AIM:Sunitinib has marked pharmacokinetic (PK) and pharmacodynamic (PD) interpatient variability. This study evaluated the utility of extensive excretory/metabolic/PD pharmacogenomics (PGx) with hepatic functional imaging (HNI) to explore their associations with sunitinib PK/PD (toxicity/response) and progression-free survival (PFS), respectively. METHODS:Eligible patients (pts) suitable for sunitinib therapy. At baseline: (i) PGx: blood analysed by the Affymetrix DMET™ Plus Array (1936 variants/225 genes) and Sanger sequencing (HNF1A, FLT3, VEGFR2, VEGFR3, RET, PDGFRα, TNFα). (ii) HNI: pts given IV 800 MBq 99mTc-MIBI, imaging data analysed for hepatic extraction/excretion parameters (CLHNI, T1/2-HNI, 1hRET, HEF, Td1/2). In cycles 1 and 2, bloods taken for sunitinib parent (SU), metabolite (SU12662) and total SU (metabolite + parent) PK. Associations evaluated between (i) HNI parameters and (2) PGx, with sunitinib PK, toxicity/response and PFS. RESULTS:N = 15 pts. The two most significant associations in either direction between PGx variants or HNI parameters (p < .05) for: (i) PK included: (a) SU logAUC0-14days with HEF, ATP7B (rs1801246) and UGT8 (rs4148254); (b) SU logAUC0-28days, with Td1/2, SLC15A1 (rs8187832) and SLC10A2 (rs188096); (c) SU12662 logAUC0-14days with HEF, ABCC3 (rs11568591), PPARD (rs1003973) and SLC15A1 (rs8187840); and (d) SU12662 logAUC0-28days with SULT1A2 (rs1059491) and SLC10A2 (rs188096). (ii) Toxicity: (a) Diarrhoea grade 1+ with HEF, VEFGR3 (rs307826) and AKAP9 (rs7785971); (b) ≥grade 3 AEs with CBR1 (rs998383); (iii) overall response rate with SULT1E1 (rs1881668) and GSTA2 (rs2180314); and (iv) PFS with CYP4Z1 (rs4926802) and CYP2A6 (rs28399442). CONCLUSIONS:Exploratory associations were observed between sunitinib PK/PD with hepatic functional imaging with extensive pharmacogenomics. Further validation is required.

BACKGROUND:MRI is recommended for men with clinical suspicion of significant prostate cancer. Those with high clinical risk but non-suspicious or equivocal MRI often undergo prostate biopsy, but have a low likelihood of clinically significant prostate cancer, and a high incidence of clinically insignificant prostate cancer. We aimed to investigate whether gallium-68 ([68Ga]Ga)-prostate-specific membrane antigen (PSMA)-11 PET-CT could reduce the number of people requiring prostate biopsy and limit biopsy to targeted cores, without compromising clinically significant prostate cancer diagnosis. METHODS:In this multicentre, non-inferiority, phase 3, randomised controlled trial, done at at seven Australian hospitals, we recruited biopsy-naive participants with clinical suspicion of significant prostate cancer, equivocal (Prostate Imaging-Reporting and Data System [PI-RADS] 3) or non-suspicious (PI-RADS 2) MRI but high clinical risk (eg, prostate-specific antigen [PSA] density of >0·1 ng/mL/mL, strong family history of prostate cancer, abnormal digital rectal examination, BRCA mutation, PSA >10 ng/mL, PSA doubling time <36 months, or PSA velocity >0·75 ng/mL per year), PSA of 20 ng/mL or less, and clinical T2 disease or less. Participants were randomly assigned (1:1) using a centralised web-based system to undergo [68Ga]Ga-PSMA-11 PET-CT (experimental group) or systematic transperineal prostate biopsy (control group), using block sizes of two or four and stratification by study site. There was no masking for participants or investigators. Participants with positive [68Ga]Ga-PSMA-11 PET-CT (PRIMARY score 3-5) underwent PSMA-PET-targeted transperineal prostate biopsies, whereas those with a negative result (PRIMARY score 1-2) avoided biopsy. The co-primary outcomes were the proportion of participants with clinically significant prostate cancer, defined as a Gleason score of 3 + 4 (≥10% pattern 4) or higher, and the proportion of participants in the [68Ga]Ga-PSMA-11 PET-CT group who avoided biopsy within 6 months of random assignment. A two-sided 95% Wald CI based on a binomial model was used to estimate the risk difference in the proportion of participants with clinically significant prostate cancer (non-inferiority margin 10%) and to estimate the proportion of participants in the experimental group who had avoided biopsy 6 months after random assignment (20% threshold), analysed based on intention to treat. This trial is registered with ClinicalTrials.gov, NCT05154162, and participant follow-up is ongoing. FINDINGS:Between March 2, 2022, and Aug 24, 2025, 660 eligible male participants were enrolled and had a median age of 61 years (IQR 56-66), a median PSA of 5·2 ng/mL (4·0-7·0), and a median PSA density of 0·13 ng/mL/mL (0·09-0·17). There were PI-RADS 2 in 335 (51%) participants and PI-RADS 3 in 325 (49%) participants. Ethnicity data were not collected. 329 (50%) were assigned to the control group with systematic transperineal prostate biopsy, and 331 (50%) were assigned to the experimental group with [68Ga]Ga-PSMA-11 PET-CT. The proportion of participants with clinically significant prostate cancer in the experimental group (39 [12%] of 331) was non-inferior to the control (51 [16%] of 329; difference -3·7% [95% CI -8·9 to 1·5%]; p=0·0093). Use of [68Ga]Ga-PSMA-11 PET-CT avoided biopsy in 163 (49%) of 331 participants (95% CI 44 to 55%; p <0·0001). After prostate biopsy, participants reported similar proportions of pain (33 [21%] in the experimental group vs 62 [21%] in the control group), haematuria (60 [38%] vs 126 [43%]), and haematospermia (77 [48%] vs 133 [45%]). INTERPRETATION:[68Ga]Ga-PSMA-11 PET-CT could have the potential to improve the diagnostic pathway of patients with a high clinical risk but non-suspicious or equivocal prostate MRI. Further research, including health-economic analyses and validation with other PSMA radiopharmaceuticals, are needed to confirm the clinical implementation and generalisability of this approach. FUNDING:Prostate Cancer Foundation, National Health and Medical Research Council, St Vincent's Curran Foundation, and Peter MacCallum Cancer Foundation.

OBJECTIVE:This study aimed to evaluate the outcomes of patients with node-positive vulvar carcinoma treated with radiotherapy, with or without chemotherapy, administered with curative intent, focusing on patterns of first failure, locoregional control, and overall survival. METHODS:Patients were eligible if they had a histologic diagnosis of node-positive vulvar cancer and were referred for curative-intent radiotherapy, with or without chemotherapy, either as the primary treatment or in the adjuvant setting following definitive surgery between January 2000 and December 2019 at our institution. Eligible patients were selected from the prospective database of the gynecology oncology unit, where clinical, histopathologic, treatment, and follow-up data were systematically collected for analysis. RESULTS:Out of 256 patients with vulvar cancer, 88 (34.4%) patients met the inclusion criteria. The median age was 65 years (range; 33-90). Sixty-two patients underwent surgery and adjuvant radiotherapy, of whom 57 (92%) received concomitant chemotherapy. Twenty-four patients received definitive chemoradiotherapy and 2 received definitive radiotherapy alone. The median total dose to the primary site was 54 Gy in the definitive setting and 45 Gy in the adjuvant setting. The median dose was 54 Gy (range; 45-60) to gross inguinal nodes (n = 48) and 54 Gy (range; 34-64) to gross primary disease (n = 26). The median follow-up was 5.3 years (range; 0.1-21.8). Five-year overall survival was 62% in the adjuvant group and 50% in the definitive group. Of 88 patients, 46 (52%) relapsed; 16 of 46 (35%) had failure at the primary site alone. Disease control at the primary site and nodes was 64% (95% CI; 48%-75%) in the adjuvant group and 49% (26%-68%) in the definitive group at 5 years. CONCLUSIONS:Locoregional control and overall survival were highest in patients treated with surgery followed by radiotherapy. Definitive chemoradiotherapy provided moderate disease control and survival outcomes in patients unfit for surgery, supporting its use as an alternative treatment strategy.

PURPOSE:Long-course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC) achieves a pathologic complete response (pCR) in approximately 10% to 30% of cases. Radiotherapy exerts both immunostimulatory and immunosuppressive effects. Inhibition of PDL1 may augment the immunostimulatory response. We hypothesize that administering avelumab following LCCRT may enhance tumor response and reduce relapse rates. PATIENTS AND METHODS:This was a phase II single-arm trial. Eligible patients had MRI stage T3b to 4/N1 to 2/M0 LARC within 12 cm from the anal verge. Treatment consisted of long-course chemoradiotherapy (LCCRT) with 50.4 Gy and 5-fluorouracil or capecitabine, followed by four cycles of avelumab (10 mg/kg every 2 weeks). Surgical resection was performed 10 to 12 weeks after completion of LCCRT. Fresh tumor biopsies/ctDNA were taken before LCCRT, before avelumab, and at surgery. The primary endpoint was pCR, reported centrally. Secondary endpoints were imaging responses and toxicity, and exploratory endpoints were translational studies (immune evaluation by multiplex IHC and biopsy-derived tumoroids), distant relapse-free survival, and relapse sites. RESULTS:Thirty-seven patients entered the trial, of whom 33 received avelumab and 32 had surgery. The overall response rate by pelvic MRI (N = 33) was 48%. By 2-[¹⁸F]fluoro-2-deoxy-D-glucose PET, there were 10 complete metabolic responses (CMR) and 18 partial metabolic responses (PMR). Regression score 0 (modified Ryan pCR) was observed in 19% of patients (N = 6), and regression score 1 in 16% (N = 5). Overall, 34% of patients (N = 11) had a major pathologic response. Tumors with greater PDL1 expression showed superior pCR/tumor regression. Tumoroid studies indicated intact cellular machinery for PDL1/HLA class-1 expression modulated by IFNγ. No immune-related grade 3 adverse events were observed, and postoperative complications were as expected. The median follow-up was 3.1 years, the 3-year estimated time to progression was 82%, distant relapse-free survival was 80%, and disease-free survival was 80%. CONCLUSIONS:The Ave-Rec phase II study demonstrated that avelumab after LCCRT is deliverable and tolerable, with significant imaging responses and a major pathologic response rate. Tumoral immune cell subsets/checkpoint expression was predictive of pathologic response. The addition of immune checkpoint inhibitors warrants further evaluation in patients with LARC.

428 Background: Rare variant non-clear cell renal cell cancer (nccRCC) have diverse biology and therapeutic response. Immune checkpoint immunotherapy (ICI) can benefit some people with nccRCC, but many experience progression. We sought to test cabozantinib (C) in people with nccRCC refractory to, or unsuitable for ICI. Methods: Eligible participants (pts) had advanced/metastatic nccRCC with good ECOG PS (<2) and either prior treatment with ICI or were unsuitable for ICI due to a contraindicating autoimmune disorder. Pts with urothelial or collecting duct tumour were excluded. Eligible pts started C at 60mg per day with dose modifications as required. Clinical cycles were 28 days and radiological assessment occurred 8-weekly for 12 months. Pts could then continue C via an access program. Results: 33 pts with nccRCC were recruited from Mar 2019 to Dec 2022. Recruitment was influenced by the COVID19 pandemic. Two pts were found ineligible (brain metastasis, concurrent CYP3A4 inducer). Pts tumour histology included papillary type 1 (10), chromophobe (7), papillary type 2 (4), Xp11 translocation (3) and other histologies (7). 24 pts had received prior ICI, mostly nivolumab alone (17) or anti-PD1-antibodies in combination with other agents (anti-CTLA4, anti-TIGIT). Median duration of therapy was 9 cycles. 17 pts ceased for unacceptable toxicity or disease progression and 12 pts completed the 12 months of treatment, with 2 remaining on trial treatment at time of analysis. A partial response was seen 7/31 (22%) pts overall, including 7/24 pts with prior ICI and 0/7 pts unsuitable for ICI. Median treatment duration was 7.5 cycles (range 2-12) in pts with prior ICI treatment, and 11 cycles (range 2-12) in pts unsuitable for ICI. 90% of pts required dose reduction, most often due to fatigue, hypertension, diarrhoea and hand-foot syndrome, with a mean C dose of 46mg/day. No new safety signals were observed. Conclusions: C is an active treatment for people with nccRCC previously treated with ICI, with similar toxicity to previous reports in other cancers. Pts unsuitable for ICI may have poorer outcomes for C therapy in nccRCC. Further follow-up will determine duration of response and overall survival. Clinical trial information: NCT03685448 .

BACKGROUND AND OBJECTIVE:There is uncertainty regarding the clinical significance of 68Ga-PSMA-11 positron emission tomography (PET) computed tomography (CT) findings in men with prostate cancer. In this prespecified objective of the proPSMA study, we report the prognostic value of PET-defined nodal involvement. METHODS:Men with intermediate- to high-risk prostate cancer (grade group 3-5, prostate-specific antigen [PSA] ≥20 ng/ml, or clinical stage ≥T3) underwent 68Ga-PSMA-11 PET-CT or CT and bone scanning as first- or second-line imaging. Patients without distant metastatic disease (miM0) in either arm were stratified by prostate-specific membrane antigen (PSMA) PET-CT negative (miN0) or positive (miN1) regional nodal status and followed for up to 54 mo. Treatment failure was defined as biochemical failure, commencement of salvage therapy, or development of distant metastatic disease. Freedom from treatment failure (FFTF) was plotted on Kaplan-Meier curves for patients with miN0 and miN1 cancer based on PET-CT and CT/bone scan classification. Cox proportional hazards were used to derive a hazard ratio (HR) for FFTF. KEY FINDINGS AND LIMITATIONS:A total of 302 patients were randomised at ten sites. Of them, 294 underwent a PSMA PET-CT. In all, 251 patients with miM0 disease were included in this analysis. Patients were treated with curative-intent surgery or radiotherapy ± androgen deprivation. FFTF was greater in the PSMA PET-CT miN0M0 group than in the miN1M0 group (HR 2.1 [95% confidence interval {CI} 1.2-3.7], p = 0.01). CT/bone scan-defined N0M0 versus N1M0 was not prognostic for FFTF (HR 0.6, 95% CI 0.1-2.4, p = 0.45). In a multivariate analysis, PSMA PET-CT miN1M0 versus miN0M0 remained prognostic after adjusting for PSA, Gleason grade group, and age (HR 2.0, 95% CI 1.10-3.64, p = 0.007). CONCLUSIONS AND CLINICAL IMPLICATIONS:PSMA PET-CT regional nodal staging at baseline is prognostic for medium-term oncological outcomes, identifying patients at a higher risk of treatment failure. PATIENT SUMMARY:Men with prostate cancer who have cancer in their nearby lymph nodes observed on a prostate-specific membrane antigen positron emission tomography scan have poorer outcomes than men who have no nearby lymph node involvement.

Background N -methyl-2-pyrrolidone (NMP) is an epigenetically active chemical fragment and organic solvent with numerous applications including use as a drug-delivery vehicle. Previously considered biologically inert, NMP demonstrates immunomodulatory and anti-myeloma properties that are partly explained by acetyllysine mimetic properties and non-specific bromodomain inhibition. We therefore evaluated orally administered NMP in a phase 1 dose-escalation trial to establish its maximum tolerated dose (MTD) in patients with relapsed/refractory multiple myeloma (RR–MM). Secondary endpoints were safety, pharmacokinetics (PK), overall response rate and immunological biomarkers of activity. Results Thirteen patients received NMP at starting doses between 50 and 400 mg daily. Intra-patient dose escalation occurred in five patients, with one attaining the ceiling protocolised dose of 1 g daily. Median number of monthly cycles commenced was three (range 1–20). Grade 3–4 adverse events (AEs) were reported in seven (54%; 95% CI 25–81%) patients. Most common AEs (> 30% of patients) of any grade were nausea and musculoskeletal pain. The only dose limiting toxicity (DLT) was diarrhoea in a patient receiving 200 mg NMP (overall DLT rate 8%; 95% CI 0–36%). Hence, the MTD was not defined. Median progression-free and overall survival were 57 (range 29–539) days and 33 (95% CI 9.7– > 44) months, respectively. The best response of stable disease (SD) was achieved in nine patients (69%; 95% CI 39–91%). PK analysis demonstrated proportional dose–concentrations up to 400 mg daily, with a more linear relationship above 500 mg. Maximum plasma concentrations (Cmax) of 16.7 mg/L at the 800 mg dose were below those predicted to inhibit BET-bromodomains. Peripheral blood immune-profiling demonstrated maintenance of natural killer (NK) cells, and a gene expression signature suggestive of enhanced T, B and NK cell functions; a subject with prolonged exposure manifested sustained recovery of B and NK cells at 12 months. Conclusions NMP demonstrated potential disease stabilising and immunomodulatory activity at sub-BET inhibitory plasma concentrations and was well tolerated in RR–MM; an MTD was not determined up to a maximum dose of 1 g daily. Further dose-finding studies are required to optimise NMP dosing strategies for therapeutic intervention.

Exposure-response relationship between CX-5461 levels and rDNA transcription rate in normal PBMCs

Long course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC) results in a complete pathological CR in 10-30% of patients (pts). Radiotherapy (RT) is immuno-stimulatory by enhancing tumour cell death, but also immunosuppressive stimulating PDL1 production and myeloid-derived suppressor cells. PDL1 inhibition may be required to enhance RT immuno-stimulatory effects. Hypothesis: In pts with resectable LARC, Avelumab given post LCCRT may enhance tumour response rates whilst reducing relapses. Phase II single arm trial. Pts had LCCRT (50.4Gy + 5FU [225mg/m2/day/CI] or Capecitabine [825mg/m2 BID]/5.5 weeks). Post LCCRT pts received 4 cycles Avelumab (AV) (10mg/kg, q2 weeks), then resection 10-12 weeks post LCCRT. Fresh tumour biopsy/ctDNA sampling taken at pre LCCRT, pre AV and at surgery. Response by FDG PET and pelvic MRI. Inclusion Criteria: pts with MRI stage T3b-4/N1-2/M0 LARC , tumoural lower border <12cm from anal verge, measurable disease, ECOG 0-1, adequate organ function. Endpoints: (a) Primary; Complete pathological response rate (Target ≥ 35%) reported centrally, (b) Secondary; Imaging responses, Toxicity. (c) Exploratory; Tumoural immune cell subsets/checkpoint expression and ctDNA analysis, Distant relapse-free survival and the sites of relapse. 37 pts entered. Baseline TNM: T3b-d 75%, T4a-b 25%. 33 pts completed LCCRT, 31 pts (83%) had all 4 cycles of AV and 32 pts (86%) had surgery. ORR Pelvic MRI (N=33): 2 CR, 14 PR, 31 DCR. FDG PET: 10 CMR, 18 PMR.. 10 pts Grade 3 AEs, 3 pts with treatment-related G3 and no G4 AEs. No immune-related G3 AEs. Post-operative complications as expected. Pathological response (Modified Ryan Score) (N=32): Complete pathCR (18.7%), near CR (15.7%), in MSI-H (N=4), 50% and 25% resp. Median followup 3.1 yrs: 3 yr est. time to progression 82%, distant relapse free survival 80%, disease free survival 80%. The Ave-Rec phase II study has shown Avelumab post LCCRT is safe with significant imaging responses and complete/near-complete path response rate of 34.3% in pts with ESMO high risk rectal cancers. Parallel translational studies are ongoing. The addition of immune checkpoint inhibitors warrants further evaluation in LARC.

Objective To evaluate the efficacy of sequential treatment with ipilimumab and nivolumab following progression on nivolumab monotherapy in individuals with advanced, non‐clear‐cell renal cell carcinoma (nccRCC). Materials and Methods UNISoN (ANZUP1602; NCT03177239 ) was an open‐label, single‐arm, phase 2 clinical trial that recruited adults with immunotherapy‐naïve, advanced nccRCC. Participants received nivolumab 240 mg i.v. two‐weekly for up to 12 months (Part 1), followed by sequential addition of ipilimumab 1 mg/kg three‐weekly for four doses to nivolumab if disease progression occurred during treatment (Part 2). The primary endpoint was objective tumour response rate (OTRR) and secondary endpoints included duration of response (DOR), progression‐free (PFS) and overall survival (OS), and toxicity (treatment‐related adverse events). Results A total of 83 participants were eligible for Part 1, including people with papillary (37/83, 45%), chromophobe (15/83, 18%) and other nccRCC subtypes (31/83, 37%); 41 participants enrolled in Part 2. The median (range) follow‐up was 22 (16–30) months. In Part 1, the OTRR was 16.9% (95% confidence interval [CI] 9.5–26.7), the median DOR was 20.7 months (95% CI 3.7‐not reached) and the median PFS was 4.0 months (95% CI 3.6–7.4). Treatment‐related adverse events were reported in 71% of participants; 19% were grade 3 or 4. For participants who enrolled in Part 2, the OTRR was 10%; the median DOR was 13.5 months (95% CI 4.8–19.7) and the median PFS 2.6 months (95% CI 2.2–3.8). Treatment‐related adverse events occurred in 80% of these participants; 49% had grade 3, 4 or 5. The median OS was 24 months (95% CI 16–28) from time of enrolment in Part 1. Conclusions Nivolumab monotherapy had a modest effect overall, with a few participants experiencing a long DOR. Sequential combination immunotherapy by addition of ipilimumab in the context of disease progression to nivolumab in nccRCC is not supported by this study, with only a minority of participants benefiting from this strategy.

All Supplementary Methods and associated references

Pharmacokinetics analysis of CX-5461 in patients with advanced hematological disease

Radiotherapy and tumour bed boost for ductal carcinoma in situ (DCIS) of the breast is the subject of many debates in tumour boards and radiotherapy departments. We thank Boon H Chua and colleagues1Chua BH Link EK Kunkler IH et al.Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3-07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 study.Lancet. 2022; 400: 431-440Summary Full Text Full Text PDF PubMed Scopus (26) Google Scholar for their well designed randomised trial comparing fractionation schedules and boost for non-low-risk DCIS. A boost lowered the 5-year local recurrence rate from 7·3% to 2·9%, resulting in 4% fewer salvage mastectomies compared with the no-boost group; however, this was at the cost of an increase of 15% acute and 11% late grade 2 or more events. Furthermore, a boost increases the intrathoracic dose and a median follow-up of 6·6 years might be too short to detect long-term cardiac events or lung cancer events.2Mulliez T Barbé K de Ridder M Estimating lung cancer and cardiovascular mortality in female breast cancer patients receiving radiotherapy.Radiother Oncol. 2020; 152: 111-116Summary Full Text Full Text PDF PubMed Scopus (12) Google Scholar The reported high grade 2 or more acute and late toxicity events, 43% (acute) and 24% (late toxicity) for the no-boost versus 58% (acute) and 35% (late toxicity) for the boost group, might be related to the large boost zone and use of older techniques.1Chua BH Link EK Kunkler IH et al.Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3-07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 study.Lancet. 2022; 400: 431-440Summary Full Text Full Text PDF PubMed Scopus (26) Google Scholar The boost area was large: clips and seroma with a 10 mm margin for microscopical extension when surgical margins were less than 10 mm and an additional margin of 5–10 mm for set-up uncertainties and respiration. Advanced treatment techniques3Van Parijs H Miedema G Vinh-Hung V et al.Short course radiotherapy with simultaneous integrated boost for stage I-II breast cancer, early toxicities of a randomized clinical trial.Radiat Oncol. 2012; 7: 80Crossref PubMed Scopus (73) Google Scholar or position alterations4Van Hulle H Desaunois E Vakaet V et al.Two-year toxicity of simultaneous integrated boost in hypofractionated prone breast cancer irradiation: comparison with sequential boost in a randomized trial.Radiother Oncol. 2021; 158: 62-66Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar with a simultaneously integrated photon boost (ie, daily boost dose during whole breast irradiation) have been shown to have a lower toxicity profile, reduced treatment time, and improved patient comfort and health economics. Further research is needed and gene expression analysis5Rakovitch E Sutradhar R Nofech-Mozes S et al.21-gene assay and breast cancer mortality in ductal carcinoma in situ.J Natl Cancer Inst. 2021; 113: 572-579Crossref PubMed Scopus (16) Google Scholar seems promising to personalise breast radiotherapy for DCIS. An individualised treatment approach is warranted to balance oncological gains with contemporary iatrogenic radiotherapy toxicity.2Mulliez T Barbé K de Ridder M Estimating lung cancer and cardiovascular mortality in female breast cancer patients receiving radiotherapy.Radiother Oncol. 2020; 152: 111-116Summary Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 3Van Parijs H Miedema G Vinh-Hung V et al.Short course radiotherapy with simultaneous integrated boost for stage I-II breast cancer, early toxicities of a randomized clinical trial.Radiat Oncol. 2012; 7: 80Crossref PubMed Scopus (73) Google Scholar, 4Van Hulle H Desaunois E Vakaet V et al.Two-year toxicity of simultaneous integrated boost in hypofractionated prone breast cancer irradiation: comparison with sequential boost in a randomized trial.Radiother Oncol. 2021; 158: 62-66Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar We declare no competing interests. Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3–07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 studyIn patients with resected non-low-risk DCIS, a tumour bed boost after WBI reduced local recurrence with an increase in grade 2 or greater toxicity. The results provide the first randomised trial data to support the use of boost radiation after postoperative WBI in these patients to improve local control. The international scale of the study supports the generalisability of the results. Full-Text PDF

AbstractPurpose:BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies.Patients and Methods:We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib.Results:Thirty-two patients with BRAF V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal KRAS, NRAS, and MAP2K1 mutations, and MET amplification.Conclusions:The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance.

TPS3622 Background: Standard neoadjuvant long course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC) results in a complete pathological response rate of 10-30%: but 20-40% of patients (pts) are non-responders, 10-15% have local recurrence. Tumoural immune infiltrates are predictive of response. Preclinical studies show that radiotherapy (RT) via interferon signaling is immuno-stimulatory, enhancing local/distant tumour cell death. RT also stimulates PDL1 production and the immunosuppressive activity of myeloid derived suppressor cells. Hence PDL1 inhibition may be required to enhance the immuno-stimulatory effects of RT. Hypothesis: In pts with resectable LARC, the anti-PDL1 antibody Avelumab post LCCRT may enhance the pathological/imaging response rates whilst potentially reducing local/distant relapse rates. Methods: (1) Trial Design: Phase II single arm trial, across 6 Australian sites (2) Endpoints: (a) Primary; Pathological response rate post-LCCRT, as documented by central pathologist, (b) Secondary; MRI/FDG PET imaging responses at 8 weeks post LCCRT (pre-surgery). Toxicity. (c) Exploratory; Tumoural immune cell subsets/checkpoint expression (by multiplex immunohistochemistry and in-vitro functional assays) and ctDNA analysis at baseline and during treatment. Distant relapse-free survival and the documentation of sites of relapse. (3) Sample size: An increase in the proportion of pathological complete responses by > 25% (from 10% to 35%) will be considered clinically important. Power = 90%, α = 0.05, 41 pts are required– an additional 4 pts to allow for drop-out. Total sample size = 45pts. Treatment: All pts to receive standard LCCRT (50.4Gy RT plus 5FU [225mg/m2/day/CI] or Capecitabine [825mg/m2 BID on RT days] over 5.5 weeks). Post LCCRT (prior to surgery), pts receive 4 cycles Avelumab (10mg/kg, q2 weeks). Surgical resection 10-12 weeks post LCCRT. Fresh tumour biopsy and ctDNA sampling pre LCCRT, pre Cycle 1 Avelumab and at surgery. Response by FDG PET and pelvic MRI pre surgery. Pts to be followed up for 2 years. Major Inclusion Criteria: Pts with LARC, MRI stage T3b-4/N1-2/M0, planned for LCCRT followed by curative resection, tumoural lower border within 12cm from the anal verge, measurable disease (RECIST1.1), ECOG 0-1, adequate organ function and no contraindications to Avelumab therapy. Current Enrolment: 11 of the planned 45 patients enrolled. Clinical trial information: NCT03299660.

Significant dermatological toxicities associated with CX-5461 treatment