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Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting EGFR gene mutations, including exon 20 insertions (EGFRex20ins), in non–small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg/d, the most common any-grade treatment-related adverse events (TRAE; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade ≥3 TRAE >5%. Among 28 EGFRex20ins patients treated at 160 mg/d, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval, 24%–63%) with median duration of response of 14 months (5.0–not reached) and median progression-free survival of 7.3 months (4.4–15.6). Mobocertinib demonstrated antitumor activity in patients with diverse EGFRex20ins variants with a safety profile consistent with other EGFR inhibitors.Significance:No oral EGFR-targeted therapies are currently approved for patients with EGFRex20ins NSCLC. Mobocertinib demonstrated antitumor activity with manageable toxicity in patients with advanced EGFRex20ins NSCLC in this study, supporting additional development of mobocertinib in this patient population.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601

Carcinoma; Càncer de pulmó de cèl·lules no petites; Seguretat del pacient Carcinoma; Cáncer de pulmón de células no pequeñas; Seguridad del paciente Carcinoma; Non–small cell lung cancer; Patient safety Background Mobocertinib has demonstrated durable clinical benefit in platinum-pretreated patients (PPP) with epidermal growth factor receptor exon 20 insertion–positive non–small cell lung cancer (NSCLC). Research design and methods Pooled safety analysis of two studies included patients with NSCLC (N = 257) treated with the recommended phase 2 dose (RP2D) of mobocertinib (160 mg once daily). We report overall safety (treatment-emergent adverse events [TEAEs]) in the RP2D population; characterization of GI and skin-related events in 114 PPP from a phase 1/2 study (NCT02716116); and clinical activity in PPP with and without dose reductions due to TEAEs. Results In the RP2D population (N = 257), the most common TEAEs were diarrhea (93%), nausea (47%), rash (38%), and vomiting (37%). In PPP (N = 114), median times to diarrhea onset and resolution were 5 and 2 days, respectively. Median times to onset and resolution of skin-related events were 9 and 78 days, respectively. Among PPP with (n = 29) or without (n = 85) dose reductions due to TEAEs, overall response rates were 21% and 31% and median durations of response were 5.7 and 17.5 months, respectively. Conclusions GI and skin-related events are common with mobocertinib; minimizing dose reductions with proactive management may improve clinical outcomes. The paper received funding from Takeda Development Center Americas Inc., Lexington, MA, USA.

Mobocertinib, an oral, first-in-class epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor selective for

Introduction: Human biological specimen (biospecimen) donation is routinely requested for clinical care and research purposes. Successfully engaging patients and research participants in biospecime...

ABSTRACT Aims: Endovenous microwave ablation (EMWA) is a relatively new catheter-based endovenous thermoablation (EVTA) system to ablate incompetent truncal veins. Early results suggest that EMWA uses more power than endovenous laser ablation (EVLA) to get the same results. Therefore, we aimed to define the parameters for EMWA, which give the same tissue ablation as EVLA, using the previously validated porcine liver model. Methods: EVLA (1470nm and 600micron radial fibre) treatments were performed at 6W, 8W and 10W, at each pullback speed of 6, 7, 8 and 9 s/cm, giving a range of Linear Endovenous Energy Densities (LEEDs) between 36 – 90 J/cm. We repeated each combination of power and pullback five times. Following a preliminary screening process to identify parameters that gave similar results, we used EMWA in the same model. Powers of 35-75W and pullback speeds of 4-9 s/cm were used (LEEDs 140-675 J/cm). Ablation tracts from both devices were analysed by two blinded observers, noting thermal spread and carbonisation. Results: For each of the commonly used parameters for EVLA, we identified a range of power and pullback parameters for EMWA that produced similar tissue ablation in the porcine liver model. To keep the pullback speeds within the usual range, we used powers of 35-75W with EMWA, with mean EMWA LEEDs 3.9 - 5.8 times higher than EVLA LEEDs. We found the quicker the pullback speed, the higher the multiple of EMWA LEED we needed to get the same effect. Conclusion: We have identified parameters for EMWA that gave equivalent tissue ablation in the validated porcine liver model to commonly used parameters and LEEDs for EVLA. As the power during EMWA is higher than EVLA, EVMA LEEDs are approximately 4-6 times higher than EVLA LEEDs to achieve the same thermal effect on the tissues.

Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting EGFR gene mutations, including exon 20 insertions (EGFRex20ins), in non–small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg/d, the most common any-grade treatment-related adverse events (TRAE; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade ≥3 TRAE >5%. Among 28 EGFRex20ins patients treated at 160 mg/d, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval, 24%–63%) with median duration of response of 14 months (5.0–not reached) and median progression-free survival of 7.3 months (4.4–15.6). Mobocertinib demonstrated antitumor activity in patients with diverse EGFRex20ins variants with a safety profile consistent with other EGFR inhibitors. Significance: No oral EGFR-targeted therapies are currently approved for patients with EGFRex20ins NSCLC. Mobocertinib demonstrated antitumor activity with manageable toxicity in patients with advanced EGFRex20ins NSCLC in this study, supporting additional development of mobocertinib in this patient population. See related commentary by Pacheco, p. 1617. This article is highlighted in the In This Issue feature, p. 1601

Acute kidney injury (AKI) is a major health problem affecting millions of patients globally. There is no effective treatment for AKI and new therapies are urgently needed. Novel drug development, testing and progression to clinical trials is overwhelmingly expensive. Drug repurposing is a more cost-effective measure. We identified 2 commonly used drugs (colchicine and metformin) that alter inflammatory cell function and signalling pathways characteristic of AKI, and tested them in models of acute and chronic kidney injury to assess therapeutic benefit. We assessed the renoprotective effects of colchicine or metformin in C57BL/6 mice challenged with renal ischemia reperfusion injury (IRI), treated before or after injury. All animals underwent analysis of renal function and biomolecular phenotyping at 24 h, 48 h and 4 weeks after injury. Murine renal tubular epithelial cells were studied in response to in vitro mimics of IRI. Pre-emptive treatment with colchicine or metformin protected against AKI, with lower serum creatinine, improved histological changes and decreased TUNEL staining. Pro-inflammatory cytokine profile and multiple markers of oxidative stress were not substantially different between groups. Metformin augmented expression of multiple autophagic proteins which was reversed by the addition of hydroxychloroquine. Colchicine led to an increase in inflammatory cells within the renal parenchyma. Chronic exposure after acute injury to either therapeutic agent in the context of reduced renal mass did not mitigate the development of fibrosis, with colchicine significantly worsening an ischemic phenotype. These data indicate that colchicine and metformin affect acute and chronic kidney injury differently. This has significant implications for potential drug repurposing, as baseline renal disease must be considered when selecting medication.

Neuroendocrine tumors are a rare type of cancer found in hormone-producing cells throughout the body. Research on disease-specific patient education assessments in this population is lacking. We previously demonstrated the feasibility and validity of NET VITALS, a patient-centered self-assessment designed to improve patients’ knowledge of their neuroendocrine tumor diagnosis/treatment and facilitate communication with their physician. In this report, we provide a brief overview of patient assessments that have been used for patients with neuroendocrine tumors. We summarize NET VITALS and present a proposed infrastructure for its implementation into standard clinical care in both academic and community practice settings at City of Hope. Incorporating NET VITALS into standard of care treatment for patients with neuroendocrine tumors may improve patients’ overall clinical care experience.

Background: Higher rates of physical inactivity and comorbid conditions are reported in Hispanic and Black cancer patients receiving chemotherapy, compared to their White counterparts. Despite the beneficial effect of exercise training for cancer patients, rates of participation in clinical cancer trials are low among disadvantaged and racial and ethnic minority groups. This is possibly due to more barriers and less access to exercise training. Therefore, there is a crucial need for better understanding of how to apply exercise interventions using novel, accessible, and cost-effective home-based exercise approaches for Hispanic and Black communities, particularly during chemotherapy. In this study, we will examine the effect of supervised and unsupervised exercise on minutes of physical activity among Hispanic and Black cancer patients undergoing chemotherapy for breast, colorectal, and prostate cancer. Methods: The THRIVE trial is an 8-month prospective, three-arm study of 135 patients who are randomized in a 1:1:1 fashion to a supervised exercise intervention (SUP), unsupervised exercise (UNSUP), or an attention control group. Eligible patients include those with early-stage breast, colorectal, or prostate cancer, planning to receive chemotherapy, are sedentary, overweight or obese, and self-identifying as Hispanic or Black. Patients randomized to the SUP group participate in a home-based 16-week periodized aerobic and resistance exercise program performed three days per week, supervised through video conference technology. Patients randomized to the UNSUP group participate in an unsupervised 16-week, telehealth-based, periodized aerobic and resistance exercise program performed three days per week using the same exercise prescription parameters as the SUP group. The attention control group receive a 16-week home-based stretching program. The primary outcome is changes in minutes of physical activity assessed by 7-day accelerometry at month 4. Secondary outcomes include cardiovascular risk factors, patient-reported outcomes, and physical function. Outcome measures are tested at baseline, post-intervention at month 4, and after a non-intervention follow-up period at month 8. Discussion: The THRIVE trial is the first study to employ a novel and potentially achievable exercise intervention for a minority population receiving chemotherapy. In addition, this study utilizes an intervention approach to investigate the biological and behavioral mechanisms underlying exercise participation in these cancer patients. Results from this study will guide and inform large randomized controlled trials to test the effect of home-based exercise on treatment outcomes and comorbid disease risk in minority patients with cancer undergoing chemotherapy. Citation Format: Huimin Yan, Noelle Merchant, Ashley Desameau, Cherardi NeiraViscue, Paola Gonzalo-Encabo, Dong-Woo Kang, Rebekah L. Wilson, Mary K. Norris, Danny Nguyen, Daniel Gundersen, Laura L. Hayman, Rachel A. Freedman, Timothy Rebbeck, Christina M. Dieli-Conwright. Testing Home-based Exercise Strategies in Underserved Minority Cancer Patients Undergoing Chemotherapy (THRIVE) Trial: A study protocol [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C109.

Drug resistance remains one of the major impediments to treating cancer. Although many patients respond well initially, resistance to therapy typically ensues. Several confounding factors appear to contribute to this challenge. Here, we first discuss some of the challenges associated with drug resistance. We then discuss how a ‘Team Medicine’ approach, involving an interdisciplinary team of basic scientists working together with clinicians, has uncovered new therapeutic strategies. These strategies, referred to as intermittent or ‘adaptive’ therapy, which are based on eco-evolutionary principles, have met with remarkable success in potentially precluding or delaying the emergence of drug resistance in several cancers. Incorporating such treatment strategies into clinical protocols could potentially enhance the precision of delivering personalized medicine to patients. Furthermore, reaching out to patients in the network of hospitals affiliated with leading academic centers could help them benefit from such innovative treatment options. Finally, lowering the dose of the drug and its frequency (because of intermittent rather than continuous therapy) can also have a significant impact on lowering the toxicity and undesirable side effects of the drugs while lowering the financial burden carried by the patient and insurance providers.

We consider Presburger arithmetic (PA) extended by scalar multiplication by an algebraic irrational number $\alpha$, and call this extension $\alpha$-Presburger arithmetic ($\alpha$-PA). We show that the complexity of deciding sentences in $\alpha$-PA is substantially harder than in PA. Indeed, when $\alpha$ is quadratic and $r\geq 4$, deciding $\alpha$-PA sentences with $r$ alternating quantifier blocks and at most $c\ r$ variables and inequalities requires space at least $K 2^{\cdot^{\cdot^{\cdot^{2^{C\ell(S)}}}}}$ (tower of height $r-3$), where the constants $c, K, C>0$ only depend on $\alpha$, and $\ell(S)$ is the length of the given $\alpha$-PA sentence $S$. Furthermore deciding $\exists^{6}\forall^{4}\exists^{11}$ $\alpha$-PA sentences with at most $k$ inequalities is PSPACE-hard, where $k$ is another constant depending only on~$\alpha$. When $\alpha$ is non-quadratic, already four alternating quantifier blocks suffice for undecidability of $\alpha$-PA sentences.

We study VC-dimensions of short formulas in Presburger Arithmetic, defined to have a bounded number of variables, quantifiers and atoms. We give both lower and upper bounds, which are tight up to a polynomial factor in the bit length of the formula.

Background Although autism spectrum disorders (ASD) have been associated with developmental outcomes and parenting stress, it is not known how all variables interact with each other. We estimated prospective associations between ASD screening scores at 24 months and socio-emotional-cognitive development at 36 months while considering parenting stress as a potential moderator of the outcome. Methods Using the Conditions Affecting Neurocognitive Development and Learning in Early Childhood data, ASD-risk behaviors at 24 months and child maturity levels in social, emotional, and cognitive domains at 36 months were reported (N = 1100). Results The number of ASD-type behaviors at 24 months was significantly associated with the socio-emotional-cognitive risk index at 36 months (B = .31, p Conclusions ASD screening scores and parenting stress interact together to have an effect on later child developmental competence. This study suggests that interventions towards early ASD symptoms and parenting stress could enhance subsequent child developmental competence, which is a strong building block for early school readiness and personal success.

3006 Background: NRG1 fusions are rare oncogenic drivers found in ̃0.2% of all solid tumors. These fusions elicit ERBB3/HER3 overactivation to drive tumor growth and cancer cell survival. Currently there are no approved targeted therapies for NRG1 fusion-positive tumors. Furthermore, patients (pts) with tumors harboring NRG1 fusions have poor outcomes with standard therapies. Seribantumab is a fully human anti-HER3 IgG2 monoclonal antibody that suppressed tumor growth in NRG1 fusion-driven preclinical models. Here, we present initial clinical data from the CRESTONE study (NCT04383210). Methods: CRESTONE is a Phase 2, global, multicenter, open-label study of seribantumab in adult pts with locally advanced or metastatic solid tumors harboring NRG1 fusions. A dose ranging phase established the RP2D as a 3g once weekly (QW) intravenous dose administered until treatment discontinuation criteria are met. In the expansion phase, cohort 1 will enroll at least 55 pts who had received at least one prior therapy and are naïve to ERBB-targeted therapy. Exploratory cohorts 2 or 3 will enroll pts previously treated with ERBB-targeted therapies and/or tumors harboring additional molecular alterations. The primary endpoint is objective response rate (ORR) by independent central review per RECIST v1.1. Initial data from cohort 1 pts who received seribantumab 3g QW with investigator (INV)-assessed response per RECIST v1.1 are reported. Results: By JAN-13-2022, 12 pts have received seribantumab 3g QW in cohort 1. Median age was 65 years (range 44–76), 67% were female, and median number of prior therapies was 1 (range 1–5). 92% (11/12) of pts had non-small cell lung cancer (NSCLC); 5 different NRG1 fusion partners ( ATP1B1, CD74, ITG B1, SDC4, SLC3 A2) were reported by local next-generation sequencing tests. Among 10 pts evaluable for INV-assessed response, the confirmed ORR was 30%, and the disease control rate was 90% (1 complete response, 2 partial responses, 6 stable disease, 1 progressive disease). 58% (7/12) of pts remain on study treatment, including 2 pts with NSCLC who achieved objective responses with an ongoing duration of response of 6 and 8.5 months. Seribantumab 3g QW was well tolerated with no drug discontinuations or dose reductions. Across all cohorts (n = 29), the most frequently (≥20%) reported treatment-related adverse events (TRAEs) were diarrhea (38%), fatigue (34%), and rash (24%), all were grade 1 or 2. One grade 3 TRAE of vomiting occurred; there were no Grade 4 or 5 TRAEs. Efficacy analysis is ongoing and updated efficacy data from evaluable pts in cohort 1 will be presented. Conclusions: Initial data indicate seribantumab induced durable responses in advanced solid tumors harboring NRG1 fusions and has a favorable safety profile. These data support the continued evaluation of seribantumab in NRG1 fusion-positive solid tumors in the ongoing CRESTONE study. Clinical trial information: NCT04383210.

9115 Background: Mobocertinib (mobo) and amivantamab (ami) are FDA-approved treatments for patients (pts) with locally advanced or metastatic NSCLC with EGFR ex20ins whose disease progressed on or after platinum-based chemotherapy. An unanchored MAIC was used to compare confirmed overall response rate (cORR), duration of response (DoR), progression-free survival (PFS) and overall survival (OS) between mobo and ami. Methods: Clinical outcomes were compared in platinum-pretreated pts with EGFR ex20ins+ NSCLC treated with mobo 160 mg QD in a phase I/II single-arm study (NCT02716116, cut-off 1 Nov 2020, n=114) or with ami 1,050 mg (1,400 mg, ≥80 kg) in a phase I single-arm study (NCT02609776, cut-off 8 June 2020, n=81). Differences in baseline characteristics reported in both studies, including age, race, sex, smoking status, Eastern Cooperative Oncology Group, histology, sites of metastasis (brain, bone and liver), time from advanced diagnosis, number of prior lines of therapy, prior immuno-oncology therapy, prior EGFR tyrosine kinase inhibitor treatment and prior EGFR ex20ins targeted therapy, were adjusted with MAIC. Results: After MAIC weighting all reported baseline characteristics were balanced between mobo and ami. OS and cORR per investigator assessment (INV) were similar between mobo and ami (Table). cORR per independent review committee (IRC) was numerically higher for ami (odds ratio [OR]=0.64, p value=0.230). For PFS per IRC, the adjusted hazard ratio (HR) was numerically favorable for mobo (HR=0.82, p value=0.417). Among the responders, DoR was longer for mobo (DoR per INV: HR=0.44, p value=0.049; DoR per IRC: HR=0.56, p value=0.149). Conclusions: Mobo and ami appear to have overall similar efficacy. As each has a different mechanism of action and route of administration, they provide multiple options in the treatment of EGFR ex20ins+ NSCLC. Clinical trial information: NCT02716116. [Table: see text]

9007 Background: EGFR ins20-mutant NSCLC has historically been challenging to treat. While new agents targeting EGFR ins20 have recently been approved, adverse events (AEs), particularly wild type (WT) EGFR-related AEs are common. CLN-081 is a novel EGFR tyrosine kinase inhibitor (TKI) with broad activity against EGFR mutations, including ins20, and increased selectivity for ins20 versus WT EGFR. CLN-081 has been granted FDA Breakthrough Therapy Designation for the treatment of pts with EGFR ins20 NSCLC. We present updated results of the initial multicenter Ph1/2a study of CLN-081 in pts with advanced, EGFR ins20-mutant NSCLC, including 39 pts treated in an expanded cohort at the dose of 100 mg twice daily (BID). Methods: Ph1 dose escalation utilized an accelerated titration (AT) and rolling six design. Individual cohorts were expanded in Phase 1 and 2a based on prespecified protocol criteria. Pts were required to have received prior platinum-based chemotherapy. Stable, treated brain metastasis (mets) were allowed. CLN-081 is dosed in 21-day cycles. Results: As of 13 December 2021, 73 pts [median age: 65 (36-82), median lines of prior therapy: 2 (1-9), 28 (39%) with a history of brain mets] received CLN-081 at 30 mg (8), 45 mg (1), 65 mg (14), 100 mg (39), and 150 mg (11), all BID. Treatment-related AEs in ≥ 15% of pts were rash (74%), diarrhea (27%), paronychia (25%), fatigue (19%), anemia (18%), dry skin (18%), nausea (16%). Treatment-related Gr ≥ 3 AEs in ≥ 4 % of pts included anemia (10%), increased ALT (4%), and increased AST (4%). Gr 3 rash and Gr 3 diarrhea were observed in 1 and 2 pts, respectively, at 150 mg BID, while no pts treated at ≤ 100 mg BID experienced Gr 3 rash or diarrhea. Treatment-related dose reductions and discontinuations across all dose levels occurred in 10 pts (14%) and 5 pts (7%) respectively. Among 70 response-evaluable pts across all dose levels, 25 (36%) had a confirmed partial response (PR), 34 (49%) had stable disease (SD), and 3 (4%) had progressive disease as a best response. Seven pts (10%) had a PR that remained unconfirmed; 1 (1%) pt was pending a confirmatory scan. Of 36 response-evaluable pts at 100 mg BID, 14 (39%) had a confirmed PR, 17 (47%) had SD, and 1 (3%) had PD. Three pts had a PR that remained unconfirmed (8%); 1 (3%) pt was pending a confirmatory scan. Notably, among Ph1 pts treated at 100 mg BID (N = 13) in whom longer follow-up is available, the mDOR and mPFS (estimated by Kaplan-Meier) was > 15 months and 12 months, respectively. Disease control (SD ≥ 6 months or any PR) was observed in 12/13 pts (92%). Updated data with additional follow-up will be presented. Conclusions: In pts with heavily-pretreated advanced EGFR ins20 NSCLC, CLN-081 has a manageable safety profile, with anti-tumor activity across the range of doses tested. Further, CLN-081 has demonstrated a favorable clinical profile at the dose of 100 mg BID, with an encouraging objective response rate, response durability, and no Gr 3 rash or diarrhea. Clinical trial information: NCT04036682.

TPS9155 Background: Oncogenic EGFR ex20ins mutations, found in ̃2% of non-small cell lung cancers (NSCLC) and a small percentage of other cancers, are generally not responsive to EGFR-targeted agents that have been approved for treatment of NSCLC with a common EGFR mutation, including L858R and exon 19 deletion. Similar to these more common types of EGFR-mutated NSCLC, CNS metastases are a challenge with EGFR ex20ins NSCLC and are associated with poor outcomes. While two EGFR ex20ins-targeting drugs were recently approved by the FDA (amivantamab and mobocertinib), neither have established CNS activity. BLU-451 is a CNS penetrant, wild type-sparing, covalent small molecule inhibitor of EGFR ex20ins as well as atypical (G719C, G719S, L861Q) and common EGFR mutants. Preclinical data have shown BLU-451 to have potent antitumor activity, including in an intracranial xenograft model, which has led to its clinical development in EGFR-mutant NSCLC. Methods: BLU-451-1101 (NCT05241873) is a phase 1/2, global, open-label study designed to evaluate single-agent BLU-451 in patients with NSCLC harboring EGFR ex20ins that has progressed following prior treatment for incurable recurrent or metastatic disease. Patients with Eastern Cooperative Oncology Group performance status 0–1 and EGFR ex20ins, exon 18 G719X or exon 21 L861Q mutant NSCLC (phases 1 and 2) or other cancers except primary CNS tumors (phase 1 only) are eligible. Patients with known ROS, RAF, ALK, or EGFR C797S mutations will be excluded. Stable, asymptomatic brain metastases are permitted, and active asymptomatic brain metastases are permitted in specific cohorts. Primary endpoints are determination of maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and tolerability (phase 1), in addition to evaluation of antitumor activity at the RP2D by RECIST v1.1 (phase 2). Secondary endpoints are evaluation of pharmacokinetics (PK) and antitumor activity by RECIST v1.1.(phase 1) and PK, safety, tolerability, and CNS antitumor activity (phase 2). Dose escalation will utilize a 3+3 design with up to 6 patients per cohort in phase 1 dose escalation and up to 12 per cohort in phase 1 dose expansion. Phase 2 will enroll patients in 3 cohorts (n = 18 each): patients with prior platinum-based chemotherapy and an EGFR ex20ins-targeted agent; patients with prior platinum but no EGFR ex20ins-targeted agent; and patients with active asymptomatic brain metastases with prior platinum with or without an EGFR ex20ins-targeted agent. The study is planned for approximately 40 centers in North America, the Asia-Pacific region, and/or Europe. Clinical trial information: NCT05241873.

We extend the Barvinok-Woods algorithm for enumerating projections of integer points in polytopes to unbounded polyhedra. For this, we obtain a new structural result on projections of semilinear subsets of the integer lattice. We extend the results to general formulas in Presburger Arithmetic. We also give an application to the k-Frobenius problem.

Importance Metastatic non–small cell lung cancer (mNSCLC) withEGFRexon 20 insertion (EGFRex20ins) mutations is associated with a poor prognosis. Mobocertinib is an oral tyrosine kinase inhibitor designed to selectively targetEGFRex20ins mutations. Objective To evaluate treatment outcomes and safety of mobocertinib in patients with previously treatedEGFRex20ins-positive mNSCLC. Design, Setting, and Participants This 3-part, open-label, phase 1/2 nonrandomized clinical trial with dose-escalation/dose-expansion cohorts (28 sites in the US) and a single-arm extension cohort (EXCLAIM; 40 sites in Asia, Europe, and North America) was conducted between June 2016 and November 2020 (data cutoff date). The primary analysis populations were the platinum-pretreated patients (PPP) cohort and the EXCLAIM cohort. The PPP cohort included 114 patients with platinum-pretreatedEGFRex20ins-positive mNSCLC who received mobocertinib 160 mg once daily from the dose-escalation (n = 6), dose-expansion (n = 22), and EXCLAIM (n = 86) cohorts. The EXCLAIM cohort included 96 patients with previously treatedEGFRex20ins-positive mNSCLC (10 were not platinum pretreated and thus were excluded from the PPP cohort). Interventions Mobocertinib 160 mg once daily. Main Outcomes and Measures The primary end point of the PPP and EXCLAIM cohorts was confirmed objective response rate (ORR) assessed by independent review committee (IRC). Secondary end points included confirmed ORR by investigator, duration of response, progression-free survival, overall survival, and safety. Results Among the PPP (n = 114) and EXCLAIM (n = 96) cohorts, the median (range) age was 60 (27-84) and 59 (27-80) years, respectively; most patients were women (75 [66%] and 62 [65%], respectively) and of Asian race (68 [60%] and 66 [69%], respectively). At data cutoff, median follow-up was 14.2 months in the PPP cohort (median 2 prior anticancer regimens; 40 [35%] had baseline brain metastases), with confirmed ORR of 28% (95% CI, 20%-37%) by IRC assessment and 35% (95% CI, 26%-45%) by investigator assessment; median duration of response by IRC assessment was 17.5 months (95% CI, 7.4-20.3). Median progression-free survival by IRC assessment was 7.3 months (95% CI, 5.5-9.2). Median overall survival was 24.0 months (95% CI, 14.6-28.8). In the EXCLAIM cohort, median follow-up was 13.0 months, with confirmed ORR by IRC assessment of 25% (95% CI, 17%-35%) and by investigator assessment of 32% (95% CI, 23%-43%). The most common treatment-related adverse events were diarrhea and rash. Conclusions and Relevance In this open-label, phase 1/2 nonrandomized clinical trial, mobocertinib was associated with clinically meaningful benefit in patients with previously treatedEGFRex20ins-positive mNSCLC, with a manageable safety profile. Trial Registration ClinicalTrials.gov Identifier:NCT02716116

3097 Background: Allosteric oncogenic mutations occur outside the canonical ATP-binding site of EGFR and HER2, and there are no approved therapies that target such mutations. BDTX-189 is a potent, selective, irreversible inhibitor of 48 allosteric EGFR and HER2 mutant variants under clinical evaluation in the ongoing MasterKey-01 trial (NCT04209465). BDTX-189 was designed to rapidly and irreversibly occupy the active site of targeted ErbB mutants, leading to sustained pharmacodynamic (PD) effects, and with selectivity over EGFR-WT in order to minimize EGFR-WT mediated toxicities. The pharmacokinetic (PK) profile was designed for rapid absorption and fast elimination to maintain target occupancy while minimizing prolonged drug exposure that could contribute to off-target associated toxicities. Methods: In MasterKey-01, BDTX-189 was administered orally once daily in continuous 21-day cycles, taken fasted. Dose escalation included cohorts of 1-2 patients receiving doses between 25 and 200 mg QD followed by 5-7 patients receiving 400 mg, 800 mg, or 1,200 mg QD fasted. The possible effects of a high fat meal on the PK of BDTX-189 were assessed in a subset of patients receiving single doses of 400 mg BDTX-189 fasted and immediately after a high-fat breakfast in a randomized crossover fashion with 3 days between doses. In addition, a dose escalation cohort investigating administration of BDTX-189 non-fasted was enrolled at 800 mg QD. Serial blood samples for analysis of plasma BDTX-189 concentrations were collected after each dose on C1D1 and C1D15. BDTX-189 levels were determined using LC-MS, and data analyzed using non-compartmental methods. Results: After single and multiple doses, BDTX-189 was rapidly absorbed (median tmax 1-2 h), with an elimination t1/2 of 2-6 h. Dose-dependent increases in exposure from 200 to 800 mg QD fasted were observed, with no apparent accumulation or decline in exposures observed at steady-state. Administration of BDTX-189 with a high-fat meal increased AUC approximately 1.7-fold with minimal effect on Cmax, relative to administration in the fasted state. At 800 mg QD, mean AUC was similar in the non-fasting state relative to fasting and was within the target efficacious range defined by mouse models harboring allo-ErbB mutated tumors. Median tmax and t1/2 values were similar after administration in the non-fasted and fasted states. Conclusions: BDTX-189 demonstrated rapid absorption and a short PK half-life consistent with the desired PK/PD profile, with exposures in the efficacious target range based on preclinical data. The pilot high fat food-effect data and non-fasting QD dosing regimen show similar or improved systemic exposure relative to dosing in the fasted state. The MasterKey-01 trial is ongoing, including refinement of the dosing regimen and identification of the recommended phase 2 dose. Clinical trial information: NCT04209465.

9077 Background: NSCLC with EGFR ins20 represents a significant area of unmet need, with no approved targeted therapies. While several agents targeting EGFR ins20 are in development, wild-type (WT) EGFR-related adverse events (AEs) have been common and challenging to manage. CLN-081 is a novel oral EGFR TKI with broad activity against clinically relevant EGFR mutations, including ins20, and has attenuated activity against WT EGFR relative to EGFR ins20 in vitro, suggesting that CLN-081 may have a more favorable clinical therapeutic window. We present interim results of a multicenter, Phase (Ph) 1/2a trial evaluating CLN-081 in advanced, EGFR ins20 NSCLC (NCT04036682). Methods: Patients (pts) with EGFR ins20 previously treated with platinum-based therapy (tx) were eligible to enroll. Ph 1 dose escalation in this adaptive trial began with an accelerated titration (AT) design, and converted to a rolling six design based upon pre-specified safety criteria or at clinically active doses. Cohort expansion in Ph 1 occurred at any dose where responses were seen. Transition from Ph 1 to 2a was based on a Simon-Two Stage design. Prior tx with EGFR ins20-specific inhibitors was allowed in AT cohorts only. CLN-081 was dosed twice daily (BID) in 21-day cycles. Results: As of 10 November 2020, 37 pts [median age 64 years (44-82); median 2 (1-9) prior lines of tx] received CLN-081 at doses of 30 mg (n = 8), 45 mg (1), 65 mg (12), 100 mg (13), and 150 mg (3) BID. The most common all-grade (gr) treatment-related AEs (TRAEs) were rash (49%), diarrhea (24%), paronychia (16%), nausea (14%), stomatitis (14%), and dry skin (11%). Gr 3 TRAEs included anemia (5%), diarrhea (3%), and increased alkaline phosphatase (ALP) (3%). There was 1 DLT, gr 3 diarrhea at 150 mg BID. No gr ≥ 3 rash or gr 4/5 TRAEs were reported. Four pts (11%) required dose reductions for rash (2), diarrhea (1), and increased ALP (1). Two pts (5%) discontinued tx due to TRAEs of gr 2 hypersensitivity reaction (1) and gr 2 pneumonitis (1); the latter also experienced pneumonitis while receiving prior osimertinib. Among the 25 response evaluable pts (RECIST 1.1), 10 (40 %) had a partial response (PR) (6 confirmed, 2 pending confirmation, 2 unconfirmed), 14 (56%) had stable disease (SD), and 1 (4%) had progressive disease as best response. Of the 4 pts that received prior EGFR ins20 inhibitors, 2 had PR and 2 SD. Of pts with SD or PR as best response, 20/24 (83 %) experienced tumor regression [median regression: -18 % (-100 to +3)]. Enrollment is ongoing and updated data will be presented. Conclusions: CLN-081 has an acceptable safety profile, including diarrhea in < 25% of pts treated to date. CLN-081 has demonstrated encouraging preliminary anti-tumor activity across the full dose range tested, in multiple distinct EGFR ins20 variants, and in heavily pre-treated pts that are either naïve or refractory to other EGFR ins20 inhibitors. Since the time of the data cut, a Ph 2a expansion has been initiated at 100 mg BID. Clinical trial information: NCT04036682.

3086 Background: BDTX-189 is an orally available, ATP-competitive and irreversible inhibitor directed against families of allosteric HER2 and EGFR oncogenic mutations. In preclinical studies BDTX-189 achieved potent inhibition of 48 allosteric HER2 and EGFR/HER2 exon 20 insertion mutant variants with selectivity versus EGFR wild-type (WT) and demonstrated tumor growth inhibition and regression in vivo. The primary objective of the Ph 1 portion of this trial (NCT04209465) is to determine the RP2D and schedule of monotherapy BDTX-189 in pts with advanced solid tumors. Methods: Eligibility includes pts with relapsed or refractory locally advanced or metastatic solid tumors with no standard therapy available whose tumor harbors an allosteric HER2 or HER3 mutation; EGFR or HER2 exon 20 insertion mutation; HER2 amplification or overexpression; or EGFR exon 19 deletion or L858R mutation. BDTX-189 is dosed continuously orally in 3-wk cycles QD and BID in separate dose escalation cohorts. A separate cohort is also evaluating the high- and low-fat food-effect (FE) on BDTX-189 PK. Results: As of 1/11/21, 46 pts have been dosed, with 36 in the QD (fasting) schedule (25-1200 mg), including pts from the FE cohort who received 800 mg QD fasting after FE evaluation: 58% female; 67% white; median age 63.5 yrs; 53% received ≥ 3 prior tx lines. Cancer types: 12 NSCLC, 5 breast, 4 ovary, 3 biliary, and 12 other. Genomic alterations: 23 HER2 amplification and the following mutations: 11 allosteric HER2, 5 EGFR exon 20 insertion, 5 HER2 exon 20 insertion, 3 EGFR exon 19 del./L858R, and 2 HER3. At ≥ 800 mg QD, 3 and 2 pts had EGFR or HER2 exon 20 mutations, respectively. The maximum tolerated dose (MTD) for QD (fasting) was 800 mg, with 2/6 pts with DLTs at 1200 mg. DLTs: gastrointestinal (G3 diarrhea; G1/2 nausea/vomiting). The most frequent (≥20%) related adverse events were diarrhea (36%, 8% G3), nausea (28%, 0% G3), and vomiting (25%, 3% G3). The rate of skin disorders was 11% with the highest severity of G2 in 1 pt. Dose-dependent exposure increases were observed, with the exposure at 800 mg QD fasting within the projected efficacious range. Pilot FE data suggest possible increased exposure with food. 27 pts were evaluable for efficacy, 15 at ≥ 800 mg QD, with 2 partial responses observed: 1 PR confirmed and ongoing (800 mg QD, CUP, HER2 amp, 3 prior lines of chemo) and 1 PR unconfirmed (NSCLC with brain mets, 1200 mg QD, HER2 amp + exon 19 del., 2 prior EGFR TKIs). 3 pts had a best response of SD and 10 with progressive disease. Conclusions: BDTX-189 has a generally manageable safety profile with early evidence of anti-tumor activity. Enrollment is ongoing in non-fasting QD and BID cohorts, and the FE cohort, prior to RP2D identification. Clinical trial information: NCT04209465.

9098 Background: There is currently no targeted therapy approved for patients with EGFR exon 20 insertion mutations (exon20ins) in NSCLC. Real world treatment outcome evidence for this rare population is limited. This study describes treatment patterns and outcomes in US patients with advanced NSCLC with EGFR exon20ins. Methods: The nationwide Flatiron Health electronic health record-derived deidentified database (cut-off 29 Feb 2020) was used to select 4 separate cohorts: (1) first-line (1L): patients receiving 1L therapy after documented exon20ins (1L start date as index date); (2) second or later line (≥2L): patients receiving ≥2L therapy after documented exon20ins (start date of ≥2L as index date); (3) ≥2L trial-aligned: ≥2L patients with baseline characteristics aligned with the key eligibility criteria of mobocertinib Trial NCT02716116 Part 3; and (4) ≥2L post platinum: ≥2L trial-aligned patients previously treated with platinum-based chemotherapy. Real-world endpoints were: confirmed overall response rate (cORR), PFS, and OS. Additional analyses were conducted for patients treated with immune-oncology therapy (IO). Results: Of 237 EGFR exon20ins patients, 129 patients were included in 1L cohort and 114 were in ≥2L cohort, including 63 ≥2L trial-aligned and 50 ≥2L post platinum patients. In 1L patients, EGFR TKI (28.7%) and platinum-based chemotherapy ± IO (56.6%) were the most common 1L regimens. In ≥2L patients, 28.1% received IO monotherapy, 17.5% received EGFR TKI, and 23.7% received platinum-based chemotherapy ± IO as index treatment. In the 1L setting, median PFS (mPFS) was 5.7 months for platinum-based chemotherapy and 4.5 months for IO + platinum-based chemotherapy. In the ≥2L setting, mPFS was 3.7 months for any therapy and 2.3 months for IO monotherapy. Full effectiveness data are provided in the accompanying table. Conclusions: This real world study provided a benchmark on the treatment outcome in patients with advanced NSCLC with EGFR exon20ins. Platinum-based chemotherapy was the most common 1L therapy and provided the longest mPFS. Immunotherapy, either as monotherapy or in combination with chemotherapy, appeared less effective for treatment of NSCLC with EGFR exon20ins. There is an unmet medical need for improved therapeutic options.[Table: see text]

Background/Aim: Acute pancreatitis (AP) is a commonly encountered emergency where early identification of complicated cases is important. Inflammatory markers like lymphocyte to monocyte ratio (LMR) and neutrophil to lymphocyte ratio (NLR) are simple and readily available markers. In this study, we evaluated the utility of these markers in the early identification of patients with complicated AP. Patients and Methods: All patients with a diagnosis of AP admitted to the University Medical Center in Las Vegas/Nevada between August 2015 and September 2018 were identified using ICD-10 codes. Medical records were reviewed retrospectively. Epidemiological measures and their associated confidence intervals were calculated using MedCalc (v. 18). Results: The LMR showed a significant difference between groups, with the non-complicated cases consistently higher than the complicated cases but without significant temporal differences. The NLR showed a significant difference with a significant temporal relation. Using the bound of the 95% confidence interval separating the two groups, LMR 10.5 was suggestive of a complicated case. High specificity (85–92%) with low sensitivity (23–69%) was noted; hence, these cut points were very good at discerning non-complicated cases. Conclusion: Our data show persistently low LMR that is associated with severe AP and a value of 10.5 that can be used to predict severe complicated AP and to monitor response to treatment over time.

We consider an expansion of Presburger arithmetic which allows multiplication by $k$ parameters $t_1,\ldots,t_k$. A formula in this language defines a parametric set $S_\mathbf{t} \subseteq \mathbb{Z}^{d}$ as $\mathbf{t}$ varies in $\mathbb{Z}^k$, and we examine the counting function $|S_\mathbf{t}|$ as a function of $\mathbf{t}$. For a single parameter, it is known that $|S_t|$ can be expressed as an eventual quasi-polynomial (there is a period $m$ such that, for sufficiently large $t$, the function is polynomial on each of the residue classes mod $m$). We show that such a nice expression is impossible with 2 or more parameters. Indeed (assuming \textbf{P} $\neq$ \textbf{NP}) we construct a parametric set $S_{t_1,t_2}$ such that $|S_{t_1, t_2}|$ is not even polynomial-time computable on input $(t_1,t_2)$. In contrast, for parametric sets $S_\mathbf{t} \subseteq \mathbb{Z}^d$ with arbitrarily many parameters, defined in a similar language without the ordering relation, we show that $|S_\mathbf{t}|$ is always polynomial-time computable in the size of $\mathbf{t}$, and in fact can be represented using the gcd and similar functions., Comment: 14 pages, 1 figure

We prove that the problem of minimizing the number of integer points in parallel translations of a rational convex polytope in $${\mathbb {R}}^6$$ is NP-hard. We apply this result to show that given a rational convex polytope $$P\subset {\mathbb {R}}^6$$ , finding the largest integer t s.t. the expansion tP contains fewer than k integer points is also NP-hard. We conclude that the Ehrhart quasi-polynomials of rational polytopes can have arbitrary fluctuations.