulatory effects.[3]
• Split-Kinase Domain Family: This group includes key drivers of angiogenesis and cell proliferation. Sitravatinib effectively inhibits Vascular Endothelial Growth Factor Receptors (VEGFR1, VEGFR2 with an IC50​ of 5 nM, and VEGFR3), Platelet-Derived Growth Factor Receptors (PDGFR), and mast/stem cell growth factor receptor (KIT, IC50​ = 6 nM).[1]
• Other Key RTKs: The inhibitory spectrum also includes hepatocyte growth factor receptor (MET or c-Met), RET, FMS-like tyrosine kinase 3 (FLT3, IC50​ = 6 nM), the TRK family of neurotrophin receptors, Discoidin Domain Receptors (DDR1, DDR2), and members of the Ephrin (Eph) receptor family.[1]

Primary Mechanism: Modulation of the Tumor Microenvironment (TME)

The central therapeutic hypothesis for sitravatinib was to leverage its unique kinase inhibition profile to convert an immunosuppressive, or "cold," TME into an immunostimulatory, or "hot," TME. This shift was intended to restore or enhance the efficacy of immune checkpoint inhibitors, particularly PD-1/PD-L1 blockade.[3]

The foundation of this strategy lies in the potent inhibition of TAM receptors. In the TME, TAM receptors are highly expressed on myeloid cells, such as macrophages and dendritic cells. Their activation by ligands like Gas6 and Protein S triggers signaling pathways that suppress the expression of proinflammatory cytokines and promote an immunosuppressive cellular phenotype.[3] By blocking TAM receptor signaling, especially that of MerTK, sitravatinib was shown in preclinical models to exert several critical immunomodulatory effects:

1. Re-polarization of Macrophages: It prevents the polarization of monocytes into immunosuppressive M2-like macrophages, which are known to promote tumor growth, while preserving the function of anti-tumor M1-like macrophages.[3] This increases the M1/M2 macrophage ratio within the tumor, favoring an anti-tumor environment.[27]
2. Reduction of Suppressive Myeloid Cells: It reduces the populations of other key immunosuppressive cells within the tumor, including myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs).[3]
3. Enhanced T-Cell Infiltration: By dismantling the immunosuppressive myeloid cell network, sitravatinib facilitates the infiltration and activity of cytotoxic CD8+ and helper CD4+ T-cells into the tumor core.[3]

This combination of effects creates a more inflamed TME that is permissive to a robust anti-tumor immune response. This provides a strong mechanistic rationale for combining sitravatinib with a PD-1 inhibitor like nivolumab. Preclinical studies demonstrated a powerful synergy, where the combination led to superior anti-tumor activity compared to either agent alone, including complete tumor remissions and the establishment of durable immune memory that prevented tumor regrowth upon rechallenge.[3] The specific combination of potent TAM and VEGFR inhibition represents a deliberate, dual-pronged attack on the TME. TAM inhibition directly targets the immunosuppressive myeloid cell compartment, while VEGFR inhibition targets the tumor vasculature. Abnormal tumor vasculature can create a hypoxic, immunosuppressive environment and physically impede immune cell trafficking. By simultaneously targeting both pathways, the strategy aimed to create a powerful and multifaceted synergistic effect with CPIs, which directly explains why the late-stage clinical program was almost exclusively focused on combination therapy with nivolumab.

Ancillary Mechanisms of Action

Beyond its primary immunomodulatory role, sitravatinib possesses other anti-cancer properties that contribute to its overall activity.

• Anti-Angiogenic Effects: Through potent inhibition of the VEGFR and PDGFR families, sitravatinib directly disrupts angiogenesis, the process by which tumors form new blood vessels to obtain nutrients and oxygen. This is a well-established anti-cancer mechanism that can starve tumors and inhibit their growth and metastasis.[4]
• Direct Anti-proliferative Effects: In cancer cells that are addicted to signaling from RTKs within sitravatinib's target spectrum (e.g., MET, KIT, RET, FLT3), the drug can exert direct anti-proliferative and pro-apoptotic effects. This has been demonstrated in preclinical models of sarcoma and acute myeloid leukemia (AML).[1]
• Reversal of Multidrug Resistance (MDR): A distinct and notable mechanism is the ability of sitravatinib to inhibit the function of the ATP-binding cassette super-family G member 2 (ABCG2) protein.[29] ABCG2 is an efflux pump that actively transports a wide range of chemotherapy drugs out of cancer cells, conferring multidrug resistance. By inhibiting ABCG2's ATPase activity, sitravatinib blocks this efflux function, leading to increased intracellular accumulation of co-administered anticancer drugs. This suggests a therapeutic application for sitravatinib in overcoming resistance to conventional chemotherapies. This potential was largely unexplored in its primary clinical program, which focused almost exclusively on immuno-oncology combinations. The discovery of this ABCG2-inhibitory property suggests a "road not taken" in its clinical development, where sitravatinib could have been paired with an ABCG2-substrate chemotherapy agent in patient populations known to develop resistance via this specific mechanism.

Clinical Development Program: Efficacy and Outcomes

The clinical development of sitravatinib was extensive, progressing from first-in-human studies to a large, pivotal Phase III trial. The program evaluated the drug as both a monotherapy and in combination with other agents across several solid tumor types, with a primary focus on non-small cell lung cancer.

Table 2: Summary of Major Clinical Trials for Sitravatinib

NCT Identifier	Phase	Indication(s)	Intervention(s)	Status
NCT02219711	I/Ib	Advanced Solid Tumors	Sitravatinib Monotherapy	Completed
NCT02954991	II	Non-Small Cell Lung Cancer (NSCLC)	Sitravatinib + Nivolumab	Terminated
NCT03680521	II	Clear Cell Renal Cell Carcinoma (ccRCC)	Sitravatinib + Nivolumab (Neoadjuvant)	Completed
NCT03606174	II	Urothelial Carcinoma	Sitravatinib + PD-(L)1 Inhibitors	Terminated
NCT03906071	III	Non-Squamous NSCLC	Sitravatinib + Nivolumab vs. Docetaxel	Completed

Phase I/Ib First-in-Human Studies (NCT02219711)

The initial clinical evaluation of sitravatinib was conducted in an open-label, first-in-human study comprising a dose-escalation phase (Phase I) and a cohort-expansion phase (Phase Ib) for patients with advanced solid tumors who had exhausted standard therapies.[6]

• Study Design and Dosing: The Phase I portion explored oral doses of sitravatinib ranging from 10 mg to 200 mg once daily.[6] The Maximum Tolerated Dose (MTD) was established at 150 mg daily. However, based on an evaluation of long-term safety and tolerability, a dose of 120 mg once daily was selected as the Recommended Phase 2 Dose (RP2D) for subsequent studies.[6] The Phase Ib portion utilized a basket-cohort design, enrolling patients whose tumors harbored specific molecular alterations in genes targeted by sitravatinib, such as MET, RET, AXL, and loss-of-function alterations in CBL.[30]
• Pharmacokinetics (PK): Pharmacokinetic analyses demonstrated that sitravatinib was steadily absorbed following oral administration and exhibited a long terminal elimination half-life of approximately 42 to 51 hours, which provided strong support for a once-daily dosing regimen.[6]
• Efficacy: In this heavily pretreated population, the overall clinical activity of sitravatinib monotherapy was modest. The overall Objective Response Rate (ORR) in the Phase Ib expansion was 11.8%.[6] The highest response rate was observed in a small cohort of patients with RET-rearranged NSCLC (21.1%), although this finding was not statistically significant.[30] The most common outcome was disease stabilization, with 61.5% of patients achieving stable disease as their best objective response.[30]

Phase II Investigations in Key Indications

Based on its mechanism of action and the initial safety data, sitravatinib was advanced into Phase II trials, primarily in combination with immune checkpoint inhibitors.

Non-Small Cell Lung Cancer (MRTX-500 / NCT02954991)

This Phase II study was the most critical for sitravatinib's development trajectory. It was designed to evaluate the combination of sitravatinib (120 mg daily) with the PD-1 inhibitor nivolumab in patients with advanced non-squamous NSCLC.[9] The study enrolled several cohorts, including patients who were CPI-naive and patients who were CPI-experienced. The CPI-experienced group was further stratified into those who had derived a "previous clinical benefit" (PCB; defined as a response or stable disease for ≥12 weeks) from their prior CPI and those who had "no prior clinical benefit" (NPCB).[9]

• Efficacy Results: The study's primary endpoint of ORR was not formally met. However, the survival outcomes, particularly in the CPI-experienced PCB cohort, were highly encouraging and provided the rationale to proceed to a Phase III trial.[9] A post-hoc analysis of 68 patients from this cohort who matched the eligibility criteria for the planned Phase III trial showed a median Overall Survival (OS) of 14.9 months, with 32% of patients alive at 2 years.[8] This result was considered clinically meaningful in a patient population with acquired resistance to immunotherapy.

Table 3: Efficacy Outcomes of the Phase II MRTX-500 Study in NSCLC

Efficacy Endpoint	CPI-Experienced (NPCB) (n=35)	CPI-Experienced (PCB) (n=89)	CPI-Naive (n=32)
Objective Response Rate (ORR)	11.4%	16.9%	25.0%
Median Progression-Free Survival (PFS)	3.7 months	5.6 months	7.1 months
Median Overall Survival (OS)	7.9 months	13.6 months	Not Reached
Source: 9

Renal Cell Carcinoma (RCC) and Urothelial Carcinoma (UC)

Sitravatinib was also evaluated in genitourinary cancers.

• Renal Cell Carcinoma: A neoadjuvant study (NCT03680521) in patients with clear cell RCC demonstrated that preoperative treatment with sitravatinib and nivolumab was clinically active and could favorably modulate the TME before surgery.[1] An investigator-sponsored Phase I/II trial in advanced ccRCC patients who had progressed on prior anti-angiogenic therapy reported an encouraging ORR of 39% and a median PFS of 10.3 months for the combination.[37]
• Urothelial Carcinoma: A Phase II study (NCT03606174) of sitravatinib in combination with PD-(L)1 inhibitors for advanced UC was initiated but later terminated.[39] The termination was a strategic decision by the sponsor for "portfolio prioritization" and was not related to safety concerns. This decision to halt development in one indication while committing fully to the larger NSCLC market reflects a focused but high-risk corporate strategy. This approach, predicated on the promising but non-randomized Phase II NSCLC data, ultimately failed, leaving the company with no alternative late-stage development path for the asset.

The Pivotal Phase III SAPPHIRE Trial (NCT03906071)

The SAPPHIRE study was the definitive registration trial for sitravatinib.

• Design: It was a large, randomized, open-label, global Phase III study designed to confirm the survival signal observed in the Phase II MRTX-500 trial.[10]
• Patient Population: The trial enrolled patients with advanced non-squamous NSCLC whose disease had progressed on or after prior treatment with both platinum-based chemotherapy and an immune checkpoint inhibitor. This precisely mirrored the patient population that showed the most promising results in Phase II.[11]
• Intervention: Patients were randomized to receive either the experimental combination of sitravatinib plus nivolumab or the standard-of-care comparator, docetaxel chemotherapy.[11]
• Endpoints: The primary endpoint was Overall Survival. Secondary endpoints included PFS, ORR, and safety.[11]
• Outcome: Definitive Failure: In May 2023, Mirati Therapeutics announced that the SAPPHIRE trial did not meet its primary endpoint.[11] The combination of sitravatinib and nivolumab failed to demonstrate a statistically significant improvement in overall survival compared to docetaxel.

The failure of the SAPPHIRE trial is a stark example of the "valley of death" between Phase II and Phase III in oncology drug development. The promising median OS of 14.9 months observed in a selected, single-arm Phase II cohort created high expectations but was not replicated in the larger, more heterogeneous, and rigorously controlled setting of a global Phase III trial. This discrepancy highlights the inherent limitations and potential biases of relying on single-arm survival data to justify large registration studies and underscores the critical importance of randomized data for definitive confirmation of clinical benefit.

Safety and Tolerability Profile

The safety profile of sitravatinib has been characterized across its extensive clinical development program. While generally considered manageable with appropriate medical intervention, the drug was associated with a high frequency of adverse events, often necessitating dose adjustments.

Overview of Treatment-Emergent Adverse Events (TEAEs)

Across multiple clinical trials, sitravatinib, both as a monotherapy and in combination with CPIs, demonstrated a consistent safety profile characterized by:

• High Incidence of Any-Grade Events: The vast majority of patients treated with sitravatinib experienced at least one TEAE, with reported rates frequently exceeding 95%.[6]
• Significant Rate of Severe Events: The incidence of Grade ≥3 TEAEs was substantial, reported in 50% to 67% of patients in various studies. This indicates that a significant portion of patients experienced severe or medically significant toxicities.[6]
• Dose Modifications and Discontinuations: The frequent and sometimes severe nature of the adverse events often required clinical management. Dose interruptions or reductions were common, occurring in 43% of patients in the MRTX-500 study and up to 71% in another trial.[9] Treatment discontinuation due to adverse events occurred in a notable minority of patients, ranging from 14% to 23% across key studies.[9]

Common and Clinically Significant Treatment-Related Adverse Events (TRAEs)

The pattern of observed TRAEs was consistent across the clinical program and directly reflects the on-target effects of sitravatinib's kinase inhibition profile. The most frequently reported TRAEs included:

• Gastrointestinal: Diarrhea was one of the most common toxicities, affecting 41% to 61% of patients.[30]
• Constitutional: Fatigue was reported in approximately 50% of patients.[30]
• Cardiovascular: Hypertension was a very common and clinically significant TRAE, with an incidence ranging from 15% to 47%. It was frequently the most common Grade ≥3 event.[8]
• Dermatological: Palmar-plantar erythrodysesthesia, also known as hand-foot syndrome, was reported in about 34% of patients.[38]
• Laboratory Abnormalities: Common laboratory findings included elevated liver enzymes (aspartate aminotransferase and alanine aminotransferase), increased lipase and/or amylase, and proteinuria.[27]

The safety profile of sitravatinib is a direct manifestation of its mechanism of action. Hypertension is a classic on-target toxicity associated with the inhibition of VEGFR2. Diarrhea, fatigue, and skin toxicities are well-known class effects of many small molecule tyrosine kinase inhibitors. The high rates of dose modifications and discontinuations suggest that while these toxicities were deemed "manageable," their frequency and severity were significant enough to potentially compromise the ability of patients to remain on a consistently effective dose for a prolonged period. This challenge of balancing on-target efficacy with on-target toxicity may have contributed to the suboptimal outcomes observed in the Phase III setting, as the clinically tolerable dose may have been lower than the optimally effective dose for a portion of the patient population.

Table 4: Common Treatment-Related Adverse Events (TRAEs) Across Key Sitravatinib Trials

Adverse Event	Incidence (Any Grade)	Incidence (Grade ≥3)	Source(s)
Diarrhea	41% - 61%	1.6% - (not specified)	30
Fatigue	~50%	(not specified)	30
Hypertension	15% - 47%	8% - 22%	8
Increased AST/ALT	43% - 54%	0.8% - 2.5%	27
Palmar-Plantar Erythrodysesthesia	~34%	~5%	38
Decreased Appetite	~25%	0%	44

Developmental and Strategic Trajectory

The journey of sitravatinib from its early discovery to the conclusion of its late-stage clinical program provides valuable context on the strategic decision-making and inherent risks within the biotechnology industry.

Corporate and Commercial History

• Originator: The compound was originally discovered by MethylGene.[45]
• Primary Developer: Mirati Therapeutics acquired the asset and became its primary developer, leading the comprehensive clinical program from Phase I through Phase III.[2]
• Strategic Partnership: Recognizing the drug's potential, Mirati entered into a significant licensing agreement with BeiGene in 2018. This partnership granted BeiGene the rights to develop and commercialize sitravatinib in Asia (excluding Japan), Australia, and New Zealand, reflecting strong global commercial expectations for the drug at that time.[12]
• Acquisition of Mirati: In October 2023, Bristol Myers Squibb announced its acquisition of Mirati Therapeutics in a deal valued at up to $5.8 billion.[46] This acquisition was primarily driven by Mirati's approved KRAS G12C inhibitor, adagrasib (Krazati), and its promising pipeline of targeted oncology assets. By the time of this acquisition, the sitravatinib program had already been terminated following the Phase III failure.

Analysis of Clinical Failure and Discontinuation

• Pivotal Event: The definitive turning point for sitravatinib was the failure of the Phase III SAPPHIRE trial to meet its primary endpoint of overall survival, announced in May 2023.[11]
• Corporate Response: In response to the negative top-line results, Mirati Therapeutics promptly announced the discontinuation of all further development of sitravatinib.[12] This decision was echoed by its partner, BeiGene, which suspended its own related Phase III trial in China (CTR20211410) around the same period, indicating a unified conclusion based on the definitive SAPPHIRE outcome.[42]
• Regulatory Status: Sitravatinib has not received marketing approval from the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or any other major global regulatory body.[47] Given the failure of its pivotal trial, it is highly unlikely to be submitted for regulatory review in its lead indication.

Current Status and Future Perspective

• Development Halted: The development of sitravatinib has been officially halted by its primary developers.[12] While some clinical trial protocols include provisions for expanded access, allowing patients who are deriving clinical benefit to continue treatment, this does not represent active development of the drug for new indications.[39]
• Lessons Learned: The sitravatinib program serves as a critical case study in the field of immuno-oncology. It underscores the profound difficulty of translating compelling preclinical data on TME modulation and encouraging, but non-randomized, Phase II survival signals into a definitive clinical benefit in a large, controlled Phase III study. The failure to demonstrate superiority over an established standard-of-care chemotherapy like docetaxel highlights the high efficacy bar required for new agents in this setting and reinforces the significant risks inherent in oncology drug development.

The strategic trajectory of sitravatinib cannot be viewed in isolation. Its development ran parallel to Mirati's other lead asset, the KRAS G12C inhibitor adagrasib (Krazati). Adagrasib demonstrated strong clinical data and achieved FDA accelerated approval for NSCLC in December 2022, becoming the company's flagship commercial product.[12] The immense financial and strategic resources required to successfully launch and expand the adagrasib franchise likely altered the company's risk calculus. The sitravatinib program, which was already showing signs of weakness when its interim analysis in late 2022 was not positive enough to stop the trial early, became a much higher-risk proposition.[12] The ultimate failure of SAPPHIRE was a clinical disappointment, but for a company now focused on its highly successful commercial asset, it may also have represented a strategic clarification, allowing Mirati to concentrate its resources entirely on the more promising and commercially viable adagrasib program, which ultimately drove the company's acquisition by Bristol Myers Squibb.

Works cited

1. Sitravatinib | C33H29F2N5O4S | CID 25212148 - PubChem, accessed August 18, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/25212148
2. Sitravatinib Clinical Development Overview - Ontosight, accessed August 18, 2025, https://ontosight.ai/glossary/term/sitravatinib-clinical-development-overview--67a24882c445bf945aee785e
3. Sitravatinib potentiates immune checkpoint blockade in refractory ..., accessed August 18, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6238734/
4. What is Sitravatinib used for? - Patsnap Synapse, accessed August 18, 2025, https://synapse.patsnap.com/article/what-is-sitravatinib-used-for
5. Mirati's Sitravatinib Fails in Phase III Lung Cancer Trial, Nixes Development - BioSpace, accessed August 18, 2025, https://www.biospace.com/mirati-s-sitravatinib-fails-in-phase-iii-lung-cancer-trial-nixes-development
6. First-in-human phase 1/1b study to evaluate sitravatinib in patients with advanced solid tumors - PubMed, accessed August 18, 2025, https://pubmed.ncbi.nlm.nih.gov/35767205/
7. First-in-human phase 1/1b study to evaluate sitravatinib in patients ..., accessed August 18, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9395446/
8. Lasting Response With Sitravatinib Plus Nivolumab Observed After Previous Checkpoint Inhibitors and Chemotherapy For Advanced NSCLC - CancerNetwork, accessed August 18, 2025, https://www.cancernetwork.com/view/lasting-response-with-sitravatinib-plus-nivolumab-combo-after-previous-checkpoint-inhibitors-and-chemotherapy-for-advanced-nsclc
9. MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients ..., accessed August 18, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10330304/
10. Phase 3 Study of Sitravatinib Plus Nivolumab vs Docetaxel in Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer (SAPPHIRE) - ClinicalTrials.gov, accessed August 18, 2025, https://clinicaltrials.gov/study/NCT03906071
11. Sitravatinib Phase 3 SAPPHIRE Trial Misses Primary End Point in ..., accessed August 18, 2025, https://www.targetedonc.com/view/phase-3-sapphire-trial-of-sitravatinib-misses-primary-end-point-in-nsclc
12. Mirati's wait for next lung cancer med ends in phase 3 failure, accessed August 18, 2025, https://www.fiercebiotech.com/biotech/miratis-long-wait-next-lung-cancer-med-ends-phase-3-failure
13. Mirati Therapeutics Provides Update on the Phase 3 SAPPHIRE ..., accessed August 18, 2025, https://www.prnewswire.com/news-releases/mirati-therapeutics-provides-update-on-the-phase-3-sapphire-study-evaluating-sitravatinib-in-combination-with-opdivo-301833958.html
14. Sitravatinib: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 18, 2025, https://go.drugbank.com/drugs/DB15036
15. Sitravatinib - KEGG DRUG, accessed August 18, 2025, https://www.kegg.jp/entry/D11140
16. Sitravatinib free base | CAS#1123837-84-2 | RTK inhibitor - MedKoo Biosciences, accessed August 18, 2025, https://www.medkoo.com/products/7464
17. Sitravatinib - Wikipedia, accessed August 18, 2025, https://en.wikipedia.org/wiki/Sitravatinib
18. SITRAVATINIB - precisionFDA, accessed August 18, 2025, https://precision.fda.gov/ginas/app/ui/substances/CWG62Q1VTB
19. Sitravatinib - Drug Targets, Indications, Patents - Patsnap Synapse, accessed August 18, 2025, https://synapse.patsnap.com/drug/c228b04098a24f38b69bb526eaed80e0
20. Sitravatinib (MGCD-516, CAS Number: 1123837-84-2) | Cayman Chemical, accessed August 18, 2025, https://www.caymanchem.com/product/27338/sitravatinib
21. Sitravatinib | Multikinase inhibitor / Immuno-oncology agent - Focus Biomolecules, accessed August 18, 2025, https://focusbiomolecules.com/sitravatinib-multikinase-inhibitor-immuno-oncology-agent/
22. Sitravatinib Malate | C37H35F2N5O9S | CID 137796909 - PubChem, accessed August 18, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/137796909
23. SITRAVATINIB MALATE, accessed August 18, 2025, https://searchusan.ama-assn.org/usan/documentDownload?uri=/unstructured/binary/usan/sirtravatinib-malate.pdf
24. MGCD516 | Sitravatinib | RTK inhibitor | Axon 3998, accessed August 18, 2025, https://www.axonmedchem.com/product/3998
25. www.cancer.gov, accessed August 18, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/sitravatinib#:~:text=Upon%20administration%2C%20sitravatinib%20binds%20to,the%20receptor%20tyrosine%20kinase%20MER%2C
26. Sitravatinib potentiates immune checkpoint blockade in refractory cancer models, accessed August 18, 2025, https://insight.jci.org/articles/view/124184
27. Safety and efficacy of sitravatinib plus tislelizumab in patients with PD-L1-positive, locally advanced or metastatic, accessed August 18, 2025, https://www.beonemedinfo.com/CongressDocuments/Zhao_BGB-A317-Sitravatiib-103_Cohort_I_WCLC_Poster_2022.pdf
28. A phase II trial of sitravatinib + nivolumab after progression on immune checkpoint inhibitor in patients with metastatic clear cell RCC - PMC, accessed August 18, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11986416/
29. Sitravatinib, a Tyrosine Kinase Inhibitor, Inhibits the Transport Function of ABCG2 and Restores Sensitivity to Chemotherapy-Resistant Cancer Cells in vitro - PubMed Central, accessed August 18, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7236772/
30. Full article: Sitravatinib in patients with solid tumors selected by molecular alterations: results from a Phase Ib study, accessed August 18, 2025, https://www.tandfonline.com/doi/full/10.1080/14796694.2024.2418285
31. Sitravatinib in patients with solid tumors selected by molecular alterations: results from a Phase Ib study - PubMed, accessed August 18, 2025, https://pubmed.ncbi.nlm.nih.gov/39513224/
32. Phase 2 Study of Glesatinib, Sitravatinib or Mocetinostat in Combination With Nivolumab in Non-Small Cell Lung Cancer | ClinicalTrials.gov, accessed August 18, 2025, https://clinicaltrials.gov/study/NCT02954991
33. MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients With Nonsquamous NSCLC Progressing On or After Checkpoint Inhibitor Therapy or Chemotherapy - PubMed, accessed August 18, 2025, https://pubmed.ncbi.nlm.nih.gov/36842467/
34. Phase 2 Study of Glesatinib, Sitravatinib or Mocetinostat in Combination With Nivolumab in Non-Small Cell Lung Cancer - larvol clin, accessed August 18, 2025, https://clin.larvol.com/trial-detail/NCT02954991
35. MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients With Non-Squamous Non-Small Cell Lung Cancer Progressing On/After Checkpoint Inhibitor Therapy or Chemotherapy | Request PDF - ResearchGate, accessed August 18, 2025, https://www.researchgate.net/publication/368790819_MRTX-500_Phase_2_Trial_Sitravatinib_With_Nivolumab_in_Patients_With_Non-Squamous_Non-Small_Cell_Lung_Cancer_Progressing_OnAfter_Checkpoint_Inhibitor_Therapy_or_Chemotherapy
36. Study Details | Neoadjuvant Sitravatinib in Combination With Nivolumab in Patients With Clear Cell Renal Cell Carcinoma | ClinicalTrials.gov, accessed August 18, 2025, https://clinicaltrials.gov/study/NCT03680521
37. Mirati Therapeutics Announces Initial Data In Renal Cell Carcinoma From Ongoing Investigator Sponsored Clinical Trial Of Sitravatinib In Combination With Nivolumab At The 2020 ASCO Genitourinary Cancers Symposium - PR Newswire, accessed August 18, 2025, https://www.prnewswire.com/news-releases/mirati-therapeutics-announces-initial-data-in-renal-cell-carcinoma-from-ongoing-investigator-sponsored-clinical-trial-of-sitravatinib-in-combination-with-nivolumab-at-the-2020-asco-genitourinary-cancers-syposium-301005654.html
38. A phase I/II trial of sitravatinib (sitra) combined with nivolumab (nivo) in patients (pts) with advanced clear cell renal cell cancer (aCCRCC) that progressed on prior VEGF-targeted therapy. - ASCO Publications, accessed August 18, 2025, https://ascopubs.org/doi/10.1200/JCO.2020.38.6_suppl.612
39. A Phase 2 Study of Sitravatinib in Combination With PD-(L)1 Checkpoint Inhibitor Regimens in Patients With Advanced or Metastatic Urothelial Carcinoma | ClinicalTrials.gov, accessed August 18, 2025, https://clinicaltrials.gov/study/NCT03606174
40. Phase 3 Study of Sitravatinib Plus Nivolumab vs Docetaxel in Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer - UCSF Clinical Trials, accessed August 18, 2025, https://clinicaltrials.ucsf.edu/trial/NCT03906071
41. Interim Survival Analysis of Sitravatinib Allows for SAPPHIRE Study Continuation in NSCLC, accessed August 18, 2025, https://www.targetedonc.com/view/interim-survival-analysis-of-sitravatinib-allows-for-sapphire-study-continuation-in-nsclc
42. Mirati's sitravatinib stumbles in Phase III NSCLC trial, accessed August 18, 2025, https://www.clinicaltrialsarena.com/news/mirati-therapeutics-sitravatinib-nsclc/
43. Safety, tolerability, and preliminary antitumor activity of sitravatinib plus tislelizumab (TIS) in patients (pts) with unresectable locally advanced or metastatic gastric cancer/gastroesophageal junction cancer (GC/GEJC). | Journal of Clinical Oncology - ASCO Publications, accessed August 18, 2025, https://ascopubs.org/doi/10.1200/JCO.2022.40.4_suppl.281
44. SAFFRON-103: a phase 1b study of the safety and efficacy of ..., accessed August 18, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9944269/
45. Mirati Therapeutics - Sitravatinib - AdisInsight - Springer, accessed August 18, 2025, https://adisinsight.springer.com/drugs/800030073
46. Bristol Myers Squibb Strengthens and Diversifies Oncology Portfolio With Acquisition of Mirati Therapeutics, accessed August 18, 2025, https://news.bms.com/news/details/2023/Bristol-Myers-Squibb-Strengthens-and-Diversifies-Oncology-Portfolio-With-Acquisition-of-Mirati-Therapeutics/default.aspx
47. CDER Nitrosamine Impurity Acceptable Intake Limits - FDA, accessed August 18, 2025, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cder-nitrosamine-impurity-acceptable-intake-limits
48. Most FDA and EMA Oncology Drug Approvals in Q1 2025 Were New Indications for Biologics and Biosimilars - Aptitude Health, accessed August 18, 2025, https://www.aptitudehealth.com/oncology-news/most-fda-and-ema-oncology-drug-approvals-in-q1-2025-were-new-indications-for-biologics-and-biosimilars/
49. Study of Sitravatinib With or Without Other Anticancer Therapies Receiving Clinical Benefit From Parent Study | ClinicalTrials.gov, accessed August 18, 2025, https://www.clinicaltrials.gov/study/NCT04887870?cond=Cancer&aggFilters=status:not%20rec%20enr%20act&country=United%20States&state=Indiana&locStr=Indiana,%20United%20States&viewType=Table&rank=10
50. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC, accessed August 18, 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc
51. U.S. Food and Drug Administration (FDA) Accepts Mirati Therapeutics' New Drug Application for Adagrasib as Treatment of Previously Treated KRASG12C-Mutated Non-Small Cell Lung Cancer - Zai Lab, accessed August 18, 2025, https://ir.zailaboratory.com/zh-hans/news-releases/news-release-details/us-food-and-drug-administration-fda-accepts-mirati-therapeutics/