There was no evidence of a concerning safety signal from either SABR before or after start of pembrolizumab. The combination demonstrated activity with promising PFS and OS and is worthy of evaluation in larger randomized trials.

In the phase Ib/II EVICT trial, the combination of vemurafenib and erlotinib demonstrated promising efficacy with response rates of 32% (10/31; 16% -5/31 confirmed) in patients (pts) with BRAF V600E mt mCRC and 43% (3/7) in pts with other cancers. The overall clinical benefit rate (partial response + stable disease) was 71% (27/38). Here we report the utility of ctDNA as a biomarker to predict outcomes and understand mechanisms of treatment resistance. Serial plasma samples were available from 25 pts. Paired baseline and progression samples were analyzed by targeted sequencing (AVENIO ctDNA expanded assay, Roche diagnostics). Droplet digital PCR was used to serially monitor mutations of interest. BRAF V600E mt ctDNA was detected at baseline in 21/25 pts (84%). Other frequently altered genes included TP53 (60%), EGFR (52%), and MET (40%), with mutational burden higher in pts who did not derive clinical benefit (P=0.04). MET amplification was associated with inferior overall survival (OS) (median OS 4.9 vs 8.8 months; HR 2.2; [95% CI 0.84-6.0]; P=0.04). Decline in ctDNA levels (copies/mL) between baseline to week 2 was greater in pts who derived clinical benefit (P<0.001). Reduction in ctDNA variant allele fraction at 2 weeks predicted longer progression free survival (PFS) (median PFS 1.8 vs 6.4 months; HR 3.6, 95% CI 1.30-9.76, P<0.001) and OS (median OS 5.6 vs 9.9 months; HR 2.9, 95% CI 1.01-8.36, P<0.01). Of the 18 pts with plasma available at progression, 9/18 (50%) showed emergence of >1 KRAS or NRAS mutation. Polyclonal KRAS mutations were observed in 6/9 pts (67%). Other frequently acquired MAPK pathway alterations included MAP2K1 mutations (22%) and MET amplification (17%). In pts with BRAF V600E mt cancers treated with vemurafenib and erlotinib, baseline ctDNA profile and an early decline in ctDNA were predictive of clinical outcomes. ctDNA analyses provided a mechanistic understanding of intrinsic and acquired resistance, revealing frequent evidence of convergent evolution and MAPK pathway reactivation as the dominant mechanism of therapeutic escape.

Osimertinib is standard of care for advanced EGFR-mutated NSCLC following the emergence of T790M resistance mutations, with a median progression-free survival (PFS) of 10 months. Mechanisms of resistance to osimertinib include acquisition of C797S mutations and loss of T790M mutations. We hypothesised that alternating treatment with osimertinib and gefitinib would modulate clonal populations within tumors and delay the emergence of resistance. The aim of this study was to assess the activity, feasibility, and safety of alternating therapy, and to explore plasma ctDNA dynamics and mechanisms of resistance.

BACKGROUND The advent of effective adjuvant therapies for patients with resected melanoma has highlighted the need to stratify patients based on risk of relapse given the cost and toxicities associated with treatment. Here we assessed circulating tumor DNA (ctDNA) to predict and monitor relapse in resected stage III melanoma. PATIENTS AND METHODS Somatic mutations were identified in 99/133 (74%) patients through tumor tissue sequencing. Personalized droplet digital PCR (ddPCR) assays were used to detect known mutations in 315 prospectively collected plasma samples from mutation-positive patients. External validation was performed in a prospective independent cohort (n = 29). RESULTS ctDNA was detected in 37 of 99 (37%) individuals. In 81 patients who did not receive adjuvant therapy, 90% of patients with ctDNA detected at baseline and 100% of patients with ctDNA detected at the postoperative timepoint relapsed at a median follow up of 20 months. ctDNA detection predicted patients at high risk of relapse at baseline [relapse-free survival (RFS) hazard ratio (HR) 2.9; 95% confidence interval (CI) 1.5-5.6; P = 0.002] and postoperatively (HR 10; 95% CI 4.3-24; P < 0.001). ctDNA detection at baseline [HR 2.9; 95% CI 1.3-5.7; P = 0.003 and postoperatively (HR 11; 95% CI 4.3-27; P < 0.001] was also associated with inferior distant metastasis-free survival (DMFS). These findings were validated in the independent cohort. ctDNA detection remained an independent predictor of RFS and DMFS in multivariate analyses after adjustment for disease stage and BRAF mutation status. CONCLUSION Baseline and postoperative ctDNA detection in two independent prospective cohorts identified stage III melanoma patients at highest risk of relapse and has potential to inform adjuvant therapy decisions.

Background: Adjuvant immunotherapy and BRAF-targeted therapies have shown improved relapse-free survival (RFS) in patients (pts) with resected melanoma. There is a critical need to develop biomarkers to stratify pts based on risk of relapse given the cost and toxicities with these therapies. Methods: Droplet digital PCR was used to detect known mutations in circulating tumour DNA (ctDNA) from 112 pts with resected stage II-III melanoma who consented to prospective serial plasma and risk-adapted F-18-fluoro-deoxyglucose positron emission tomography (FDG-PET) monitoring. External validation was performed in a prospective independent cohort. Results: In 92/112 pts who did not receive adjuvant therapy, 55/92 (60%) pts relapsed at a median follow-up of 21 months. Plasma samples were available in 67/92 pts at baseline and 59/92 pts postoperatively (median 2 weeks post surgery). ctDNA was detected at baseline and postoperatively in 21/67 (31%) pts and 15/59 (25%) pts respectively. 19/21 and 14/15 pts with ctDNA detected at baseline and the postoperative visit relapsed. Detection of ctDNA predicted patients at high risk of relapse at baseline (RFS hazard ratio [HR] 4.7; 95% confidence interval [CI] 2.3-9.6; p < 0.0001) and postoperatively (HR 9.3; 95% CI 4-22; p < 0.0001). Inferior distant metastasis-free survival (DMFS) was associated with ctDNA detection at baseline (HR 5.3; 95% CI 2.5-11; P < 0.0001) and postoperatively (HR 14; 95% CI 5.4-37; P < 0.0001). These findings were validated in an independent cohort. Postoperative ctDNA detection remained an independent predictor of both RFS (HR 8; 95% CI 3-20; P < 0.0001) and DMFS (HR 11; 95% CI 4-30; P < 0.0001) after adjustment for disease stage and BRAF mutation status. In 20/112 pts who received adjuvant therapy, 3/18 pts with a postoperative plasma sample had detectable ctDNA. Serial plasma samples were available in 2 of 3 cases and showed clearance of ctDNA post immunotherapy. At a median follow-up of 7 months, none of the pts with detectable ctDNA who received adjuvant therapy have relapsed. Conclusions: Detection of ctDNA at baseline and after surgical resection in two independent prospective cohorts identifies pts with stage II/III melanoma at highest risk of relapse with potential to guide adjuvant therapy decisions. Legal entity responsible for the study: Peter MacCallum Cancer Centre. Funding: National Health and Medical Research Council, Cancer Research UK, Wellcome Trust. Disclosure: S.K. Sandhu: Honorarium: Merck, Bristol-Myers Squibb. M. Shackleton: Travel support: BMS, Merck; Consultancy: BMS, Merck, MSD; Honoraria: BMS, Merck, MSD Research support: BMS. A. Haydon: Advisory board: Novartis, MSD. D. Gyorki: Advisory board: Amgen; Honorarium: Amgen. P. Lorigan: Consultancy/ Advisory work: Amgen, GSK, Roche, BMS, Merck, Novartis; Speaker bureau: Merck, BMS, Novartis, Roche; Support for travel: Merck, BMS, Roche. R. Marais: Research funding: Basilea Pharmaceuticals. All other authors have declared no conflicts of interest.

SUMMARYMost patients presenting with malignant mesothelioma of the pleura (MMP) are only suitable for palliative treatment. Radiotherapy has not been shown to improve survival in patients with this disease, but is of use in the palliation of symptoms. In this retrospective review of 111 patients with MMP referred to the Peter MacCallum Cancer Institute, the palliative effect of radiotherapy was analysed. More than half of the patients whose response could be assessed had some symptomatic relief from the radiotherapy treatment. No dose–response relationship could be found.