Verastem's VS-7375: The New Kid On The KRAS Block

Disclosure: The author holds a beneficial long position in Verastem, Inc. (NASDAQ: VSTM) and no position, long or short, in Revolution Medicines, Inc. (NASDAQ: RVMD) or GenFleet Therapeutics (Shanghai) Inc. (HKEX: 2595). This article is for informational and educational purposes only and is not financial advice. Although the author is a physician, this content is commentary on the underlying science and does not constitute medical advice, diagnosis, or treatment recommendation. The author receives no compensation for this article and has no business relationship with the companies mentioned. See the full Legal Information and Disclosures section below.

In April I simulated four non-covalent KRAS G12D inhibitors. My computational model suggested that Verastem's oral KRAS G12D (ON/OFF) inhibitor VS-7375 may reach the deepest signaling suppression of the group. In July I discussed the first efficacy update from Verastem's TARGET-D 101 trial in previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC), a reported CA19-9 reduction of more than 50% in 13 of 14 patients at 900 mg. Follow-up was then still too short for an objective response rate (ORR). As in both earlier articles, I focus on PDAC in what follows, because it falls within my own clinical field and I do research on it myself. Verastem's update also reported results in colorectal and non-small cell lung cancer.

On October 14 Verastem reported an update on 22 patients with previously treated mPDAC who received 900 mg of VS-7375 once daily as monotherapy. With a median follow-up of 6.4 months, nine of the 22 had a confirmed response (41%), four of eight in the second line and five of 14 in the third or fourth line. Two patients reached a complete response, one of them confirmed, meaning that a second scan at least four weeks after the first showed the response again, as RECIST 1.1 requires. Sixteen of the 22 patients stay on treatment. The six-month progression-free survival (PFS) rate was 67% and the six-month overall survival (OS) rate 80%.

Verastem counted only confirmed responses, so the unconfirmed complete response is reported as a confirmed partial response. The 22 patients also include two who died or withdrew before their first scan. Excluding these two, the response rate would be nine of 20 (45%).

Verastem licensed VS-7375 in January 2025 from the Shanghai-based biotech GenFleet, which develops it in China as GFH375. At ESMO 2025 GenFleet reported a response rate of 40.7% (24 of 59) at 600 mg in previously treated advanced PDAC with confirmed and unconfirmed responses combined. The response rate reported in a Chinese trial has thus now been reproduced in a smaller US cohort with confirmed responses only, though at a higher dose.

Verastem reported a lower ORR at 600 mg than GenFleet, with four confirmed and four unconfirmed responses in 27 patients. Grade 3 or higher treatment-related adverse events were also less frequent, with 19% in Verastem’s 600 mg cohort, pooled across tumor types, vs. 32% of GenFleet’s 600 mg cohort. Both the lower ORR and the lower adverse event rate at 600 mg could be explained if US patients need a higher dose than Chinese patients to reach the drug exposure Verastem targets. Verastem reported that 900 mg reaches the company’s target plasma levels in most patients. It is not uncommon that different populations and ethnicities differ in pharmacokinetics. Verastem’s two cohorts together show a dose response in the US population, with a higher ORR and deeper tumor reductions at 900 mg than at 600 mg.

The reported 41% ORR at 900 mg VS-7375 needs some context. Trials in oncology usually report the ORR first because it needs only a few months of follow-up, so the ORR serves as an early proxy for PFS and OS, the results that really matter. The ORR only counts patients whose target lesions shrank by at least 30%. Depending on the cancer type, this is of limited predictive value for survival. So what can the ORR tell us about the survival benefit of KRAS inhibition in mPDAC?

The FDA approved Revolution Medicines’ multi-selective RAS(ON) inhibitor daraxonrasib for previously treated metastatic PDAC on August 26, based on the randomized phase 3 trial RASolute 302, whose topline results I discussed in April. The FDA’s multi-discipline review of the application breaks the trial results down by KRAS mutation. Since daraxonrasib is the first RAS inhibitor tested in a large randomized trial in pancreatic cancer, these are, as far as I know, the only randomized mutation-specific survival data of that size for a RAS inhibitor in this disease.

In the subgroup with KRAS G12V tumors, the ORR was 50% (47 of 94) on daraxonrasib vs. 15% (11 of 73) on standard-of-care (SOC) chemotherapy with a hazard ratio for OS of 0.32. For KRAS G12D, an ORR of 24% (23 of 95) vs. 9% (11 of 116) was reported, and the hazard ratio for OS was 0.49. In KRAS G12R, the ORR was 7% (2 of 27) vs. 14% (4 of 29), and the hazard ratio for OS was 0.61. Notably the ORR in the subgroup with KRAS G12R was lower than on SOC chemotherapy while patients on daraxonrasib nevertheless showed a trend toward longer survival.

Across the three mutations, a higher ORR to daraxonrasib thus went with a lower hazard ratio for death, meaning a larger survival benefit. For PFS, the hazard ratio was again highest in G12R, 0.80, while G12V and G12D lay close together at 0.54 and 0.48. However, the conclusions one could draw from this trend are limited, as different KRAS mutations differ in their biochemical behavior, with many complex molecular consequences. The subgroups are small and the FDA calls the analyses exploratory, so the pattern could still be chance. Even so, the G12D patients, with a response rate of 24%, saw their risk of death roughly halved in this analysis.

VS-7375's 41% confirmed response rate in KRAS G12D appears higher than daraxonrasib's 24% in the same mutation. This comparison, though, is cross-trial and rests on only 22 VS-7375 patients. If the relation between response rate and survival seen across daraxonrasib's G12 subgroups also holds for a non-covalent G12D-selective inhibitor like VS-7375, a higher ORR may translate into longer survival. Nevertheless, although both drugs inhibit KRAS, the mechanism of action is different: Daraxonrasib binds the active, GTP-bound form of mutant and wild-type RAS alike, while VS-7375 selectively binds KRAS G12D in both its active and its inactive form. The durability of VS-7375's responses is also not yet reported in a US population.

So far the only median OS reported for VS-7375 in PDAC comes from the phase 1 part of GenFleet’s trial, published in Nature Medicine in September, which gives a median OS of 9.9 months and a median PFS of 5.5 months in 43 PDAC patients treated at 400 to 900 mg daily. Of these 43 patients, 13 received 400 mg, 23 received 600 mg, one received 300 mg twice daily (600 mg per day), three received 750 mg and three received 900 mg, implying that about 30% (13 of 43) received 400 mg, a dose below the recommended phase 2 dose of 600 mg.

Notably, this was a heavily pretreated cohort, 74% with at least two prior lines, 72% with liver metastases and 44% with prior checkpoint inhibitor therapy. Most of them received 400 or 600 mg (86%, 37 of 43), well below Verastem's 900 mg. Their confirmed ORR was 35.1% (13 of 37 evaluable patients), with a median duration of response of 5.6 months. The ORR fell with each line of therapy, from 63% (5 of 8) in the second line to 31% (5 of 16) in the third and 23% (3 of 13) in the fourth or later, and median PFS fell from 6.9 to 5.5 to 4.1 months.

Median OS, by contrast, stayed between 9 and 10 months across lines, with at least nine months of follow-up for every patient at the January 2026 cutoff. Plasma exposure rose with dose only up to 600 mg in this trial, whereas Verastem reports higher exposure at 900 mg than at 600 mg in its US cohort, one more hint that the pharmacokinetics may differ between populations. Grade 3 or higher treatment-related adverse events occurred in 37% of all 74 patients. Grade 3 or higher liver toxicity was concentrated in patients with prior checkpoint inhibitor therapy, 16.7% vs. 3.1%. Hepatotoxicity after sequential checkpoint and KRAS inhibition is a known problem and has been described for sotorasib in NSCLC.

In RASolute 302, the six-month progression-free survival rate was 56% on daraxonrasib and 33% on SOC chemotherapy, and the six-month overall survival rate 78% and 55%. So VS-7375's 67% and 80% in 22 patients may be comparable or better, within the limits of a cross-trial comparison in which a single additional progression or death can shift the PFS or OS rate by several points.

However, fourteen of the 22 patients on VS-7375 were in their third or fourth line of treatment, while all RASolute 302 patients were in the second line. Later lines usually do worse, as daraxonrasib's own phase 1 data and the GFH375 phase 1 data above show, so VS-7375's cohort enters this comparison at a disadvantage. Its six-month rates may therefore understate what VS-7375 would achieve in second-line patients alone. However, the RASolute 302 six-month PFS and OS rates cover all randomized patients regardless of RAS mutation status, as the FDA review provides no six-month rates for KRAS G12D alone. So these 6-month figures are not strictly comparable.

Revolution Medicines develops its own KRAS G12D inhibitor, the G12D-selective RAS(ON) inhibitor zoldonrasib. As monotherapy at 1200 mg daily it reached an ORR of 30% (12 of 40, confirmed or pending confirmation) in previously treated PDAC. Across the whole study, patients had received a median of two prior therapies. Combined with daraxonrasib, it reached an ORR of 50% in 30 second-line patients and 47% in 30 patients in later lines, with six-month PFS rates of 71% and 59% and six-month OS rates of 89% and 82%.

VS-7375's 41% confirmed response rate as monotherapy therefore appears higher than zoldonrasib's as monotherapy and close to that of the doublet. The VS-7375 cohort is small and its follow-up short, so these cross-trial comparisons may shift as the data mature. In the first line, zoldonrasib plus chemotherapy reached an ORR of 82% with mFOLFIRINOX and 61% with gemcitabine and nab-paclitaxel, a high mark for the arm of TARGET-D 301 that combines VS-7375 with gemcitabine and nab-paclitaxel.

Both TARGET-D 101 and the registrational phase 2 trial TARGET-D 201 are uncontrolled. TARGET-D 201 randomizes second-line patients between two VS-7375 arms, 900 mg monotherapy and 900 mg plus an anti-EGFR antibody, with up to 80 patients per cohort and confirmed response rate by blinded central review as the primary endpoint. Verastem expects the initial readout in the second quarter of 2027. The phase 3 trial TARGET-D 301 in first-line metastatic PDAC, which Verastem plans to open by year-end, randomizes patients between VS-7375 plus an anti-EGFR antibody, VS-7375 plus gemcitabine and nab-paclitaxel, and SOC chemotherapy alone, with PFS and response rate as dual primary endpoints and OS as secondary. It will be Verastem’s first controlled VS-7375 trial that compares survival against SOC chemotherapy. As far as I know, a combination of VS-7375 with mFOLFIRINOX or NALIRIFOX is not planned.

I am looking forward to more mature survival data from TARGET-D 101, which would give a first glimpse of how durable the responses to VS-7375 at 900 mg are. The first read of TARGET-D 201 will tell whether the response rate holds up in a larger cohort of second-line patients and whether an anti-EGFR antibody adds to it. TARGET-D 301 will then measure survival with VS-7375 plus an anti-EGFR antibody and VS-7375 plus gemcitabine and nab-paclitaxel against SOC chemotherapy alone. Daraxonrasib is far ahead, approved by the FDA in August as the first RAS inhibitor in pancreatic cancer. But there is a new kid on the KRAS block, at least for KRAS G12D-driven tumors.

Follow me on X for frequent updates (@chaotropy).

Legal Information and Disclosures

General Disclaimer & No Financial Advice: The author is not a registered investment advisor or financial analyst, and nothing here is financial, legal, tax, or investment advice, a personal recommendation, or an offer, solicitation, or recommendation regarding any security. This is not a securities research report. It has not been peer-reviewed or audited, represents the author's opinion as of the publication date, and may change without notice. Readers should conduct their own due diligence and consult a licensed financial professional before making any investment decision. Readers act on this content at their own risk, and to the fullest extent permitted by applicable law the author accepts no liability for any loss or damage arising from reliance on it.

Medical Disclaimer: The author is a physician, but this article discusses clinical trials and drug mechanisms as general scientific and educational commentary. It is not medical advice, diagnosis, or a treatment recommendation, and it establishes no physician-patient relationship. Readers should never disregard or delay professional medical advice because of anything written here, and should consult a qualified healthcare provider about any medical condition.

Accuracy and Third-Party Data: Data here come from company and institutional press releases and presentations, FDA documents, clinical trial registries, peer-reviewed journals, conference abstracts, and news reports, believed reliable but not guaranteed complete, current, or correct. The TARGET-D 101, GenFleet 600 mg and zoldonrasib figures come from company communications and conference presentations and have not been peer-reviewed. The daraxonrasib mutation subgroup figures come from exploratory analyses in the FDA's multi-discipline review rather than from prespecified endpoints, and the RASolute 302 six-month rates are read from the Kaplan-Meier figures in that review. All comparisons between these cohorts are cross-trial, the explanations offered for the differences between them are the author's hypotheses, and the inference from daraxonrasib's mutation subgroups to VS-7375 is the author's interpretation. Despite the author's efforts to verify the sources cited, this article may contain errors of fact or interpretation.

Disclosure of Interest: The author holds a beneficial long position in Verastem, Inc. (NASDAQ: VSTM), and holds no position, long or short, in Revolution Medicines, Inc. (NASDAQ: RVMD), GenFleet Therapeutics (Shanghai) Inc. (HKEX: 2595), or any other company mentioned. The author reserves the right to buy or sell securities of Verastem at any time without further notice. He received no compensation for this article, maintains no business relationship with any company mentioned, and has no access to non-public trial data, unblinded interim results, or internal company information. His position in Verastem creates a potential for confirmation bias in interpreting the data, which hedged language and citation of primary sources may reduce but not remove.

Forward-Looking Statements & Risk: Statements here about clinical results, regulatory outcomes, and trial timelines are expectations subject to significant risks and uncertainties, and actual results may differ materially. The VS-7375 data come from TARGET-D 101, an ongoing, non-randomized trial with few patients and short follow-up, and its response and six-month survival rates may change as the data mature. Biotechnology and pharmaceutical investing carries a high degree of risk, including total loss of principal, and past performance does not indicate future results.

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