Clinical Outcomes of a Large, Prospective Series of Gastric Electrical Stimulation Patients Using a Multidisciplinary Protocol.

BACKGROUND: Gastric electrical stimulation (GES) is an intervention used in the treatment of medically refractory gastroparesis. There are few large series demonstrating efficacy over a long-term follow-up period. This study reports clinical outcomes for patients from a single institution up to 5 years. STUDY DESIGN: A prospective database of patients undergoing GES implantation for gastroparesis was collected and reviewed. Patients were selected according to a multi-disciplinary institutional protocol. Baseline characteristics, including age, sex, smoking history, etiology of gastroparesis, and duration of gastroparesis symptoms, were collected. Symptomatic response was evaluated utilizing Gastroparesis Cardinal Symptom Index (GCSI) surveys pre-operatively and at subsequent follow-up visits. Other clinical outcome variables include medication use, hospitalizations due to gastroparesis, and overall satisfaction with symptom relief. Patient outcomes regarding reoperation and explantation were also recorded. RESULTS: 157 patients underwent GES at our institution since 2012. GCSI scores were collected in all patients at baseline, in 141 patients at 1 year follow-up, and in 110 patients at 5 years follow-up. Symptom severity in all 9 gastroparesis symptoms evaluated by the GCSI, as well as the total GCSI score, was reduced significantly at 1 year post-operatively, and these results were sustained at 5-year follow-up. Use of prokinetic and antiemetic medications was reduced during the follow-up period. Hospitalizations due to gastroparesis symptoms were also reduced. GES devices were explanted in 5 patients, 12 patients required generator exchanges, and 7 patients required reoperation due to displaced/eroded device leads during the study period. CONCLUSION: Gastric electrical stimulation is associated with sustained symptomatic relief, reduced reliance on medications, and reduced hospitalizations in gastroparesis patients selected utilizing our institutional protocol.

The impact of virtual interviews on the Fellowship Council application and main match process.

BACKGROUND: The COVID-19 pandemic led the Fellowship Council (FC) to transition rapidly from in-person to virtual interviews. We investigated the impact of this transition on the FC application and main match process. METHODS: Five years (2018-2022) of deidentified FC applicant, program, and match rank data were used to assess differences between in-person (2018-2019) and virtual interview (2021-2022) cycles. Data are expressed as mean ± SD and one-way and two-way MANOVA tests were applied. RESULTS: Trainees applied to an average of 30.4 ± 24.3 programs and ranked an average of 10.7 ± 9.7 programs with a 57% match rate and average rank position of 3.6 ± 3.3. Fellowship programs received an average of 64.9 ± 28.6 applications and ranked an average of 15.4 ± 8.8 applicants with a 95% match rate and average applicant rank position of 3.0 ± 3.4. Applicants who interviewed virtually applied to a greater number of programs (32.7 vs. 27.0; p < 0.001) and ranked a greater number of programs (11.5 vs. 10.0; p = 0.004) with no difference in match rates (58% vs. 55%, p = 0.291). Among matched applicants, there was a significant difference in average rank position (3.20 vs. 4.30, p < 0.001), favoring the in-person cohort. Fellowship programs had more applicants per program (69.2 vs. 57.8; p < 0.001) and ranked more applicants (17.4 vs. 13.3; p < 0.001) during the virtual interview cycles. No difference in either match rates (93% vs. 96%, p = 0.178) or applicant rank position (3.09 vs. 2.93, p = 0.561) was seen between in-person and virtual application cycles. CONCLUSION: Virtual interviews were associated with an increased number of applications for fellowship and applicants ranked by programs but did not impact match rates of either group. Rank match position declined somewhat for applicants but not for fellowship programs. Virtual interviews offer more opportunities for applicants and a greater number of candidates for fellowship programs with only a slight decrement in fellow match rank position.

Impact of Rater Training on Residents Technical Skill Assessments: A Randomized Trial.

OBJECTIVE: The ACS/APDS Resident Skills Curriculum's Objective Structured Assessment of Technical Skills (OSATS) consists of task-specific checklists and a global rating scale (GRS) completed by raters. Prior work demonstrated a need for rater training. This study evaluates the impact of a rater-training curriculum on scoring discrimination, consistency, and validity for handsewn bowel anastomosis (HBA) and vascular anastomosis (VA). DESIGN/ METHODS: A rater training video model was developed, which included a GRS orientation and anchoring performances representing the range of potential scores. Faculty raters were randomized to rater training or no rater training and were asked to score videos of resident HBA/VA. Consensus scores were assigned to each video using a modified Delphi process (Gold Score). Trained and untrained scores were analyzed for discrimination and score spread and compared to the Gold Score for relative agreement. RESULTS: Eight general and eight vascular surgery faculty were randomized to score 24 HBA/VA videos. Rater training increased rater discrimination and decreased rating scale shrinkage for both VA (mean trained score: 2.83, variance 1.88; mean untrained score: 3.1, variance 1.14, p = 0.007) and HBA (mean trained score: 3.52, variance 1.44; mean untrained score: 3.42, variance 0.96, p = 0.033). On validity analyses, a comparison between each rater group vs Gold Score revealed a moderate training impact for VA, trained κ=0.65 vs untrained κ=0.57 and no impact for HBA, R1 κ = 0.71 vs R2 κ = 0.73. CONCLUSION: A rater-training curriculum improved raters' ability to differentiate performance levels and use a wider range of the scoring scale. However, despite rater training, there was persistent disagreement between faculty GRS scores with no groups reaching the agreement threshold for formative assessment. If technical skill exams are incorporated into high stakes assessments, consensus ratings via a standard setting process are likely a more valid option than individual faculty ratings.

Interprofessional Trauma Team Training: Leveraging Each Specialties' Expertise to Teach Procedural-Based Skills.

OBJECTIVE: The goal of this study was to utilize interprofessional trauma team training to teach procedural-based skills, teamwork, and assess the impact on the procedural comfort and interprofessional collaboration. DESIGN: Interdisciplinary skills sessions were created to focus on chest tube placement and advanced ultrasound techniques. Chest tube sessions were taught by senior general surgery (GS) residents and faculty. Ultrasound sessions were taught by emergency medicine (EM) fellows and faculty. Mock trauma simulations for EM and GS residents and EM nurses, were developed to also focus on improving interprofessional trauma-bay collaboration. Sessions were held throughout the year for 2 consecutive academic years. After completing skills sessions and trauma scenarios, participants were surveyed on skill comfort, session utility, and willingness to collaborate with the other specialty. Likert scale responses were analyzed by specialty cohort and in aggregate. Free-text feedback responses were analyzed for common themes. SETTING: Large, tertiary, urban academic medical center PARTICIPANTS: Forty seven EM residents and 32 GS residents completed instructional chest tube and ultrasound simulations, respectively. Twenty two EM residents, 24 GS residents, and 29 EM nurses participated in interprofessional trauma simulations. RESULTS: For chest tube placement: 71% of EM residents reported feeling uncomfortable with the procedure prior to the session, with 100% reporting improved confidence afterwards. Seventy percent stated the model was realistic. One hundred percent thought it improved their procedural skills. All participants thought it was worthwhile, should be offered again in future years, and planned to incorporate what they learned in their future practice. For the ultrasound sessions: 61% of GS residents felt uncomfortable with the Focused Assessment with Sonography in Trauma prior to the simulation. Ninety four percent reported the improved skill and confidence, and felt the model was realistic. All participants felt sessions were worthwhile, should be offered again, and planned to incorporate what they learned in their future practice. For trauma simulations: 97% of participants felt scenarios were realistic and clinically relevant and planned to incorporate lessons learned in their future clinical practice. All participants thought participation was worthwhile. Ninety seven percent thought it improved their confidence with trauma clinical management and 56% reported it improved their skills. Many participants reported they appreciated learning from the other specialty's perspective, with greater than 95% of all participants reporting improved comfort and willingness to collaborate across disciplines when caring for future trauma patients. All participants requested the simulation sessions continue in future academic years. CONCLUSION: Interprofessional trauma simulation sessions can harness the unique skill sets of different disciplines to teach procedural-based skills and improve interprofessional collaboration within the trauma bay.

Transfer of virtual reality endoscopy training to live animal colonoscopy: a randomized control trial of proficiency vs. repetition-based training.

BACKGROUND: Low first-time pass rates of the Fundamentals of Endoscopic Surgery (FES) exam stimulated development of virtual reality (VR) simulation curricula for test preparation. This study evaluates the transfer of VR endoscopy training to live porcine endoscopy performance and compares the relative effectiveness of a proficiency-based vs repetition-based VR training curriculum. METHODS: Novice endoscopists completed pretesting including the FES manual skills examination and Global Assessment of GI Endoscopic Skills (GAGES) assessment of porcine upper and lower endoscopy. Participants were randomly assigned one of two curricula: proficiency-based or repetition-based. Following curriculum completion, participants post-tested via repeat FES examination and GAGES porcine endoscopy assessments. The two cohorts pre-to-post-test differences were compared using ANCOVA. RESULTS: Twenty-two residents completed the curricula. There were no differences in demographics or clinical endoscopy experience between the groups. The repetition group spent significantly more time on the simulator (repetition: 242.2 min, SD 48.6) compared to the proficiency group (proficiency: 170.0 min, SD 66.3; p = 0.013). There was a significant improvement in porcine endoscopy (pre: 10.6, SD 2.8, post: 16.6, SD 3.4; p < 0.001) and colonoscopy (pre: 10.4, SD 2.7, post: 16.4, SD 4.2; p < 0.001) GAGES scores as well as FES manual skills performance (pre: 270.9, SD 105.5, post: 477.4, SD 68.9; p < 0.001) for the total cohort. There was no difference in post-test GAGES performance or FES manual skills exam performance between the two groups. Both the proficiency and repetition group had a 100% pass rate on the FES skills exam following VR curriculum completion. CONCLUSION: A VR endoscopy curriculum translates to improved performance in upper and lower endoscopy in a live animal model. VR curricula type did not affect FES manual skills examination or live colonoscopy outcomes; however, a proficiency curriculum is less time-consuming and can provide a structured approach to prepare for both the FES exam and clinical endoscopy.

A multisite study of medical student perspectives on the core surgical clerkship.

BACKGROUND: The surgical clerkship is the primary surgical learning experience for medical students. This study aims to understand student perspectives on the surgery clerkship both before and after the core surgical rotation. METHODS: Medical students at 4 academic hospitals completed pre and postclerkship surveys that included open-ended questions regarding (1) student learning goals and concerns and (2) how surgical clerkship learning could be enhanced. Thematic analysis was performed, and interrater reliability was calculated. RESULTS: Ninety-one percent of students completed both a pre and postclerkship survey (n =162 of 179), generating 320 preclerkship and 270 postclerkship responses. Mean kappa coefficients were 0.83 and 0.82 for pre and postclerkship primary themes, respectively. Thematic analysis identified 5 broad themes: (1) core learning expectations, (2) understanding surgical careers, culture, and work, (3) inhabiting the role of a surgeon, (4) inclusion in the surgical team, and (5) the unique role of the medical student on clinical clerkships. Based on these themes, we propose a learner-centered model of a successful surgical clerkship that satisfies discrete student learning and goals and career objectives while ameliorating the challenges of high-stakes clinical surgical environments such as the operating room. CONCLUSION: Understanding student perspectives on the surgery clerkship, including preclerkship motivations and concerns and postclerkship reflections on surgical learning, revealed potential targets of intervention to improve the surgery clerkship. Future investigation may elucidate whether the proposed model of the elements of a successful surgery clerkship learning facilitates improvement of the surgical learning environment and enhanced surgical learning.

Simulation versus reality: what can interprofessional simulation teach us about team dynamics in the trauma bay?

Purpose: Surgical consultation and the joint management of trauma patients is a common scenario in the emergency department. The goal of this study was to utilize interprofessional trauma team training to understand the role of simulation and its impact on the overall culture of trauma-related care. Methods: Interdisciplinary trauma simulation scenarios were completed by 12 groups of emergency medicine residents, general surgery residents, and emergency medicine nurses across two academic years. Following each simulation, a debriefing session was held to reflect on the scenario, focusing on team interactions. Debriefing sessions were audio-recorded, transcribed, deidentified, and independently, inductively coded by two members of the research team. Using the constant comparative method, a codebook was developed and refined until interrater reliability was confirmed with a kappa of > 0.9. Codes were organized into higher level themes. Results: There were 72 participants, including 23 general surgery residents, 19 emergency medicine residents, and 30 emergency medicine nurses. 214 primary codes were collapsed into 29 coding categories, with 6 emerging themes. Pre-trauma bay impact describes how interactions prior to the trauma scenario can impact how team members communicate, trust one another, and ultimately care for the patient. Role and team identity explores the importance of one knowing their individual role in the trauma bay and how it impacts overall team identity. Resource allocation describes the balance of having appropriate resources to efficiently care for patients while not negatively impacting crowd control or role identity. Impact of the simulation experience highlights the impact of the lower stakes simulation scenario on learning and reflection as well as concerns with simulation fidelity. Trauma leader traits and actions outlines inherent traits and learned actions of trauma leaders that impact how the trauma scenario unfolds. Interprofessional team performance describes the overall performance of the trauma team, including but not limited to the type of communication used, teamwork behaviors, and transition of care of the patient. Conclusions: Interdisciplinary trauma simulations and structured debriefing sessions provide insights into team dynamics and interprofessional relationships. Simulations and debriefing sessions can promote understanding, respect, and familiarity of team members' roles; recognition of key characteristics of high functioning leaders and teams; and discovery of conflict mitigating strategies for future interdisciplinary team improvement. Simulation sessions allow implementation of quality improvement measures and communication and leadership strategy practice in a safe, collaborative learning environment. The lessons learned from these sessions can encourage participants to reexamine how they interact and function as a team within the real-life trauma bay.

A Needs Assessment of Video-based Education Resources Among General Surgery Residents.

BACKGROUND: Video-based education (VBE) is an effective tool for knowledge and skill acquisition for medical students, but its utility is less clear for resident physicians. We sought to determine how to incorporate VBE into a general surgery resident operative curriculum. METHODS: We conducted a single-institution, survey-based needs assessment of general surgery residents to determine desired content and format of an operative VBE module. RESULTS: The response rate was 84% (53/63), with 66% senior (postgraduate year ≥3) resident respondents. VBE was the most commonly cited resource that residents used to prepare for an operation (93%) compared with surgical textbooks (89%) and text-based website content (57%). Junior residents were more likely to utilize text-based website content than senior residents (P < 0.01). The three most important operative video components were accuracy, length, and cost. Senior residents significantly preferred videos that were peer-reviewed (P < 0.05) and featured attending surgeons whom they knew (P = 0.03). A majority of residents (59%) believed 5-10 min is the ideal length of an operative video. Across all postgraduate year levels, residents indicated that detailed instruction of each operative step was the most important content of a VBE module. Senior residents believed that the overall indications and details of each step of the operation were the most important contents of VBE for a junior resident. CONCLUSIONS: At this institution, general surgery residents preferentially use VBE resources for operative preparation. A centralized, standardized operative resource would likely improve resident studying efficiency, but would require personalized learning options to work for both junior and senior surgery residents.

Implementation of the ACS/ APDS Resident Skills Curriculum reveals a need for rater training: An analysis using generalizability theory.

BACKGROUND: The American College of Surgeons (ACS)/Association of Program Directors in Surgery (APDS) Resident Skills Curriculum includes validated task-specific checklists and global rating scales (GRS) for Objective Structured Assessment of Technical Skills (OSATS). However, it does not include instructions on use of these assessment tools. Since consistency of ratings is a key feature of assessment, we explored rater reliability for two skills. METHODS: Surgical faculty assessed hand-sewn bowel and vascular anastomoses in real-time using the OSATS GRS. OSATS were video-taped and independently evaluated by a research resident and surgical attending. Rating consistency was estimated using intraclass correlation coefficients (ICC) and generalizability analysis. RESULTS: Three-rater ICC coefficients across 24 videos ranged from 0.12 to 0.75. Generalizability reliability coefficients ranged from 0.55 to 0.8. Percent variance attributable to raters ranged from 2.7% to 32.1%. Pairwise agreement showed considerable inconsistency for both tasks. CONCLUSIONS: Variability of ratings for these two skills indicate the need for rater training to increase scoring agreement and decrease rater variability for technical skill assessments.

Let's Not Throw the Baby Out with the Bath Water - Keep the ABSITE a Numerically Scored Exam.

The American Board of Surgery In-Training Examination (ABSITE) is a low-stakes, validated, objective measure of the medical knowledge of our surgical residents and is an important predictor of ABS Qualifying Exam (QE) passage. It was never intended to serve as a global assessment of resident performance or aptitude, to assess any competency other than medical knowledge, or to serve as the sole criterion by which to judge resident promotion to the next PGY level. Though the scoring of the ABSITE and the use of the exam by some PDs and fellowship directors may be imperfect, let's not throw the baby out with the bath water and destroy the utility of the ABSITE by changing its grading to pass/fail. Rather, let's set rigorous, high standards for our residents in preparation for the ABSITE, as well as for PDs and fellowship directors in the proper interpretation of the ABSITE as a formative assessment of resident knowledge progression as opposed to a high-stakes summative exam.

The Surgical Knowledge "Growth Curve": Predicting ABSITE Scores and Identifying "At-Risk" Residents.

OBJECTIVE: Resident performance on the American Board of Surgery In-Training Examination (ABSITE) is used for evaluation of surgical knowledge and guides resident selection for institutional remediation programs. Remediation thresholds have historically been based on ABSITE percentile scores; however, this does not account for predictors that can impact a resident's exam performance. We sought to identify predictors of yearly ABSITE performance to help identify residents "at-risk" for performing below their expected growth trajectory. DESIGN: The knowledge of the residents, as measured by standardized ABSITE scores, was modeled as a function of the corresponding postgraduate year via a linear mixed effects regression model. Additional model covariates included written USMLE-1-3 examination scores, gender, number of practice questions completed, and percentage correct of practice questions. For each resident, the predicted ABSITE standard score along with a 95% bootstrap prediction interval was obtained. Both resident-specific and population-level predictions for ABSITE standard scores were also estimated. SETTING: The study was conducted at a single, large academic medical center (Massachusetts General Hospital, Boston, MA). PARTICIPANTS: Six years of general surgery resident score reports at a single institution between 2014 and 2019 were deidentified and analyzed. RESULTS: A total of 376 score reports from 130 residents were analyzed. Covariates that had a significant effect on the model included USMLE-1 score (PGY1: p = 0.013; PGY2: p = 0.007; PGY3: p = 0.011), USMLE-2 score (PGY1: p < 0.001; PGY2: p < 0.001; PGY3: p < 0.001; PGY4: p < 0.001; PGY5: p = 0.032), male gender (PGY1: p = 0.003; PGY2: p < 0.001; PGY3: p < 0.001; PGY4: p = 0.008), and number of practice questions completed (p=0.003). Five residents were identified as having "fallen off" their predicted knowledge curve, including a single resident on 2 occasions. Population prediction curves were obtained at 7 different covariate percentile levels (5%, 10%, 25%, 50%, 75%, 90%, and 95%) that could be used to plot predicted resident knowledge progress. CONCLUSION: Performance on USMLE-1 and -2 examinations, male gender, and number of practice questions completed were positive predictors of ABSITE performance. Creating residency-wide knowledge growth curves as well as individualized predictive ABSITE performance models allows for more efficient identification of residents potentially at risk for poor ABSITE performance and structured monitoring of surgical knowledge progression.

Surgical autonomy: A resident perspective and the balance of teacher development with operative independence.

BACKGROUND: This study aims to understand the perspectives of operative autonomy of surgical residents at various postgraduate levels. METHODS: Categorical general surgery residents at a single academic residency were invited to participate in focus groups to discuss their opinions and definitions of operative autonomy. Employing constructivist thematic analysis, focus groups were audio recorded, transcribed, and inductively analyzed using a constant comparative technique. RESULTS: Twenty clinical surgical residents participated in 6 focus groups. Overarching themes identified include autonomy as a dynamic, progressive path to operative independence and the complex interaction of resident-as-teacher development and operative autonomy. Four within operative case themes were intrinsic factors, extrinsic factors, autonomy promoting or inhibiting behaviors, and the relationship between residents and attendings. CONCLUSION: Residents define operative autonomy as a progressive and dynamic pathway to operative independence. Teacher development is viewed as both an extension beyond operative independence and potentially in conflict with their colleagues' development.

A qualitative study of the perceived value of participation in a new Department of Surgery Research Residents as teachers program.

OBJECTIVE: This study aims to understand the perspectives of surgical residents who completed a Research Residents as Teachers Program (RRATP). METHODS: Our RRATP included a 6 h workshop followed by formal teaching opportunities across one academic year. Resident teachers participated in semi-structured interviews, which were inductively analyzed for prominent themes. RESULTS: Eight surgical research residents completed the RRATP workshop and taught 330 h (median = 26 h, range: 8-105). Interview participation rate was 100%; kappa was 0.81. Residents reported four themes: 1) increased knowledge of teaching principles with subsequent teaching changes, specific factors that contributed to their development as a teacher, numerous personal benefits to participation, and broad positive consequences for the surgical department including improved culture and patient care. CONCLUSION: A RRATP can generate a significant number of formal teaching hours by surgical research residents, who perceive a high value of formal education training to themselves and their surgical residency program.

Identification of Specific Educational Targets to Improve the Student Surgical Clerkship Experience.

BACKGROUND: This study describes the relationship between medical student perception of surgery, frequency of positive surgery clerkship activities, and overall surgical clerkship experience. METHODS: Medical students at four academic hospitals completed pre- and post-clerkship surveys assessing 1) surgery clerkship activities/experiences and 2) perceptions of surgery during the 2017-2018 academic year. RESULTS: Ninety-one percent of students completed both a pre- and post-clerkship survey (n = 162 of 179). Student perception of surgery significantly improved across the clerkship overall (P < 0.0001) and for 7 of 21 specific items. Eighty-six percent of students agreed that the clerkship was a meaningful experience. Sixty-six percent agreed that the operating room was a positive learning environment. Multivariable logistic regression identified one-on-one mentoring from a resident (OR [95% CI] = 2.12 [1.11-4.04], P = 0.02) and establishing a meaningful relationship with a surgical patient (OR = 2.21 [1.12-4.37], P = 0.02) as activities predictive of student agreement that the surgical clerkship was meaningful. Making an incision (OR = 2.92 [1.54-5.56], P = 0.001) and assisting in dissection (OR = 1.67 [1.03-2.69], P = 0.035) were predictive of student agreement that the operating room was a positive learning environment. Positive student perception of surgery before the clerkship was associated with increased frequency of positive clerkship activities including operative involvement (r = 0.26, P = 0.001) and relationships with surgical attendings (r = 0.20, P = 0.01), residents (r = 0.41, P < 0.0001), and patients (r = 0.24, P = 0.003). CONCLUSIONS: Interventions to improve surgery clerkship quality should target enhancing student relationships with residents and surgical patients as well as providing opportunity for student operative involvement beyond just suturing. In addition, fostering positive perceptions of surgery in the preclinical period may increase meaningfulness and experience with the later surgery clerkship.

#SurgEdVidz: Using Social Media to Create a Supplemental Video-Based Surgery Didactic Curriculum.

BACKGROUND: A general surgery resident may have competing clinical responsibilities that limit the ability to participate in educational didactics. Social media is an alternative delivery method for educational content that can be viewed at a resident's convenience. We sought to assess the feasibility of using social media to provide educational content for surgical residents. MATERIALS AND METHODS: We created a novel, supplemental surgical curriculum consisting of two-minute videos based on the This Week in SCORE modules. Videos were posted to Twitter weekly, indexed with the #SurgEdVidz hashtag and uploaded to YouTube to create a catalog of videos. Twitter and YouTube analytics were used to calculate public viewership and impact. RESULTS: A total of 43 videos were disseminated between January 30, 2019 and January 31, 2020. An average of 6.9 h (SD: 1.4; range: 5.0-10.0) was required to generate each video, including 1.5 h (SD: 0.6; range: 0-2.0) for content review and 5.4 h (SD: 1.1; range: 4.0-8.0) for video production. Between the two platforms, videos generated a total of 51,313 views with an average of 1193 views (SD: 715; range: 412-4096) per video. Account followers are geographically distributed across 28 states, 28 countries, and six continents. CONCLUSIONS: Social media can serve as an effective tool for the distribution of surgical educational content. Twitter, in conjunction with YouTube, allows for rapid dissemination of didactic content packaged into brief videos that is flexible in viewership with low time commitment. Social media offers visibility and engagement beyond the classroom without geographical or temporal borders.

The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients.

Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor that exhibits favorable drug-like properties, selectively modifies mutant cysteine 12 in GDP-bound KRASG12C, and inhibits KRAS-dependent signaling. MRTX849 demonstrated pronounced tumor regression in 17 of 26 (65%) KRASG12C-positive cell line- and patient-derived xenograft models from multiple tumor types, and objective responses have been observed in patients with KRASG12C-positive lung and colon adenocarcinomas. Comprehensive pharmacodynamic and pharmacogenomic profiling in sensitive and partially resistant nonclinical models identified mechanisms implicated in limiting antitumor activity including KRAS nucleotide cycling and pathways that induce feedback reactivation and/or bypass KRAS dependence. These factors included activation of receptor tyrosine kinases (RTK), bypass of KRAS dependence, and genetic dysregulation of cell cycle. Combinations of MRTX849 with agents that target RTKs, mTOR, or cell cycle demonstrated enhanced response and marked tumor regression in several tumor models, including MRTX849-refractory models. SIGNIFICANCE: The discovery of MRTX849 provides a long-awaited opportunity to selectively target KRASG12C in patients. The in-depth characterization of MRTX849 activity, elucidation of response and resistance mechanisms, and identification of effective combinations provide new insight toward KRAS dependence and the rational development of this class of agents.See related commentary by Klempner and Hata, p. 20.This article is highlighted in the In This Issue feature, p. 1.