Late toxicity after peposertib-enhanced chemoradiation in rectal cancer patients managed with organ preservation

Highlights

• •The DNA-PK inhibitor peposertib was well-tolerated during chemoradiotherapy for rectal cancer.
• •The addition of peposertib to chemoradiation achieved promising rates of tumor response and organ preservation.
• •Peposertib treatment resulted in a high risk of late grade 3 + toxicity among patients in “watch-and-wait” surveillance.
• •Trials in nonoperative management of rectal cancer must focus on the toxicity and response profiles of novel regimens.

Abstract

Background and purpose

Combining peposertib, a DNA-PK inhibitor, with capecitabine-based chemoradiation may improve tumor response and organ preservation in rectal cancer. We assessed how adding peposertib to chemoradiation impacts organ preservation-specific outcomes and toxicities.

Materials and methods

In a recent phase Ib trial, rectal cancer patients underwent neoadjuvant capecitabine-based chemoradiation with peposertib. Patients were then restaged: those with clinical complete responses (cCRs) were offered “watch-and-wait” (WW), while those with non-cCRs (near complete and incomplete responses) were recommended surgery, although most opted for consolidation chemotherapy. Six patients were selected for this post-hoc analysis with primary endpoints of organ preservation rate, tumor response rates, and characterization of late grade 3 + toxicities.

Results

Tumor response rates showed 50 % of patients (3/6) achieved cCR and entered WW. Additionally, the frequency of late grade 3 + toxicity was 50 % (3/6). Late grade 3 + toxicity was exclusively observed in patients with cCR entering WW, and all toxicities were specific to the rectum (severe proctitis and bowel fistulization). In contrast, no late grade 3 + toxicities were seen when disease was managed by oncologic surgical resection. Finally, while overall three-year organ preservation rate was 60 % (3/5), patients with organ preservation also had increased rates of late grade 3 + rectal toxicities (66 %, 2/3).

Conclusion

Combining peposertib with capecitabine-based chemoradiation was associated with disproportionately high risks of severe late rectal toxicities, particularly in patients entering WW. Thus, careful assessment of the toxicity and response profiles of novel neoadjuvant regimens is critically important in future clinical trials focused on organ preservation and the nonoperative management of rectal cancer.

Introduction

Rectal cancer incidence is rising rapidly among young adults, making it the leading cause of cancer-related deaths in individuals under the age of 50 [1], [2]. Standard treatment involves trimodality therapy (chemoradiation, chemotherapy, and radical surgery), often leading to significant lifelong morbidity [3], [4], [5]. This impact is especially pronounced in patients with low rectal tumors, where surgery can necessitate a permanent colostomy and profoundly affect quality of life. Consequently, there is an urgent need for novel therapeutic strategies to facilitate organ preservation and reduce long-term morbidities [6], [7].

The therapeutic effect of chemoradiation largely stems from radiation-induced double-stranded DNA breaks, which can initiate tumor cell death through both intrinsic and extrinsic pathways [8]. However, tumor cells can circumvent these effects through innate DNA damage repair mechanisms, enabling tumor cell survival. Among these pathways, non-homologous end-joining (NHEJ) plays a central role, facilitated by the serine/threonine protein kinase DNA-dependent protein kinase (DNA-PK) [9], [10]. Consequently, small molecule DNA-PK inhibitors have been developed to enhance the antitumor effects of radiation by inhibiting NHEJ-mediated DNA repair [9], [10]. Peposertib (M3814), an oral DNA-PK inhibitor with subnanomolar potency, represents a promising strategy to enhance chemoradiation efficacy in the treatment of rectal cancer.

A recent phase Ib clinical trial (NCT03770689) evaluated peposertib combined with neoadjuvant capecitabine-based chemoradiation in patients with locally advanced rectal cancer, demonstrating potent radiosensitizing effects but a narrow therapeutic index [11]. While the study’s overall trial results have already been published [11], the safety and efficacy of peposertib-enhanced chemoradiation has not been fully investigated or characterized in the context of total neoadjuvant therapy (TNT) or organ preservation.

Materials and methods

Study design and participants

All patients provided written informed consent for treatment following the Memorial Sloan Kettering Cancer Center (MSK) Institutional Review Board (IRB)-approved treatment protocol (IRB #19–067) in accordance with the Declaration of Helsinki. Patients with rectal cancer who enrolled in an open-label, single-arm, phase Ib trial evaluating peposertib dose escalation in combination with chemoradiation (IRB #19–067) and who received treatment at MSK were eligible for this post-hoc analysis [11]. A waiver of informed consent was approved by the MSK IRB (IRB #16–370), and six patients (of nineteen total) were selected for this secondary analysis, representing the complete subset of patients treated at MSK and the only trial participants for whom detailed long-term follow-up information was available through the MSK electronic medical record for this study. Patient selection for this post-hoc analysis is shown in Fig. 1. Data was collected starting on March 20, 2019, and patients were followed until March 12, 2025.

Fig. 1.

Flow Diagram Depicting Patient Selection for Post-Hoc Analysis. Flow diagram depicting patient selection for post-hoc analysis from the parent phase Ib trial of peposertib with chemoradiation for rectal cancer. Nineteen patients were treated on the parent trial. Six patients received treatment at MSK; these patients were included in the present post-hoc analysis due to availability of detailed long-term follow-up data. Thirteen treated at other participating sites were not included in this secondary analysis. Abbreviations: CRT, chemoradiation therapy; MSK, Memorial Sloan Kettering Cancer Center.

Neoadjuvant treatment and assessment of tumor response

All patients in the phase Ib trial were treated with neoadjuvant capecitabine-based chemoradiation with the addition of peposertib. Peposertib was administered once daily, 1.5–2 h prior to chemoradiation, at doses ranging from 50 to 150 mg. The capecitabine dose was 825 mg/m² split between morning and evening on the days of radiation treatment. Peposertib dosages were assigned prospectively, as previously described [11].

Patients were treated with intensity-modulated radiotherapy. Most patients were treated to 4,500 cGy in 25 fractions of 180 cGy to high-risk lymph nodes with a simultaneous integrated boost to gross disease, reaching a total dose of 5,000 cGy in 25 fractions of 200 cGy. One patient received 4,500 cGy in 180 cGy fractions targeting high-risk lymph nodes, followed by a sequential boost of 540 cGy in 180 cGy fractions to gross disease (with total dose reaching 5,040 cGy in 28 fractions).

Eight weeks following chemoradiation, patients were restaged by clinical exam, endoscopic evaluation, and imaging (rectal MRI). The MSK Rectal Cancer Tumor Regression Schema was used to define tumor response [12]. Patients who achieved a clinical complete response (cCR) were offered “watch-and-wait” (WW) surveillance. Patients with a non-cCR (encompassing near complete and incomplete responses) who had previously received induction chemotherapy (now followed by consolidative chemoradiation) were recommended surgical management at 9 ± 2 weeks after completion of chemoradiation. Similarly, patients with a non-cCR to induction chemoradiation were recommended surgical resection; however, most patients opted for consolidative chemotherapy with the hope of converting to a cCR.

Patient demographics and clinical data were collected by post-hoc analysis of trial data and by chart review of selected patients. Primary endpoints included rate of organ preservation, rates of cCR and non-cCR, and characterization of late toxicities. Late toxicities were defined as persisting or occurring greater than 90 days from the initiation of chemoradiation by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5·0 [13]. The data generated in this study are available upon request from the corresponding author. Funding sources had no role in conducting this study or in the writing and submission of this manuscript.

Results

Patient demographics and tumor characteristics

Six patients (four biological males and two biological females) with a median age of 60 years (range 49 to 78 years) were included in the post-hoc analysis. All six patients had tumors with preserved mismatch repair (MMR) proteins by immunohistochemical staining. Comprehensive patient demographics and clinical data are shown in Table 1. The median follow-up duration from the time of treatment initiation was 57 months (range 9 to 70 months).

Table 1.

Patient Demographics and Clinical Information. Abbreviations: ECOG (Eastern Cooperative Oncology Group); MMR (mismatch repair); CEA (carcinoembryonic antigen).

Patient Demographics and Clinical Data	n (%)
Total	n = 6
Median Age at Diagnosis – years (range)	60 (49–78)
Female	2 (33 %)
Male	4 (67 %)
Race
Caucasian	6 (100 %)
Black/African American	0 (0 %)
Other	0 (0 %)
ECOG
0	5 (83 %)
1	1 (17 %)
Clinical Stage
T2N + M0	1 (17 %)
T3N + M0	4 (67 %)
T4N + M0	1 (17 %)
Median Distance from Anal Verge – cm (range)	3.1 (1.9–6.8)
MMR Preserved	6 (100 %)
Median Initial CEA – ng/mL (range)	4.2 (1·4-9·3)
Chemotherapy*
Consolidative FOLFOX	4 (67 %)
Induction CAPEOX	1 (17 %)

* One patient did not receive chemotherapy due to treatment toxicity.

Neoadjuvant treatment and tumor response

In this study, five of six patients (83 %) completed TNT. Four patients underwent induction chemoradiation (with peposertib) followed by consolidative FOLFOX. One patient had induction CAPEOX with subsequent endoscopic and MRI-confirmed residual disease before initiating peposertib-enhanced consolidative chemoradiation. The final patient completed only induction chemoradiation (with peposertib), as their post-treatment evaluation showed no evidence of tumor and severe treatment toxicity precluded the initiation of consolidative FOLFOX. Treatment information for each patient is summarized in Table 2.

Table 2.

Summary of treatment characteristics and clinical endpoints for each patient. Abbreviations: P1-P6 (Patient 1–6); RT (radiation therapy); cCR (clinical complete response); Non-cCR (encompasses near complete and incomplete responses); APR (abdominoperineal resection); NED (no evidence of disease).

Patient ID	Age/ Sex	Stage	Peposertib Dose (mg)	Capecitabine Dose (mg) (AM/PM)	RT Dose (Planned)	RT Dose (Received)	Chemotherapy	Clinical Tumor Response	Surgery	Follow-up Since Treatment Initiation (months)	Current Status
P1	60 M	T3bN+	50	1500/1500	45/50 Gy in 25 Fractions	45/50 Gy in 25 Fractions	Consolidative FOLFOX	Non-cCR	APR (Oncologic)	68	NED
P2	49F	T3cN+	100	1500/1000	45/50 Gy in 25 Fractions	45/50 Gy in 25 Fractions	Induction CAPEOX	cCR	None	71	NED
P3	78F	T4bN+	100	1500/1500 for 12 fractions, reduced to 1000/1000 for 13 fractions	45/50 Gy in 25 Fractions	45/50 Gy in 25 Fractions	Consolidative FOLFOX	Non-cCR	None	9	Lost to Follow-Up
P4	73 M	T2N+	100	1500/1000	45/50 Gy in 25 Fractions	45/50 Gy in 25 Fractions	None	cCR	APR (Palliative)	22	Deceased with NED
P5	60 M	T3cN+	100	2000/2000	45/50.4 Gy in 28 Fractions	45/50.4 Gy in 28 Fractions	Consolidative FOLFOX	cCR	None	61	NED
P6	51 M	T3cN+	150	2000/1500	45/50 Gy in 25 Fractions	45/50 Gy in 25 Fractions	Consolidative FOLFOX	Non-cCR	None	56	Deceased with Metastatic Progression

Upon initial restaging after completing neoadjuvant treatment, 50 % of patients (3 of 6) achieved a cCR. All three complete responders entered WW: two patients remain alive with a sustained cCR at last follow-up (71 and 61 months, respectively), while the third patient died 22 months after treatment initiation. Importantly, none of these three cCR patients developed local or metastatic recurrent disease. The remaining three patients had a non-cCR and were recommended for total mesorectal excision. Two of these patients refused surgery, while the third patient underwent uncomplicated abdominoperineal resection (APR). Each patient’s clinical course is shown in Fig. 2.

Fig. 2.

Summary of Each Patient’s Treatment Course and Outcomes in Terms of Tumor Response and Organ Preservation. In this analysis, 60 % of patients (3 of 5) had organ preservation at three years. Further, 50 % of patients (3 of 6) achieved a clinical complete response, and 100 % of complete responders had late grade 3 + toxicities of the rectum. Legend: Timeline symbols denote key treatments and events: chemoradiation (lightning bolt), systemic chemotherapy (black circle), surgery (black trapezoid), late severe toxicity (orange burst), no evidence of disease (black arrow), progression of disease (black triangle), deceased (black X), loss to follow-up (black star), and orange preservation (yellow circle). Background shading indicates tumor response (green = clinical complete response; blue = non-clinical complete response). Abbreviations: P1 (patient 1); P2 (patient 2); P3 (patient 3); P4 (patient 4); P5 (patient 5); P6 (patient 6).

Treatment toxicity

There were no acute grade 3 + toxicities noted in the studied patients. However, late grade 3 + toxicities were noted in 50 % of patients (3 of 6). The three patients who developed late grade 3 + toxicities were the same three patients with a cCR who entered WW surveillance. The median time from completion of chemoradiation to onset of late grade 3 + toxicity was 6 months (range, 5–14 months). No late grade 3 + toxicity was noted in non-cCR patients who did not enter WW.

The late grade 3 + toxicities of all three cCR patients in WW were all specific to the rectum. One patient (treated with peposertib 100 mg) developed a rectal fistula to small bowel with associated obstruction in the setting of grade 4 proctitis 14 weeks after completing chemoradiation. Given his malnourishment and acute on chronic obstructive symptoms, he was managed with a palliative APR. Surgical pathology showed a pathologic complete response (pCR). This patient ultimately died 21 months after treatment initiation (and 16 months after surgery) with no evidence of tumor recurrence locoregionally or distantly. The other two WW patients developed grade 3 chronic proctitis five and six months after completing capecitabine-based chemoradiation with peposertib (both within the 100 mg cohort). These two patients required multiple blood transfusions and hyperbaric oxygen therapy. One of these patients continues to have persistent grade 2 proctitis with daily rectal bleeding 64 months after completing chemoradiation, while the other has occasional symptoms (1–2 times per week) 59 months after completing chemoradiation. Neither are transfusion dependent at this time. A summary of late grade 3 + toxicities stratified by tumor response can be found in Fig. 3.

Fig. 3.

Patient Outcomes and Toxicities. Patients with and without a clinical complete response (cCR) are further stratified by three-year organ preservation status. Toxicities for each group are described. Notably, patients with a cCR were the only subjects to have late severe toxicities, and all of these toxicities were limited to the rectum. * One patient with a non-cCR was lost to follow-up after nine months and was censored in the three-year organ preservation analysis. Abbreviations: cCR (clinical complete response); WW (watch-and-wait).

Organ preservation

The overall three-year organ preservation rate was 60 % (3 of 5 patients, with one patient censored due to loss of follow-up). Among the three patients with a cCR who entered WW surveillance, the three-year organ preservation rate was 67 % (2 of 3 patients). The one patient with a cCR who did not have organ preservation at three years had required a palliative APR due to late grade 3 + toxicity in the absence of tumor regrowth (though was noted to have a pCR).

Among the three patients with a non-cCR, all of whom were recommended surgery, the three-year organ preservation rate was 50 % (1 of 2 patients). Only one patient agreed to upfront surgery, undergoing an uncomplicated APR with final pathology demonstrating ypT3N0 disease. The second patient declined surgery, stating that they were not interested in any type of stomal diversion in the curative, palliative, or salvage setting; they retained their rectum with persistent tumor until death due to metastatic disease 53 months later. The final patient also declined APR because they preferred a more limited operation and subsequently declined further follow-up; they were lost to follow-up after nine months and therefore censored from three-year organ preservation analysis. A summary of treatment outcomes can be found in Table 3.

Table 3.

Rates of Tumor Response, Organ Preservation, and Late Grade 3 + Toxicity. Abbreviations: cCR (clinical complete response); non-cCR (encompasses near complete and incomplete responses).

Outcomes and Toxicities	n (%)
Tumor Response
cCR	3/6 (50 %)
non-cCR	3/6 (50 %)
Three-Year Organ Preservation
Overall	3/5 (60 %)
cCR patients (n = 3)	2/3 (67 %)
non-cCR patients (n = 2)*	1/2 (50 %)
Late Grade 3 + Toxicity
Overall	3/6 (50 %)
cCR patients (n = 3)	3/3 (100 %)
non-cCR patients (n = 3)	0/3 (0 %)

* One patient was censored due to loss of follow-up at nine months after treatment initiation.

Discussion

Although chemoradiation for rectal cancer has traditionally been studied in the preoperative setting, there is growing interest in nonoperative management for patients who achieve a cCR with neoadjuvant therapy. However, data on late toxicities and long-term bowel function in the setting of organ preservation remain sparse, particularly in the setting of novel therapeutic strategies [14], [15]. In this study, we evaluated the impacts of peposertib-enhanced chemoradiation on organ preservation and function. Although the combination of peposertib with capecitabine-based chemoradiation yielded promising tumor response rates and a relatively high three-year organ preservation rate, the incidence of severe late toxicities, especially among patients who entered WW surveillance, raised concerns regarding the clinical feasibility of this therapeutic approach.

The overall rate of severe late toxicity was high at 50 % (3 of 6 patients). Notably, severe late toxicities were limited to the rectum and were observed exclusively in patients who achieved a cCR and entered WW (3 of 3 patients), a disproportionately high rate compared to contemporary trials studying the nonoperative management of rectal cancer [7], [16], [17]. The severe late rectal toxicities seen in the cCR patients who entered WW significantly compromised their health and quality of life — from persistent grade 2 + rectal proctitis five years after completing treatment to the loss of organ preservation after requiring palliative surgery. In contrast, no severe late toxicities were seen when disease was managed by oncologic surgical resection. This underscores the importance of assessing and reporting toxicity profiles separately for patients with and without organ preservation, particularly in the setting of novel therapeutics.

In our cohort, peposertib doses were 50 mg (n = 1), 100 mg (n = 4), and 150 mg (n = 1). Given the small sample size and limited dose range, dose–toxicity relationships could not be inferred within this post-hoc cohort. In the parent phase Ib trial, dose-limiting toxicities increased at 250 mg, whereas late toxicities were reported across the dose range without a discernible dose-dependent pattern [11].

One plausible explanation for the observed toxicity with peposertib-enhanced chemoradiation is radiosensitization of normal rectal tissues through inhibition of DNA double-strand break repair. DNA-PK is a central mediator of NHEJ, a predominant pathway for repair of ionizing radiation–induced double-strand breaks [9], [10]. Inhibiting DNA-PK during chemoradiation may therefore increase the burden of unrepaired DNA damage in intestinal stem cells, impair epithelial regeneration and wound healing, and predispose to ulceration, mucosal sloughing/necrosis, and subsequent fibrotic remodeling. Collectively, these mechanisms provide biologic context for the increased RT-associated toxicities and narrow therapeutic index reported in the parent phase Ib trial evaluating peposertib with capecitabine-based chemoradiation in locally advanced rectal cancer [11].

In addition to concerning levels of toxicity, the surveillance of rectal tumors proved challenging after treatment with peposertib-enhanced chemoradiation. After completing TNT as described, five patients achieved organ preservation at the time of restaging (i.e., the three patients with a cCR who entered WW and the two patients with a non-cCR who declined surgery). Treatment-related endoscopic findings — such as ulceration of the mucosa, sloughing, fibrosis, and necrosis — often mimicked findings of local tumor recurrence in patients with a cCR on WW (Fig. 4). Furthermore, among the two patients with a non-cCR who refused surgery, differentiating symptoms of local tumor progression from developing late treatment-related toxicity also proved difficult. Since endoscopic restaging and surveillance are critical components of the WW approach, therapeutics such as peposertib, which may be associated with clinically significant rectal toxicity, can hinder the accurate diagnosis of clinical response status and may be of limited clinical use. This again underscores the importance of assessing and characterizing toxicity of novel radiosensitizers specifically within the context of organ preservation.

Fig. 4.

Late Toxicity to the Rectum in Patients with Organ Preservation. Endoscopy reveals the sequelae of peposertib-enhanced chemoradiation toxicity to the rectum in patients who achieved organ preservation at any point during treatment or follow-up. Panels A–E depict pre-treatment endoscopy for P2, P4, P5, P3, and P6, respectively. Panels F–J depict restaging endoscopy for the corresponding patients (F: P2; G: P4; H: P5; I: P3; J: P6). Patients who achieved a clinical complete response (cCR) included P2, P4, and P5 (panels F–H), whereas patients without a cCR (non-cCR) included P3 and P6 (panels I–J). At restaging, endoscopic findings included features consistent with radiation proctitis (F [P2] and H [P5]), mucosal necrosis and sloughing (G [P4] and J [P6]), and fibrosis (I [P3]). These findings can mimic the appearance of local tumor recurrence in patients with a cCR or of tumor progression in patients with a non-cCR. Further, distinguishing tumor progression from developing treatment-related changes in non-cCR patients also proved challenging. Abbreviations: cCR (clinical complete response); P2 (patient 2); P3 (patient 3); P4 (patient 4); P5 (patient 5); P6 (patient 6).

Although our cohort provides an in-depth characterization of six patients, the small sample size limits definitive conclusions and statistical correlations; thus, our hypothesis-generating findings are not powered for outcome comparison and should be interpreted descriptively. The lack of comparator arm treated with standard fluoropyrimidine-based chemoradiation without peposertib limits causal inference regarding the contribution of peposertib to observed late rectal toxicity. Furthermore, treatment was heterogeneous, including variation in sequencing of systemic therapy (induction vs consolidative chemotherapy) which may have influenced both response and toxicity and introduced confounding that cannot be addressed in this dataset. Finally, attribution of late gastrointestinal symptoms and endoscopic findings is inherently challenging in this setting, where overlapping etiologies, including treatment toxicity and disease progression, may contribute to the observed clinical findings.

Nonetheless, the disproportionately high rate of severe late toxicity among WW patients is an important consideration for future organ preservation studies. While our data demonstrate rectum-specific toxicity among patients who achieved cCR and entered WW, the two patients with non-cCRs who declined surgery experienced no severe toxicity; however, in the latter patients, clinical interpretation was limited by the challenges of differentiating symptoms of treatment morbidity from tumor progression.

Because long-term rectal toxicity cannot be meaningfully assessed in patients who proceed to surgery, caution is warranted when interpreting the safety of radiosensitizing drugs in these patients. The toxicity profiles of radiosensitizing strategies meant to facilitate non-operative management (NOM) should be evaluated specifically within the context of organ preservation. Trials that fail to integrate organ preservation endpoints represent a missed opportunity to facilitate NOM and personalized treatment strategies for patients, which is particularly problematic when evaluating the safety and efficacy of novel therapeutics in TNT [18]. Future studies should pre-specify toxicity endpoints specifically within the organ-preservation population and stratify efficacy and safety of novel radiosensitizers by definitive management (NOM vs TME).

Conclusion

In conclusion, while the addition of peposertib to capecitabine-based chemoradiation demonstrated relatively high rates of complete tumor response and organ preservation, it was accompanied by a disproportionately high risk of severe late rectal toxicity, particularly among WW patients. Especially as treatment paradigms in rectal cancer evolve to emphasize nonoperative management, these findings underscore the necessity for future trials to carefully evaluate efficacy and toxicity profiles specifically in the setting of organ preservation.

Data sharing statement

The data generated in this study are available upon written request to the corresponding author, specifically de-identified clinical data of the patients who consented to this study. The study consent form is also available upon request. The study protocol and documents for the original trial have been published previously.

Funding statement

The original trial was funded by the health care business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: https://doi.org/10.13039/100009945). Writing and editorial support were also funded by the health care business of Merck KGaA, Darmstadt, Germany. No funding was given from these sources to the post-hoc study.

The post-hoc study was supported by the National Cancer Institute Surgical Oncology T32 Research Training Grant (T32CA009501-34) [WZ], the National Institutes of Health/National Cancer Institute grant (R37CA248289) [JJS], the National Institutes of Health/National Cancer Institute grant (K08CA255574) [PBR], and the National Institutes of Health/National Cancer Institute grant (1R37CA304010-01) [PBR]. This work was supported in part by National Institutes of Health/National Cancer Institute (NIH/NCI) Memorial Sloan Kettering Cancer Center (MSK) Support Grant [P30 CA008748]. Funding sources had no role in conducting this study or in the writing and submission of this manuscript. No individual, company, or agency has paid the authors to write this article.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Crane received honoraria from Elekta, owns stock in Oncturnal, and serves as a consultant for Trisalus.

Dr. Saltz serves as a consultant for Genor BioPharma.

Dr. Cercek receives research funding from Seagen, Rgenix, and GlaxoSmithKline. She also serves as a consultant for Bayer, GlaxoSmithKline, Incyte, Merck, Janssen, Seagen, and G1 Therapeutics.

Dr. Garcia-Aguilar owns stock in Intuitive Surgical and receives honoraria for Johnson & Johnson and Intuitive Surgical. He is also a consultant for Medtronic, Intuitive Surgical, and Johnson & Johnson.

Dr. Smith received travel support for fellow education from Intuitive Surgical (August 2015). He also served as a clinical advisor for Guardant Health (March 2019) and as a clinical advisor for Foundation Medicine (April 2022). He served as a consultant and speaker for Johnson and Johnson (May 2022). He served as a clinical advisor and consultant for GlaxoSmithKline (2023-24).

Dr. Romesser received research funding (2019) and serves as a consultant for EMD Serono (2018-present) and receives research funding from XRAD Therapeutics (2022-present). He also serves as a consultant for Faeth Therapeutics (2022-present), Natera (2022-present), Urogen, and Incyte, and is a volunteer on the advisory board for the HPV Cancers Alliance and Anal Cancer Foundation non-profit organizations.

All other authors have no conflicts of interest to disclose.