RegulationBreakthrough Therapy (United States), Fast Track (United States), Accelerated Approval (United States), Orphan Drug (United States), Breakthrough Therapy (China), Orphan Drug (South Korea), Orphan Drug (Australia), Conditional marketing approval (United States), Priority Review (United States)

Structure/Sequence

Molecular FormulaC30H30F2N6O3

InChIKeyNXQKSXLFSAEQCZ-UHFFFAOYSA-N

CAS Registry2296729-00-3

Clinical Trials associated with Sotorasib

NCT06892054

/ Not yet recruitingPhase 2IIT

Sotorasib Combined with First-line Chemotherapy for Advanced Pancreatic Adenocarcinoma with KRAS P.G12C Mutation

The main objective of this trial is to evaluate the safety and tolerability of sotorasib combined with first-line chemotherapy for advanced pancreatic adenocarcinoma harboring KRAS p.G12C mutation.

Start Date30 Jun 2025

Sponsor / Collaborator

Groupe Coopérateur Multidisciplinaire en Oncologie

[+1]

NCT06068153

/ WithdrawnPhase 2IIT

A Multicentre, Single-arm Phase II Trial of Sotorasib Plus Lenvatinib, As Second-line Treatment in Patients with KRASG12C-mutant, Metastatic NSCLC

AMBER is a multicentre, single-arm phase II trial. The protocol treatment consists of of sotorasib plus lenvatinib, as a second-line treatment. The primary objective of the trial is to evaluate the clinical efficacy of sotorasib plus lenvatinib, in terms of objective response rate, for patients with KRASG12C-mutant, metastatic NSCLC.

Start Date01 Mar 2025

Sponsor / Collaborator

Amgen, Inc.

[+1]

NCT06804824

/ RecruitingPhase 1

A Phase 1/1b, Open-Label, Multicenter, First-in-Human Dose Escalation and Dose Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Anti-Tumor Activity of VVD-159642, a RAS-PI3Kα Inhibitor, as a Single Agent and in Combination in Participants With Advanced Solid Tumors

A FIH study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of VVD-159642, a rat sarcoma viral oncogene-phosphatidylinositol 3-kinase alpha (RAS-PI3Kα) inhibitor, as a single agent and in combination with either sotorasib or trametinib in participants with advanced solid tumors.

Start Date25 Feb 2025

Sponsor / Collaborator

Vividion Therapeutics, Inc.

100 Clinical Results associated with Sotorasib

100 Translational Medicine associated with Sotorasib

100 Patents (Medical) associated with Sotorasib

628

Literatures (Medical) associated with Sotorasib

01 Dec 2025·CANCER CHEMOTHERAPY AND PHARMACOLOGY

Evolution of computational techniques against various KRAS mutants in search for therapeutic drugs: a review article

Review

Author: Subramaniyan, Vetriselvan ; Ogaly, Hanan A ; Mehmood, Ayesha ; Khalid, Asaad ; Wadood, Abdul ; Hakami, Mohammed Ageeli

KRAS was (Kirsten rat sarcoma viral oncogene homolog) revealed as an important target in current therapeutic cancer research because alteration of RAS (rat sarcoma viral oncogene homolog) protein has a critical role in malignant modification, tumor angiogenesis, and metastasis. For cancer treatment, designing competitive inhibitors for this attractive target was difficult. Nevertheless, computational investigations of the protein's dynamic behavior displayed the existence of temporary pockets that could be used to design allosteric inhibitors. The last decade witnessed intensive efforts to discover KRAS inhibitors. In 2021, the first KRAS G12C covalent inhibitor, AMG 510, received FDA (Food and drug administration) approval as an anticancer medication that paved the path for future treatment strategies against this target. Computer-aided drug designing discovery has long been used in drug development research targeting different KRAS mutants. In this review, the major breakthroughs in computational methods adapted to discover novel compounds for different mutations have been discussed. Undoubtedly, virtual screening and molecular dynamic (MD) simulation and molecular docking are the most considered approach, producing hits that can be employed in subsequent refinements. After comprehensive analysis, Afatinib and Quercetin were computationally identified as hits in different publications. Several authors conducted covalent docking studies with acryl amide warheads groups containing inhibitors. Future studies are needed to demonstrate their true potential. In-depth studies focusing on various allosteric pockets demonstrate that the switch I/II pocket is a suitable site for drug designing. In addition, machine learning and deep learning based approaches provide new insights for developing anti-KRAS drugs. We believe that this review provides extensive information to researchers globally and encourages further development in this particular area of research.

01 Jul 2025·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Synthetic approaches and clinical application of KRAS inhibitors for cancer therapy

Review

Author: Chen, Kuanbing ; Ma, Shaowei ; Jiang, Min ; Xuan, Ying

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are among the most common oncogenic alterations in various cancers, including pancreatic, colorectal, and non-small cell lung cancer (NSCLC). Targeting KRAS has long been considered a difficult challenge due to its high affinity for guanosine triphosphate (GTP) and the lack of a druggable binding site. However, recent advancements in small-molecule inhibitor design have led to the development of targeted therapies aimed at KRAS mutations, particularly the KRAS^G12C mutation. Inhibitors such as Sotorasib and Adagrasib have shown promise in preclinical and clinical studies by irreversibly binding to the mutant KRAS protein, locking it in an inactive state and disrupting downstream signaling pathways critical for tumor growth and survival. These inhibitors have demonstrated clinical efficacy in treating patients with KRAS^G12C-mutated cancers, leading to tumor regression, prolonged progression-free survival, and improved patient outcomes. This review discusses the synthetic strategies employed to develop these KRAS inhibitor and also examines the clinical application of these inhibitors, highlighting the challenges and successes encountered during clinical trials. Ultimately, KRAS inhibitors represent a breakthrough in cancer therapy, offering a promising new treatment option for patients with KRAS-driven tumors.

01 Jul 2025·CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY

KRAS G12C inhibitors as monotherapy or in combination for metastatic colorectal cancer: A proportion and comparative meta-analysis of efficacy and toxicity from phase I-II-III trials

Review

Author: Öksüz, Nejat Emre ; Akkus, Erman ; Erul, Enes

BACKGROUND:

1-2 % of metastatic colorectal cancers (mCRC) harbor an activating KRAS-G12C mutation. This study aims to pool the results of available clinical trials of KRAS-G12C inhibitors, comparing monotherapy and combinations.

METHODS:

A systematic literature search was conducted in the MEDLINE database and ESMO/ASCO meeting abstracts. Phase I-II-III trials that investigated a KRAS-G12C inhibitor in patients with mCRC were included. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Pooled proportions and comparative subgroup analyses for monotherapy and combinations were presented with the random effects model.

RESULTS:

596 patients with previously treated mCRC in 14 study cohorts treated with one of sotorasib, adagrasib, divarasib, or olomorasib as monotherapy or in combination with cetuximab/panitumumab were included. Combination treatment revealed an ORR of 33.9 % (95 %CI: 20.7-48.4) (I²: 87.1), which is significantly higher than monotherapy [16.7 %, (95 %CI: 8.3-27.3) (I²: 73.2)] (p = 0.045). Median PFS was significantly longer with the combination [5.7 months (95 %CI: 4.4-7.1) (I²: 80.8) vs. 4.2 months (95 %CI: 3.6-4.7) (I²:0.0), p = 0.027]. Grade 3-4 treatment-related adverse events (TRAEs) were significantly more frequent with the combination [32.8 % (95 %CI: 26.4-39.6) (I²:42.5) vs.16.5 % (95 %CI: 4.9-33.1) (I²: 84.2), p = 0.047]. Common adverse events specific to the combinations were skin toxicities, paronychia, and hypomagnesemia.

CONCLUSION:

This analysis suggests that KRAS-G12C inhibitors in combination with anti-EGFR agents may provide a doubled ORR and 1.5-month PFS benefit compared to monotherapy in previously treated mCRC patients, but with a doubled grade 3-4 TRAEs, including skin toxicities, paronychia, and hypomagnesemia. Treatment preferences should be individualized in these highly pretreated patients.

435

News (Medical) associated with Sotorasib

09 May 2025

·pipelinereview.com

FDA Approves the AVMAPKI™ FAKZYNJA™ Combination Therapy as the First-Ever Treatment for Adult Patients with KRAS-mutated Recurrent Low-Grade Serous Ovarian Cancer

AVMAPKI plus FAKZYNJA to be commercially available by prescription as a convenient oral combination co-packaged together and will be known as “AVMAPKI FAKZYNJA CO-PACK” Accelerated approval, well ahead of the June 30, 2025 PDUFA action date, was based on the Phase 2 RAMP 201 study that demonstrated a 44% overall response rate in patients with KRAS mutant recurrent LGSOC Verastem to host investor conference call and webcast today at 2:30 pm ET BOSTON, MA, USA I May 08, 2025 I Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for patients with RAS/MAPK pathway-driven cancers, today announced that the U.S. Food and Drug Administration (FDA) has approved AVMAPKI™ FAKZYNJA™ CO-PACK (avutometinib capsules; defactinib tablets) for the treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who received prior systemic therapy. AVMAPKI FAKZYNJA CO-PACKis the first and only FDA-approved medicine for this disease. This indication is approved under accelerated approval based on the tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. AVMAPKI plus FAKZYNJA is only commercially available in the U.S. as an oral combination co-pack with the two prescription products, known as “AVMAPKI FAKZYNJA CO-PACK.” “Today’s approval of AVMAPKI FAKZYNJA CO-PACK for patients with KRAS-mutated recurrent low-grade serous ovarian cancer represents not only the first-ever FDA-approved treatment specifically for this rare cancer but also a new day for people living with this disease who have been in desperate need of new treatment options,” said Dan Paterson, president and chief executive officer of Verastem Oncology. “We are very proud to bring two innovative medicines in one combination treatment to the LGSOC community. We thank the researchers, patients, and their families participating in our clinical trials, the patient advocacy community, the FDA, and everyone at Verastem for their dedication and commitment to helping us bring AVMAPKI FAKZYNJA CO-PACK to patients in the U.S.” The accelerated approval of AVMAPKI FAKZYNJA CO-PACKis based on the Phase 2 RAMP 201 clinical trial, which evaluated the combination of AVMAPKI and FAKZYNJA in adult patients with measurable KRAS-mutated recurrent LGSOC. “Low-grade serous ovarian cancer is a rare and highly recurrent cancer with limited effective treatment options. This first-ever FDA approval in this disease was based on the primary analysis of the Phase 2 RAMP 201 trial, in which the combination of avutometinib and defactinib resulted in a significant overall response rate for patients with a KRAS mutation while being generally well tolerated,” said Rachel Grisham, M.D., Section Head, Ovarian Cancer at Memorial Sloan Kettering Cancer Center in New York, NY and Global Lead Principal Investigator of GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301. “The approval of avutometinib plus defactinib brings a much-needed therapeutic option to patients and establishes this combination as the new standard of care for women with recurrent low-grade serous ovarian cancer harboring a KRAS mutation. I look forward to progressing the confirmatory Phase 3 trial, RAMP 301, where we look to continue to support the ongoing body of research of this combination in women with and without a KRAS mutation.” “To see our early research in both the FRAME and RAMP 201 trial in recurrent low-grade serous ovarian cancer advance the combination of avutometinib and defactinib to now be the first-ever FDA-approved therapy for this disease is what gives us real hope when treating patients with rare or difficult-to-treat gynecological cancers,” said Professor Susana Banerjee, M.B.B.S., M.A., Ph.D., F.R.C.P, Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust and Team Leader in Women’s Cancers at The Institute of Cancer Research, London and Global Lead Principal Investigator of ENGOTov60/GOG3052 /NCRI/RAMP201. “With this approval, we thank all of the patients and researchers who participated in this trial, and the low-grade serous ovarian cancer community for their contributions to help bring the first FDA-approved treatment for KRAS-mutated recurrent LSGOC and changing the treatment possibilities for RAS/MAPK-pathway-driven cancers. We now need to build on this milestone to bring this new treatment to patients around the world.” Prior to this approval, there were no FDA-approved treatments specifically for KRAS-mutated recurrent LGSOC, a rare and distinct ovarian cancer that differs from high-grade serous ovarian cancer in both its biology and how it responds to treatment. “One of the most devastating aspects of my LGSOC diagnosis was learning there are no FDA-approved treatments for this rare cancer. While there were some treatment options at the time that I could try, I made it my mission to advocate for research specific to my disease,” said Nicole Andrews, chair of the STAAR Low-Grade Serous Ovarian Cancer Foundation. “Today we’re celebrating a milestone with the first-ever FDA-approved treatment option specifically for patients with recurrent LGSOC with a KRAS mutation. The low-grade serous ovarian cancer community is hopeful and excited about the potential benefits of this treatment and the progress toward improving the diagnosis, awareness, and research for LGSOC.” AVMAPKI FAKZYNJA CO-PACK is the first treatment to receive regulatory approval anywhere in the world, specifically for KRAS-mutated recurrent LGSOC. The Company believes AVMAPKI FAKZYNJA CO-PACK is also the first-ever oral, novel/novel combination therapy approved in oncology. Verastem initiated a rolling new drug application (NDA) with the FDA in May 2024 and completed its NDA submission in October 2024. The FDA granted Priority Review, and the approval was received in advance of its Prescription Drug User Fee Act (PDUFA) action date of June 30, 2025. The FDA granted Breakthrough Therapy Designation for the treatment of patients with recurrent LGSOC after one or more prior lines of therapy, including platinum-based chemotherapy, in May 2021. Avutometinib alone or in combination with defactinib was also granted Orphan Drug Designation by the FDA for the treatment of LGSOC. The AVMAPKI FAKZYNJA CO-PACK is expected to be available for adult patients with KRAS-mutated recurrent LGSOC in the U.S. in one week. Verastem’s Commitment to Patient Support Verastem Oncology is committed to providing patient access and reimbursement support through its Verastem Cares™ program in the U.S. Verastem Cares™ offers a range of patient access and reimbursement support services to help U.S. patients prescribed AVMAPKI FAKZYNJA CO-PACK receive treatment access. Verastem Cares™ case managers can be reached at 1-866-351-8372 between 8:00 am-8:00 pm Eastern Time, Monday through Friday. Verastem to Host Investor Call on AVMAPKI FAKZYNJA CO-PACK FDA Approval Verastem will hold an investor conference call and webcast today at 2:30 pm ET, to discuss the FDA approval of AVMAPKI FAKZYNJA CO-PACK. To access the conference call, please dial (844) 763-8274 (local) or (412) 717-9224 (international) at least 10 minutes prior to the start time and ask to be joined into the Verastem Oncology conference call. A live audio webcast of the call, along with accompanying slides, will be accessible under “Events & Presentations” in the Investors & Media section of the Company’s website at www.verastem.com . Basis of Approval: RAMP 201 Trial Results The efficacy of AVMAPKI and FAKZYNJA, in combination, was evaluated in the RAMP 201 clinical trial (NCT04625270), an open-label, multicenter study that included 57 adult patients with measurable KRAS -mutated recurrent LGSOC. Patients were required to have received at least one prior systemic therapy, including a platinum-based drug. Patients received AVMAPKI 3.2 mg orally twice weekly for the first three weeks out of a four-week cycle and FAKZYNJA 200 mg orally twice daily for the first three weeks out of a four-week cycle until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate (ORR) assessed by blinded independent review committee (BIRC) according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. An additional efficacy outcome measure was duration of response (DOR). Tumor response assessments occurred every eight weeks for the first 72 weeks and every 12 weeks thereafter. In the study, AVMAPKI and FAKZYNJA, in combination, showed in patients with a KRAS mutation a confirmed ORR by BICR of 44% (25/57; 95% CI: 31-58). The median DOR ranged from 3.3 to 31.1 months in the KRAS mutant population. The safety of AVMAPKI and FAKZYNJA, in combination, was evaluated in 57 patients with KRAS- mutated recurrent LGSOC. Possible serious side effects with AVMAPKI FAKZYNJA CO-PACK include ocular disorders, skin toxicities (rash), hepatotoxicity, rhabdomyolysis, and fetal harm when administered during pregnancy. The most common side effects, including laboratory changes, of AVMAPKI FAKZYNJA CO-PACK include increased levels of an enzyme in the blood (CPK), nausea, fatigue, abnormal liver test (AST), and rash. About Low-Grade Serous Ovarian Cancer (LGSOC) LGSOC is a rare ovarian cancer that is insidious and persistent. LGSOC is distinct and different from high-grade serous ovarian cancer (HGSOC) and requires different treatment. LGSOC is highly recurrent and less sensitive to chemotherapy compared to HGSOC. Approximately 6,000-8,000 women in the U.S. and 80,000 worldwide are living with this disease. LGSOC affects younger women with bimodal peaks of diagnosis at ages between 20-30 and 50-60 and has a median survival of approximately ten years. Approximately 70 percent of LGSOC shows RAS pathway-associated mutations, and 30 percent of people with LGSOC have a KRAS mutation. The majority of patients report a negative impact of LGSOC on their mental and physical health, fertility, and long-term quality of life. The current standard of care for LGSOC includes hormone therapy and chemotherapy. About AVMAPKI and FAKZYNJA Combination Therapy AVMAPKI (avutometinib) inhibits MEK kinase activity while also blocking the compensatory reactivation of MEK by upstream RAF. RAF and MEK proteins are regulators of the RAS/RAF/MEK/ERK (MAPK) pathway. Blocking RAF and/or MEK activates FAK, a key mediator of drug resistance. FAKZYNJA (defactinib) is a FAK inhibitor and together, the avutometinib and defactinib combination was designed to provide a more complete blockade of the signaling that drives the growth and drug resistance of RAS/MAPK pathway-dependent tumors. Additional clinical investigations: Verastem Oncology is conducting clinical trials with avutometinib with and without defactinib in RAS/MAPK-driven tumors as part of its Raf And Mek Program or RAMP. RAMP 301 (GOG-3097/ENGOT-ov81/GTG-UK) (NCT06072781), is an international Phase 3 confirmatory trial evaluating the combination of avutometinib and defactinib versus standard chemotherapy or hormonal therapy for the treatment of recurrent low-grade serous ovarian cancer (LGSOC) with and without a KRAS mutation. RAMP 203 (NCT05074810) is a Phase 1/2, multicenter, open-label, dose evaluation/expansion study, being conducted in collaboration with Amgen, evaluating the efficacy and safety of avutometinib and sotorasib with or without defactinib in patients with KRAS G12C mutant non-small cell lung cancer (NSCLC) who have not been previously treated with a KRAS G12C inhibitor as well as in patients who have been previously treated with a KRAS G12C inhibitor (NCT05074810). RAMP 205 (NCT05669482), a Phase 1b/2 clinical trial evaluating avutometinib and defactinib with gemcitabine/nab-paclitaxel in patients with front-line metastatic pancreatic cancer, is supported by the PanCAN Therapeutic Accelerator Award. Avutometinib and defactinib are not approved by the FDA or any other regulatory authority, either in combination or with other therapies, for any of these investigative uses. Neither avutometinib nor defactinib are approved by the FDA or any other regulatory authority on a stand-alone basis for any use. Additional media assets are available on Verastem Oncology’s website . AVMAPKI FAKZYNJA CO-PACK U.S. Indication Indication AVMAPKI FAKZYNJA CO-PACK is indicated for the treatment of adult patients with KRAS -mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy. This indication is approved under accelerated approval based on tumor response rate and duration of response . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Click here for full Prescribing Information . About Verastem Oncology Verastem Oncology (Nasdaq: VSTM) is a biopharmaceutical company committed to developing and commercializing new medicines to improve the lives of patients diagnosed with RAS/MAPK pathway-driven cancers. Verastem markets AVMAPKI™ FAKZYNJA™ CO-PACK in the U.S. Our pipeline is focused on novel small molecule drugs that inhibit critical signaling pathways in cancer that promote cancer cell survival and tumor growth, including RAF/MEK inhibition, FAK inhibition, and KRAS G12D inhibition. For more information, please visit www.verastem.com and follow us on LinkedIn . SOURCE: Verastem Oncology

Clinical ResultDrug ApprovalPhase 3Phase 2Breakthrough Therapy

09 May 2025

·firstwordpharma.com

Revolution ramps up KRAS attack with more promising lung cancer data

Revolution Medicines is stepping up its challenge to existing KRAS-blocking cancer drugs with a fresh wave of clinical data, as it looks to shake up treatment options for lung cancer patients. The biotech this week teased some early results aimed at KRAS-driven non–small-cell lung cancer (NSCLC), including monotherapy and combination approaches.The biotech's data presentation at the American Association for Cancer Research (AACR) meeting last month centred on zoldonrasib (RMC-9805) in KRAS G12D NSCLC (see – Spotlight On: Revolution coming for KRAS G12D). It has now unveiled encouraging results for two other investigational therapies in its RAS(ON) inhibitor portfolio for G12C-mutant NSCLC.Elironrasib monotherapyOne standout is elironrasib (RMC-6291), a G12C-selective covalent inhibitor. In 36 patients with previously treated NSCLC, monotherapy with elironrasib showed a 56% objective response rate (ORR) and disease control (DCR) in 94% of cases at the 200-mg twice-daily dose. The compound also showed an estimated median progression-free survival (PFS) of 9.9 months in these patients.The results stack up favourably against KRAS inhibitors already on the market. Amgen's Lumakras (sotorasib) achieved a 36% ORR in the CodeBreaK 100 trial, while Bristol Myers Squibb's Krazati (adagrasib) reported a 43% ORR in the KRYSTAL-1 study.Side effects with elironrasib appeared manageable with predominantly low-grade treatment-related adverse events (TRAEs). The company said 19% of patients experienced Grade 3 reactions, although there were no life-threatening events tied to the drug.Combo approachesRevolution also shared data from various combination approaches in lung cancer, including elironrasib with Merck & Co.'s Keytruda (pembrolizumab), which led to response and disease control rates of 100% in a group of five first-line NSCLC patients with tumour proportion scores (TPS) ≥50%. The duo had an "acceptable" tolerability profile with Grade 3 or higher TRAEs reported in a quarter of patients.Meanwhile, a doublet pairing Keytruda with daraxonrasib (RMC-6236), the company's RAS(ON) multi-selective inhibitor, delivered an 86% ORR and 100% DCR in seven first-line patients with TPS expression ≥50% — a population where Keytruda is the preferred standard of care. When chemotherapy was added for 10 patients with TPS <50% — a setting where Keytruda plus chemotherapy is the preferred standard — the ORR was 60% and DCR held strong at 90%.Revolution also tested its own drugs together — elironrasib and daraxonrasib — in 33 patients previously treated with a KRAS G12C(OFF) inhibitor. That pairing produced a 62% response rate and DCR of 92%. Grade 3 TRAEs were reported in nearly half of patients, but there were no Grade 4 or 5 toxicities. Revolution said the combination avoided two key concerns: hepatotoxicity was not detected as a safety signal, while QT prolongation — an irregular heart rhythm — was "limited" to one patient who experienced an asymptomatic Grade 3 event.Triplet on the horizonNext up, the company is eyeing a triplet regimen combining elironrasib, daraxonrasib and Keytruda as a "chemotherapy-sparing" option for newly diagnosed metastatic RAS G12C NSCLC patients, though no efficacy data for this approach has been shared yet.During an investor call, Chief Medical Officer Wei Lin addressed questions about the tolerability of this triple. "We're optimistic given the profile we've seen so far. Obviously, we're still in the dose optimisation and have not yet defined the final dose for the triplet combination... we're not seeing any new safety signaling emerging."The company said it continues building its commercial capabilities in the US in anticipation of potential product launches, recently appointing Anthony Mancini as chief global commercialisation officer.Meanwhile, the company is also pushing into late-stage testing. Two pivotal Phase III studies of daraxonrasib are underway — one in previously treated pancreatic ductal adenocarcinoma (RASolute 302, with results expected in 2026) and another in NSCLC (RASolve 301).

Clinical ResultPhase 3AACRPhase 1Executive Change

06 May 2025

·endpts.com

Exclusive: Degradation startup raises $39M for pivot to PROTACs and clinical entry

PAQ Therapeutics has taken a new direction. The startup shifted its protein degradation approach to the more common PROTAC lane, pivoted to cancer, hired a chief medical officer from Frontier Medicines, and secured $39 million in Series B funding, the startup exclusively told Endpoints News . The Burlington, MA-based drug developer emerged in 2021 with $30 million and a focus on autophagosome-tethering compounds, or ATTECs. The goal was to adopt the body’s “most versatile mechanism” to initiate degradation, CEO Nan Ji said at the time of the Series A . But a few years ago, PAQ adjusted course and made a “pretty significant change in trajectory of the science we do,” Ji told Endpoints. When it was working on the autophagy approach — with small molecules concentrated on genetic neurodegenerative disorders like Huntington’s disease — PAQ came to the fork in the road that every biotech faces: target selection. “We were looking for disease or cell types with autophagy upregulation, hoping that an autophagy-based molecule can work better in those settings,” Ji said. “One of the few diseases that we were able to identify with solid data was PDAC, the major form of pancreatic cancer. It’s been reported that 80% to 90% of PDAC patients have KRAS mutations.” PAQ’s team dug further into KRAS. And instead of pursuing the relatively new ATTEC approach, the company opted to go with the more mature PROTAC route, an area of clinical development that’s been championed by companies like Arvinas . PAQ made the switch to KRAS-driven cancers in 2023, putting the ATTEC work on hold, and moving forward supported by its Series A. For the Series B, PAQ attracted Merck and Johnson & Johnson’s corporate venture arms, plus Bayland Capital, LAV Fund, BioTrack Capital and existing backer Sherpa Healthcare Partners. The company also recently hired Andrew Krivoshik as chief medical officer. He joined from the same position at Frontier Medicines, another KRAS-focused biotech. Prior to that, he was head of development at Astellas, where he worked on treatments like the antibody-drug conjugate Padcev. He’s now responsible for shepherding one of the company’s KRAS degraders through clinical trials. The biotech earlier this year entered Phase 1 testing for PT0253, a KRAS G12D degrader that is injected via IV once a week. PAQ plans to submit an IND for a second KRAS program by the end of the year, Ji said. It has nine employees. “Even though KRAS has been a clinically validated target for a while, and there are a couple of approved therapies in the KRAS G12C space, this field still needs a lot of treatment for patients, especially outside of G12C,” he added. Amgen got the first KRAS approval with Lumakras in 2021. Mirati Therapeutics, now owned by Bristol Myers Squibb, was next, with the first FDA nod for Krazati the following year. While many companies in the KRAS field are developing inhibitors, Ji and Krivoshik believe a degradation approach could yield greater benefits. Arvinas is also in the preclinical stages of developing pan-KRAS mutant and mutant-specific KRAS degraders. “It comes down to finding the best target to mesh the technology,” Ji said, “and we believe KRAS is one of the best targets, at least in our mind.”

Drug ApprovalPhase 1PROTACs

100 Deals associated with Sotorasib

External Link

KEGG	Wiki	ATC	Drug Bank
-	Sotorasib	L01XE	DB15569

R&D Status

Approved

10 top approved records.

to view more data

Indication	Country/Location	Organization	Date
KRAS G12C mutant Colorectal Cancer	United States	Amgen, Inc.	16 Jan 2025
KRAS G12C mutant Non-small Cell Lung Cancer	United States	Amgen, Inc.	28 May 2021

Developing

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Non-Small Cell Lung Cancer	Phase 3	United States	Amgen, Inc.	16 Nov 2023
Non-Small Cell Lung Cancer	Phase 3	China	Amgen, Inc.	16 Nov 2023
Non-Small Cell Lung Cancer	Phase 3	Japan	Amgen, Inc.	16 Nov 2023
Non-Small Cell Lung Cancer	Phase 3	Argentina	Amgen, Inc.	16 Nov 2023
Non-Small Cell Lung Cancer	Phase 3	Australia	Amgen, Inc.	16 Nov 2023
Non-Small Cell Lung Cancer	Phase 3	Austria	Amgen, Inc.	16 Nov 2023
Non-Small Cell Lung Cancer	Phase 3	Belgium	Amgen, Inc.	16 Nov 2023
Non-Small Cell Lung Cancer	Phase 3	Brazil	Amgen, Inc.	16 Nov 2023
Non-Small Cell Lung Cancer	Phase 3	Bulgaria	Amgen, Inc.	16 Nov 2023
Non-Small Cell Lung Cancer	Phase 3	Canada	Amgen, Inc.	16 Nov 2023

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05198934 (CodeBreaK 300 \| CodeBreak300, NEWS \| Pubmed) Manual	Phase 3	KRAS G12C mutant Colorectal Cancer KRAS G12C	160	960 mg索托拉西布联合帕尼单抗	qldxkvibvw(myenuozqde) = zixfiflzvm jytxpzbiop (uvuzdmowja ) View more	Positive	07 May 2025
				240 mg索托拉西布联合帕尼单抗	qldxkvibvw(myenuozqde) = mlbtooicpw jytxpzbiop (uvuzdmowja ) View more
AACR2025	Not Applicable	KRAS G12C	-	Nanosuspension with sotorasib	tvvarmvgop(oycwdwluvh) = sronnfvany ddprvzesaq (szwstakgsl, 1346.66) View more	-	28 Apr 2025
NCT05198934 (CodeBreaK 300, FDA_CDER) Manual	Phase 3	KRAS G12C mutant Colorectal Cancer KRAS G12C	107	LUMAKRAS 960 mg + Panitumumab	quatzhtzri(uikamplijs) = rchegoneec hdbakchzdv (uyvudvhvqy, 4.2 - 6.3) View more	Positive	16 Jan 2025
				SOC (trifluridine/tipiracil or regorafenib)regorafenib)	quatzhtzri(uikamplijs) = ngadyikrxe hdbakchzdv (uyvudvhvqy, 1.9 - 3.9) View more
NCT05074810 (RAMP 203, BusinessWire) Manual	Phase 1/2	KRAS G12C mutant Non-small Cell Lung Cancer KRAS G12C	3	Defactinib，Avutometinib, sotorasib	nifbafqzna(qvntfpkfpc) = None lcntfqlbjv (xisbmvwnsx ) View more	Positive	18 Dec 2024
NCT04185883 (CodeBreaK 101, ESMO2024) Manual	Phase 1	KRAS G12C mutant Colorectal Cancer First line KRAS G12C–mutated	40	Sotorasib (soto) + Panitumumab (pani) + FOLFIRI	gdbshdnrrl(wgpakvwtwq) = jdtobqmbzv pdttohefnk (qizlmlnnfd ) View more	Positive	15 Sep 2024
ESMO2024 Manual	Not Applicable	Non-Small Cell Lung Cancer	125	Sotorasib	dypmincnrs(ujqjfsphuy) = gofdsvvpay vyaopqzeeu (wgcbtvzzpk ) View more	Positive	14 Sep 2024
				Sotorasib (CodeBreak 100)	dypmincnrs(ujqjfsphuy) = laexcfuafn vyaopqzeeu (wgcbtvzzpk ) View more
NCT04380753 \| NCT04303780 \| NCT04185883 \| NCT03600883 (CodeBreaK 100, ESMO2024) Manual	Not Applicable	KRAS G12C mutant Non-small Cell Lung Cancer KRAS G12C	549	Sotorasib 960 mg once daily	fsuhlsyonz(fewmjmhocu) = iktkjaosnx lgdgauzddj (rmizbihixk ) View more	Positive	14 Sep 2024
WCLC2024 Manual	Not Applicable	KRAS G12C mutant Non-small Cell Lung Cancer KRAS G12C	150	Sotorasib 960 mg once daily	cqfjvfwlaj(udqxyurxmv) = pdzvnrdbbl edgparkmau (skxfkvtmjq, 5.0 - 7.3) View more	Positive	09 Sep 2024
				Sotorasib 960 mg once daily (with CNS metastases)	khevdjcvme(fafpeewiwu) = ttksfzromq kptfgxmuue (ghftnmpeue, 7.2 - 12.7) View more
WCLC2024 \| Pubmed Manual	Not Applicable	KRAS G12C mutant Non-small Cell Lung Cancer Second line KRAS G12c-Mutated	383	Sotorasib	rrdvpsslia(mtpxhcwste) = yxsesvcwuh miwssixtjc (pzsyttxlkm, 7.6 - 16.3) View more	Positive	09 Sep 2024
				Docetaxel	rrdvpsslia(mtpxhcwste) = bwnlgwfzah miwssixtjc (pzsyttxlkm, 4.2 - 11.0) View more
WCLC2024	Phase 3	metastatic non-small cell lung cancer KRAS G12C+	-	Divarasib	tehrutgxqb(lsxkhwkxmc) = hvghwaeuae vcxokldivg (jmfjvcufem, 39.6 - 72.2) View more	-	09 Sep 2024

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