Nuvectis Pharma's AACR Abstracts Point to a SRC/YES1 Kinase Blockbuster Molecule
NXP900’s ability to maintain near-complete SRC suppression makes it one the most potent TKI’s ever developed.
Key Highlights:
Nuvectis to present first in human phase 1 trial of the SRC family kinase NXP900 in advanced solid tumors at AACR in April.
Management’s recent comments point to near-complete inhibition of SRC/YES1 signaling, an exceptionally high level of target engagement, with favorable safety.
The Phase 1 data and profound tumor shrinkages seen in multiple preclinical in vivo models are a significant de-risking event.
Nuvectis is planning multiple expansion studies as a single agent in NSCLC and in combination with EGFR inhibitors and ALK inhibitors for acquired resistance in EGFR-mutated and ALK fusion-positive NSCLC.
For lung, in particular, in vivo preclinical models are extremely strong indicators of clinical results because lung cancer subsets are driven by a single dominant molecular driver.
Given the early clinical de-risking of NXP900, we estimate NVCT shares should be currently valued at approximately $30, representing 200% upside from recent trading levels of $10. Our 2026 price target is $200, based on the sizable opportunity in NSCLC.
NXP900 AACR Annual Meeting Abstracts
The abstracts for the AACR Annual Meeting 2025 were released late-yesterday. Nuvectis (NVCT) will present five abstract posters on NXP900, including presentations of the first in human clinical data for the molecule and an in vivo NXP900 and osimertinib combination study in non-small cell lung cancer (NSCLC).
The phase 1 data and profound tumor shrinkages seen in multiple in vivo models are a huge de-risking event for the program. The phase 1 data is expected to show near total inhibition in the context of very good safety and the type 1.5 mechanism means the total inhibition is maintained between doses. This implies complete inhibition of the SRC/YES1 tumor driver. For lung, in particular, in vivo preclinical models are extremely strong indicators of clinical results because lung cancer subsets, such as EGFR, ALK, and SRC/YES1 have cancers driven by a single dominant molecular driver.
SRC/YES1-driven NSCLC cancers represent a large unmet need, with approximately 40,000 new patients annually with YES1 or FAT1 amplifications (10,000 patients), or for patients who have acquired resistance to EGFR inhibitors and ALK inhibitors in EGFR-mutated (20,000) and ALK fusion-positive (8-10,000) NSCLC.
NVCT’s valuation does not reflect the significant potential of NXP900. At its IPO in July 2021, Nuvalent (NUVL) had a market capitalization of approximately $700 million as a preclinical-stage company focused on targeted therapies for NSCLC. By October, 2023, after reporting preliminary Phase 1 data from ALKOVE-1 in ALK fusion-positive NSCLC, its market cap had surged to around $5 billion, reflecting the significant value assigned to a now somewhat de-risked clinical-stage oncology asset. In contrast, NVCT currently trades at a fraction of that valuation, despite NXP900 transitioning into a clinical-stage asset. Abstracts to be released at AACR, along with management’s recent comments at a recent investor conference, further support the de-risking of NXP900, yet the market has yet to re-rate NVCT accordingly.
Adding to the valuation disconnect, NXP900’s NSCLC target market is roughly four times the size of Nuvalent’s ALK and ROS1 programs, yet Nuvalent trades at a $5.3 billion market cap today, while Nuvectis sits at just $200 million. Expanding beyond NSCLC, NXP900's initial total addressable market includes approximately 70,000 new patients annually, further widening the valuation gap.
With NXP900 now a clinical asset demonstrating early validation, NVCT remains highly undervalued relative to its substantial market potential and larger industry peers. Given its clinical progress, we believe NVCT should be valued similarly to NUVL’s $700 million IPO, implying a share price of $30—roughly 200% above current levels. Furthermore, if any of the upcoming NSCLC trial readouts are favorable, NVCT could warrant a valuation in line with NUVL’s current $5.3 billion market cap, suggesting a 2026 price target of approximately $200 per share based on our estimate of 23-25 million shares outstanding.
NXP900 AACR Abstracts:
Abstract: CT153 / 19 - First in human phase 1 trial of the SRC family kinase inhibitor NXP900 in patients with advanced solid tumors — abstract embargoed
While the abstract for the first in human phase 1 trial of NXP900 is embargoed, NVCT management provided a preview of the phase 1 data at a recent investor conference.
Management commented that NXP900 is nearing the completion of dose escalation trials, having tested 20mg, 40mg, 80mg, 150mg, and 200mg doses, with the 250mg cohort almost finished. While a maximum tolerated dose (MTD) has not been identified, further escalation beyond 250mg is unlikely, as pharmacokinetic (PK) curves are plateauing and pharmacodynamic (PD) data shows 90-95% inhibition at 200mg—an exceptionally high level of target engagement rarely seen among the 80 approved tyrosine kinase inhibitors (TKIs).
Management described the dose-response relationship as "elegant," emphasizing that with 90-95% inhibition of SRC phosphorylation, further gains would be challenging. The 250mg dose was expected to yield similar or slightly better results than 200mg, suggesting it is nearing saturation.
Regarding target occupancy, management noted that 150mg provides significant coverage, while 200mg achieves near-complete engagement. Even at 80mg, substantial occupancy (70-80%) is evident.
On safety, management stated that adverse effects have been primarily gastrointestinal, including mild diarrhea and nausea—common for oral medications in this patient population. No concerning safety signals have emerged, reinforcing the potential for a very wide therapeutic window and flexible dose titration, particularly for combination therapies.
Abstract: 5599 / 9 - NXP900, a novel YES1/SRC kinase inhibitor currently in clinical development, blocks YAP1 signaling in NSCLC cell lines
The aim of this study was to examine the signaling pathways targeted by NXP900, including the Hippo pathway, and unravel potential synergy mechanism of NXP900 with existing targeted therapies against NSCLC.
Results: NXP900 inhibited cancer cell proliferation of NSCLC cell lines. NXP900 showed dose-dependent decreases in YAP1 and YES1 nuclear localization across all cell lines and prevented SRC phosphorylation.
Conclusions: NXP900 prevents YAP1 nuclear localization and cell cycle progression in a panel of NSCLC cell lines, decreasing expression of total YAP1 and YES1. Our data suggests that NXP900, currently in a Phase1 dose escalation study, is an attractive and translatable combination partner that could synergize with existing targeted therapies against NSCLC when the Hippo pathway is dysregulated
Abstract 5984 / 11 - Overcoming osimertinib resistance in NSCLC with NXP900, a phase 1, highly selective and potent first-in-class total YES1/SRC inhibitor
The aim of this study was to examine the signaling pathways targeted by NXP900, including the Hippo pathway, and unravel potential synergy mechanism of NXP900 with existing targeted therapies against NSCLC.
Results: NXP900 and osimertinib combination treatment demonstrates statistically significant and potent synergy in osimertinib resistant NSCLC cell lines in vitro. In vivo studies demonstrate significantly increased duration of anti-cancer response to the NXP900 and osimertinib combination treatment arm relative to corresponding monotherapy arms in an EGFR mutant lung cancer model.
Conclusions: Despite high response rates to osimertinib in EGFR mutant lung cancer patients acquired resistance almost universally arises. Here we demonstrate that NXP900 in combination with osimertinib demonstrates potent synergy and prolonged inhibition of tumor growth in in vitro and in vivo NSCLC models of acquired osimertinib resistance. Altogether, these data suggest that NXP900 may have therapeutic potential in EGFR mutant cancers with acquired resistance to osimertinib.
This abstract will include the first in vivo studies combining NXP900 and osimertinib. While we await the details, we show an in vivo combo study included in the NVCT corporate presentation, as illustrated below. In this 60-day study, mice were treated for 28 days and then observed post-treatment. The results for the combination arm demonstrate a very potent reversal of resistance, with remarkable tumor shrinkage:
In the osimertinib single-agent arm (purple line), tumors rapidly regrew after therapy was discontinued.
In contrast, the NXP900/osimertinib combination arm (gray line) exhibited dramatic tumor shrinkage approaching zero (complete response), which was maintained long after treatment ended. Tumors only began to return toward baseline near the end of the study.
Had dosing continued, it is possible that complete responses could have been sustained indefinitely or for an extended period. This suggests that NXP900’s Type 1.5 mechanism achieves total SRC inhibition, contributing to both deep responses and prolonged durability—a potentially groundbreaking approach to overcoming acquired resistance (AR) in EGFR-mutated NSCLC.
AstraZeneca’s osimertinib (Tagrisso) is its top-selling drug, generating approximately $7 billion in sales as a targeted EGFR inhibitor for EGFR-mutated NSCLC. While most patients initially respond well, approximately one-third develop resistance within 12 months, primarily due to bypass mechanisms driven by YES1 amplification. Thus, reversing AR to osimertinib may represent a greater than $2 billion annual sales opportunity to AstraZeneca.
Abstract: 5520 / 15 - NXP900, a phase 1, first-in-class YES1/SRC inhibitor demonstrates potent single agent activity and synergy with ALK inhibitors in ALK resistant NSCLC models
Results: NXP900 single agent potently inhibited cell proliferation of ALK resistant cell lines, with a median GI50=30nM. At the same concentration range, NXP900 potently inhibited the activating SRC autophosphorylation, and demonstrated synergy in combination with lorlatinib in lorlatinib-resistant cell lines derived from NCI-H2228 (EML4-ALKv3) and NCI-H3122 (EML4-ALKv1) cells.
Conclusions: Despite high response rates to lorlatinib and long duration of response, acquired resistance almost universally arises. Here we demonstrate that NXP900 can potently inhibit cell proliferation of ALK resistant cell lines as a single agent and is synergistic with lorlatinib in NSCLC models harboring different variants of the ALK gene fusion. Altogether, these data suggest that NXP900 may have therapeutic potential in cancers with acquired resistance to ALK inhibitors.
NXP900/ALK combos have seen similarly striking reversal of AR in cell lines with ALK fusion-positive NSCLC, as shown in the chart below from an NVCT corporate presentation. The NXP900/ALK TKI combo cell line data was similar to NXP900/EGFR TKI combos, suggesting that in vivo models for NXP900/ALK TKIs should look very similar to the EGFR chart above. Similar to AR with EGFR TKIs, AR with ALK TKIs is driven by bypass mechanisms via YES1 amplification.
Importantly, this abstract is implying single agent inhibition of ALK resistant cell lines, which may represent an emerging opportunity.
ALK fusion-positive NSCLC represents a $2.5 billion market for existing targeted TKIs, such as Roche’s Alecensa (alectinib), and Pfizer’s Lorbrena (lorlatinib).
Abstract: LB292 / 15 Endocrine therapy-resistant luminal A breast cancer cell lines are sensitive to the novel YES1/SRC tyrosine kinase inhibitor, NXP900 — Late breaking abstract embargoed
Luminal A breast cancer is characterized by the presence of estrogen and or progesterone receptors (ER+/PR+) and low levels of HER2. Luminal A breast cancer is the most common form of breast cancer, accounting for 40-50% of the 250,000 newly diagnosed cancer patients annually, representing 100-125,000 new patients. These patients are treated with endocrine (hormonal) therapies. While the prognosis is generally favorable for these cancers, tens of thousands of these patients may acquire resistance to these therapies via a bypass mechanism driven by SRC/YES1 signaling.
While this late breaking abstract is embargoed, we highlight a prior preclinical study of NXP900 in breast cancer:
A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability — abstract
In this study, screening across 16 breast cancer cell lines shows that e506 (NXP900) exhibits high anti-proliferative effects in triple-negative and ER+ breast cancer by inhibiting the cell cycle. It is a highly potent SRC kinase inhibitor, achieving full inhibition at just 0.03–0.1 μmol/L, outperforming other SRC/ABL inhibitors.
The investigators performed a head-to-head efficacy study between dasatinib and NXP900 in a primary breast cancer model, Metastasis Tumor-Associated Protein 2 (MetBo2), which is associated with estrogen receptor-negative (ER−) breast cancer subtypes. Studies have shown that MetBo2 enhances metastatic behavior and is linked to poor outcomes in these cancers in immunocompetent FVB mice (n = 8/group). The initial treatment phase was run for 28 days, with follow up treatment after relapse, if necessary.
As shown in the chart below, NXP900 showed superior (statistically significant) anti-tumor efficacy over dasatinib in immunocompetent mice with sustained tumor suppression and delayed relapse post-treatment. While both drugs initially halted tumor growth, dasatinib-treated tumors rebounded quickly, requiring re-treatment by day 35. In contrast, NXP900-treated tumors relapsed much more slowly, with two mice remaining tumor-free (complete response) until day 148, the endpoint of the study, and a third mouse surviving nearly until the end of the study. NXP900 also induced higher T-cell infiltration and less cardiac toxicity than dasatinib, despite a 2x higher dose for NXP900, which caused heart enlargement and myocyte damage, limiting its therapeutic index.
From Preclinical Promise to Clinical Proof
We believe NXP900 has been de-risked and has achieved "proof of concept" based on the Phase 1 data, which aligns with preclinical findings. Preclinical models showed that NXP900 selectively targets tumors driven by SRC/YES1 activation while sparing cells without these genomic alterations. This specificity supports a clear therapeutic window, now reinforced by the emerging tolerability data from the phase 1 study. Moreover, preclinical studies demonstrated strong tumor inhibition when YES1 gene amplification or other SRC/YES1-dependent alterations were present. While detailed phase 1 data will not be available until AACR on April 25, we believe NVCT’s preview of the study confirms these findings, strengthening our confidence in NXP900’s potential as a blockbuster molecule.
The historical context of SRC inhibitors further supports this outlook. While previous SRC-targeting drugs showed efficacy in solid tumors, they were limited by safety (dasatinib, bosutinib) or potency (saracatinib) concerns that prevented regulatory approval in solid tumors. However, case studies, such as a lung adenocarcinoma patient with YES1 over-expression robustly responding to SRC inhibition, suggest that targeting this pathway can yield meaningful clinical activity. NXP900 presents an opportunity to revisit this approach with a superior safety profile and high potency, potentially unlocking the therapeutic potential of SRC inhibition in solid tumors.
NXP900’s ability to maintain near-complete SRC suppression — for 24 hour dosing period — makes it one the most potent TKI’s ever developed. While some high-potency TKIs achieve long-lasting inhibition in their targets, NXP900's ability to maintain near-complete SRC suppression for 24 hours—while binding the inactive state—is unique. This mechanism reduces the risk of reactivation flares seen in other inhibitors, setting it apart from conventional SRC TKIs.
Clinical Data Strongly Validates the Stunning Tumor Shrinkages Seen Across Many In Vivo Models/Clinical Case Studies
NXP900 appears to be significantly de-risked, particularly in the context of NSCLC, with highly compelling data showing 90-95% inhibition of key oncogenic signaling pathways. This high level of sustained inhibition, combined with the deep tumor responses observed across multiple preclinical in vivo models, suggests the potential for profound—if not complete responses— in patients with SRC/YES1-driven cancers. Notably, in vivo models consistently show remarkable tumor shrinkage at a human dose equivalent of just 100 mg—well below the 200-250 mg doses that NVCT is likely advancing.
Mice in vivo data is a very strong predictor of clinical success in lung cancer, more so than in many other cancer types, particularly in the context of targeted therapies. Lung cancer, unlike some other solid tumors, tends to have dominant driver mutations that dictate tumor growth and survival. When a tumor is dependent on a specific genomic alteration (e.g., YES1 amplification, EGFR mutations, or ALK rearrangements), effective inhibition of that pathway often translates into meaningful clinical responses. Since in vivo models are designed to reflect these same genetic drivers, the responses observed in mice are very likely to be relevant to human disease.
Lung cancer has a well-documented history where preclinical models have successfully predicted clinical efficacy of targeted therapies. Examples include: EGFR inhibitors (e.g., osimertinib, erlotinib), ALK inhibitors (e.g., crizotinib, alectinib), KRAS inhibitors (e.g., sotorasib, adagrasib). These inhibitors showed strong responses in in vivo studies before proving effective in patients. Because lung cancer subtypes tend to be homogeneous within their genetic driver groups, a targeted therapy that works in in vivo models with the correct alteration (e.g., YES1 amplification) has a higher likelihood of success in patients.
Unlike some cancers where multiple pathways drive disease, such as in colorectal or pancreatic cancers, lung cancer subtypes tend to be addicted to single dominant pathways. This is why KRAS inhibitors, for example, fail in colorectal cancer but succeed in lung cancer (because lung tumors are more reliant on KRAS). And EGFR inhibitors show dramatic responses in EGFR-mutant lung cancer but have limited impact in wild-type EGFR tumors.
NXP900 in vivo data is not just showing run-of-the-mill tumor regression—it’s showing regression in a context where targeted therapies have historically worked. This is different from a model where the tumor shrinks, but the pathway isn’t well understood. Since lung cancer targeted therapies have a proven track record of translation, the in vivo results should be taken very seriously.
Further bolstering the validity of NXP900 in NSCLC is a lung cancer patient who achieved a 69% tumor reduction on just 60mg of dasatinib—a less potent SRC inhibitor (shown below). Comparatively, NXP900 achieves near-total pathway inhibition at doses between 100mg and 250mg, suggesting it could also deliver robust clinical efficacy.
NXP900: A Game-Changing SRC/YES1 Kinase Inhibitor
As described in our initiation report on NVCT, Nuvectis Pharma’s Truffle Pig Moment, NXP900 is a highly selective SRC/YES1 tyrosine kinase inhibitor (TKI) with a novel Type 1.5 mechanism of action that completely shuts down the SRC signaling pathway. This groundbreaking approach addresses limitations of traditional SRC TKIs, positioning NXP900 as the first and only SRC inhibitor targeting solid tumors.
SRC/YES1-driven cancers represent a large unmet need, with over 70,000 new patients annually, including NSCLC, head and neck, cervical, and esophageal cancers, among others. This total includes approximately 30,000 patients with acquired resistance (AR) in EGFR-mutated and ALK fusion-positive NSCLC, where NXP900 can be used in combination with the primary TKIs.
Currently completing Phase 1a dose-escalation studies, NXP900 is set to begin multiple Phase 1b efficacy trials in mid-2025. These trials will likely explore single-agent use in NSCLC and other YES1-driven cancers, as well as combination therapies addressing acquired resistance in EGFR-mutated and ALK fusion-positive NSCLC.
If NVCT delivers strong response data, particularly in combination trials with osimertinib or lorlatinib, major players like AstraZeneca or Pfizer, respectively, could move quickly to acquire NVCT. Given the molecule’s potential $10+ billion valuation and a share count in the mid-20 million range, this could imply a share price in the hundreds within the next year.
The $5 billion valuation of Nuvalent (NUVL), primarily based on Phase 1 data for its next-gen ALK TKI, highlights the enormous value potential of NVCT, especially considering that ALK (8,000 patients) is a relatively small subset of the total SRC/YES1 opportunity of 70,000 new patients annually, including 40,000 patients in NSCLC.
In the near term, NVCT is poised for a significant run-up into AACR in April. Additionally, its likely inclusion in the Russell 2000 Index could trigger the acquisition of 1 million shares—against a small float— by index funds.
With NXP900 effectively shutting down nearly all oncogenic signaling in its target cancers, we are confident that this molecule will be a major value driver. The market is completely overlooking this opportunity, making it even more compelling.
Other NXP900 publications on Nuvectis Pharma’s website can be found here
Risks of Investing in Development-Stage Biotech Stocks
Investing in development-stage biotech stocks carries significant risks that investors should carefully consider. These companies are typically focused on research and development of new therapies, drugs, or technologies, and their success is often contingent upon achieving regulatory approval, securing funding, and commercializing their products. Key risks include:
1 Regulatory Approval: The majority of development-stage biotech companies rely on successful clinical trials and subsequent approval from regulatory bodies such as the FDA. Failure to meet clinical endpoints or obtain regulatory approval can lead to significant financial losses.
2 High Failure Rates: Many therapies and drugs in development never reach the market due to safety concerns, lack of efficacy, or other unforeseen challenges.
3 Capital Intensity: Developing biotechnology products is costly, and these companies often depend on external financing. Dilution of existing shareholders through equity offerings is common.
4 Market Competition: Even if a product is successfully developed, it may face intense competition from other biotech firms or larger pharmaceutical companies with more resources.
5 Uncertain Revenue: Until a product is approved and commercialized, development-stage biotech companies often have little to no revenue, making their valuation speculative and highly volatile.
6 Economic and Market Conditions: Broader market or economic downturns can disproportionately impact biotech stocks, especially those reliant on high-risk capital.
Investors should thoroughly research and understand the unique risks associated with individual companies and consider their own risk tolerance before investing in development-stage biotech stocks.
Disclosure Statement
This report on Nuvectis Pharma Inc has been prepared solely for informational purposes. We confirm that we are not being compensated for the preparation or dissemination of this report. Furthermore, we currently own shares of NVCT. Please note that we are under no obligation to provide updates to the market regarding the sale or purchase of NVCT shares in the future.
We are not registered investment advisers, and this report does not constitute investment advice. Additionally, we do not make any representations or warranties regarding the accuracy, completeness, or reliability of the information contained herein. Readers are encouraged to conduct their own due diligence and consult with a qualified financial professional before making any investment decisions. We believe that this disclosure is made in compliance with applicable regulations and to provide transparency about our position in the subject of this report.