Kathryn C. Arbour, MD, is a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center in New York. 

Preliminary Safety and Antitumor Activity of Zoldonrasib (RMC-9805), an Oral, RAS(ON) G12D-Selective, Tri-Complex Inhibitor in Patients with KRAS G12D NonSmall Cell Lung Cancer (NSCLC) from a Phase 1 Study in Advanced Solid Tumors

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Dr. Kathryn C. Arbour presents preliminary findings from a Phase 1 study showing that zoldonrasib, a selective RAS(ON) G12D inhibitor, demonstrates encouraging antitumor activity and a manageable safety profile in patients with previously treated KRAS G12D–mutant non–small cell lung cancer.

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, 

 covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, supported by Revolution Medicines, we spoke with Kathryn C. Arbour, MD, a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, about 2 important abstracts presented at the 2024 AACR Annual Meeting that explore novel RAS-targeted approaches in non–small cell lung cancer (NSCLC).

Our discussion focused on early clinical findings with zoldonrasib (RMC-9805) and daraxonrasib (RMC-6236), both of which are RAS(ON) inhibitors under investigation for the treatment of patients with 

-mutant NSCLC. Zoldonrasib, a KRAS G12D-selective tri-complex inhibitor, was evaluated in a phase 1 trial (NCT06040541) in patients with previously treated, advanced 

 G12D–mutated solid tumors, including NSCLC. Daraxonrasib, a multi-selective RAS(ON) inhibitor, was highlighted in another phase 1 trial (NCT05379985) in patients with advanced RAS-mutant tumors, including previously treated NSCLC; notably, this AACR presentation focused on the association between early on-treatment circulating tumor DNA level reduction and clinical response with the agent.

In this episode, Dr Arbour shared insights into the mechanisms of action behind these therapies, their respective clinical trial designs, and the potential implications that early data with the agents may have for the evolving 

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Dr Arbour discusses the mechanisms of action of zoldonrasib and daraxonrasib and shares early data with these agents in RAS-mutant NSCLC. 

Early-Phase RAS Inhibitor Research Sparks Interest in NSCLC: With Kathryn C. Arbour, MD

Kathryn C. Arbour, MD, highlights the safety and early efficacy of zoldonrasib in patients with non–small cell lung cancer harboring KRAS G12D mutations.

Dr Arbour on the Role of Zoldonrasib in KRAS G12D–Mutant NSCLC 

“Zoldonrasib was well tolerated across all dose levels, including in the subset of patients who were treated at the candidate recommended phase 2 dose of 1200 mg once daily.”

Kathryn C. Arbour, MD, a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, detailed the safety profile and preliminary efficacy of zoldonrasib (RMC-9805) for the treatment of patients with 

 G12D–mutated non–small cell lung cancer (NSCLC).

Within the safety population (n = 90), zoldonrasib was well tolerated across all dose levels, which included those treated with the recommended phase 2 dose of 1200 mg once daily, Arbour began. She noted that common treatment-related adverse effects (TRAEs) that occurred in at least 10% of patients comprised nausea (grade 1, 33%; grade 2, 6%; grade 3, 0%), diarrhea (20%; 3%; 1%), vomiting (13%; 4%; 0%), and rash (12%; 0%; 0%). Findings from the study also revealed that TRAEs were mostly grade 1 (54%), grade 2 (18%), or grade 3 (2%). TRAEs of interest regarding RAS inhibitors are commonly transaminitis and mucositis; however, these were considered rare within this patient population, she emphasized.

Notably, there were no grade 4/5 TRAEs or serious AEs observed. Additionally, any grade TRAES led to dose reduction in 4% of patients, dose interruptions in 9%, and and treatment discontinuations in 1%.

Of the 28 patients with NSCLC treated with the 1200-mg dose of zoldonrasib, 18 were treated at least 8 weeks before the data cutoff of December 2, 2024, Arbour explained. At the data cutoff, the objective response rate (ORR) was 61% per RECIST 1.1 criteria in the group, and the disease control rate (DCR) was 89%, which included complete responses, partial responses, and stable disease. Notably, the median time to response was 1.4 months (range, 1.2-2.8), and the median time on treatment was 2.6 months (range, 1.3-8.0).

The depth of response and disease control observed in the study highlight the potential role for zoldonrasib in this patient population, Arbour concluded.

Isabel Preeshagul, DO, MBS, and colleagues share updates from across the lung cancer space as discussed in a recent State of the Science Summit.

Lung Cancer State of the Science Summit Recap

 on Lung Cancer chaired by Isabel Preeshagul, DO, MBS, she and colleagues highlight key takeaways from their presentations, which covered updates from across the lung cancer treatment paradigm. Preeshagul is a thoracic medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center.

Preeshagul discusses the clinical implications of 

data from the phase 3 ADRIATIC trial (NCT03703297)

, which showed that patients with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following platinum-based concurrent chemoradiotherapy experienced a median overall survival of 55.9 months (95% CI, 37.3-not evaluable) when treated with durvalumab (Imfinzi; n = 264) compared with 33.4 months (95% CI, 25.5-39.9) when given placebo (n = 266; HR, 0.73; 95% CI, 0.57-0.93; 

 = .0104). Based on these data, In August 2024, 

 to the supplemental biologics license application seeking the approval of durvalumab for the treatment of patients with LS-SCLC whose disease has not progressed following platinum-based concurrent chemoradiotherapy.

Next, Alissa J. Cooper, MD, a thoracic medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center, highlights the evolving understanding of the role of antibody-drug conjugates in the treatment of patients with non–small cell lung cancer (NSCLC). Cooper expands on the challenges posed in the clinical study of these agents and how biomarkers could help refine the understanding of which patients may benefit most from these agents.

Kathryn C. Arbour, MD, a thoracic medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center, then delves into the current treatment paradigm for patients with NSCLC harboring 

 G12C mutations. She details the prevalence of 

 mutations in this patient population and how ongoing research could build upon the targeted therapies available for those with 

Interested in attending a future State of the Science Summit or Institutional Perspectives in Cancer meeting? 

Lung Cancer State of the Science Summit Recap | Chaired by: Isabel Preeshagul, DO, MBS

Dr Arbour on the Safety and Efficacy of RMC-6236 in KRAS-Mutant NSCLC

Kathryn C. Arbour, MD, assistant attending physician, Memorial Sloan Kettering Cancer Center, discusses preliminary safety and efficacy data with the RAS inhibitor RMC-6236 in patients with 

-mutated non–small cell lung cancer (NSCLC).

At the 2023 ESMO Congress, Arbour presented findings from the phase 1 RMC-6236-001 trial (NCT05379985) which evaluated treatment with RMC-6236 at 80 mg and above in patients with NSCLC and pancreatic ductal adenocarcinoma (PDAC) harboring 

 G12C mutations. Evaluating the safety profile of this agent in patients with NSCLC is important because the tolerability of pan-RAS inhibitors is unknown, Arbour says.

RMC-6236 was well tolerated at clinically active doses in patients with NSCLC, Arbour explains. The most common treatment-related adverse effects (TRAEs) reported in all safety-evaluable patients with NSCLC and PDAC treated with at least 80 mg of RMC-6236 per day (n = 111) were rash, nausea, diarrhea, vomiting, stomatitis, and fatigue, most of which were grade 1/2 and generally well managed with supportive medications such as topical steroids and oral antibiotics, Arbour notes. Importantly, only 14% of patients with NSCLC or PDAC required dose reduction because of TRAEs of any grade, and only 1 patient (1%) discontinued treatment due to TRAEs. The safety findings with RMC-6236 supplement the efficacy findings by showing that patients can maintain treatment with consistent doses of this agent, Arbour emphasizes.

Regarding the clinical activity of RMC-6236, of 40 patients with NSCLC who initiated treatment with RMC-6236 at 80 mg per day or more at least 8 weeks prior to data cutoff, 1 patient (3%) achieved a complete response, and 14 patients (35%) experienced a partial response, translating to an overall response rate of 38%. Furthermore, 48% of patients had a best overall response of stable disease, and the disease control rate was 85%. Twenty-eight patients remained on treatment at the data extract date.

The responses seen with RMC-6326 in patients with NSCLC are durable, and further follow-up data may show deepening of these responses over time, Arbour emphasizes. Moreover, the median time to response was 1.4 months (range, 1.2-2.7), indicating that this agent provided symptom relief for patients shortly after treatment initiation, Arbour concludes.

Dr Arbour reports consulting roles with Amgen, Novartis, G1 Therapeutics, AstraZeneca, and Sanofi-Genzyme; and institutional research funding from Genentech (local PI), Mirati Therapeutics (local PI), and Revolution Medicines (local PI).

Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.

Kathryn C. Arbour, MD, discusses preliminary safety and efficacy data with the RAS inhibitor RMC-6236 in patients with KRAS-mutated non–small cell lung cancer.

Kathryn C. Arbour, MD

Articles

Preliminary Safety and Antitumor Activity of Zoldonrasib (RMC-9805), an Oral, RAS(ON) G12D-Selective, Tri-Complex Inhibitor in Patients with KRAS G12D NonSmall Cell Lung Cancer (NSCLC) from a Phase 1 Study in Advanced Solid Tumors

Early-Phase RAS Inhibitor Research Sparks Interest in NSCLC: With Kathryn C. Arbour, MD

Dr Arbour on the Role of Zoldonrasib in KRAS G12D–Mutant NSCLC

Lung Cancer State of the Science Summit Recap | Chaired by: Isabel Preeshagul, DO, MBS

Dr Arbour on the Safety and Efficacy of RMC-6236 in KRAS-Mutant NSCLC