Colorectal cancer remains a leading source of cancer mortality worldwide. Initial response is often followed by emergent resistance that is poorly responsive to targeted therapies, reflecting currently undruggable cancer drivers such as KRAS and overall genomic complexity. Here, we report a novel approach to developing a personalized therapy for a patient with treatment-resistant metastatic KRAS-mutant colorectal cancer. An extensive genomic analysis of the tumor’s genomic landscape identified nine key drivers. A transgenic model that altered orthologs of these nine genes in the Drosophila hindgut was developed; a robotics-based screen using this platform identified trametinib plus zoledronate as a candidate treatment combination. Treating the patient led to a significant response: Target and nontarget lesions displayed a strong partial response and remained stable for 11 months. By addressing a disease’s genomic complexity, this personalized approach may provide an alternative treatment option for recalcitrant disease such as KRAS-mutant colorectal cancer.

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Summary Adenoid cystic carcinoma (ACC) is a rare cancer type that originates in the salivary glands. Tumors commonly invade along nerve tracks in the head and neck, making surgery challenging. Follow-up treatments for recurrence or metastasis including chemotherapy and targeted therapies have shown limited efficacy, emphasizing the need for new therapies. Here, we report a Drosophila-based therapeutic approach for a patient with advanced ACC disease. A patient-specific Drosophila transgenic line was developed to model the five major variants associated with the patient's disease. Robotics-based screening identified a three-drug cocktail—vorinostat, pindolol, tofacitinib—that rescued transgene-mediated lethality in the Drosophila patient-specific line. Patient treatment led to a sustained stabilization and a partial metabolic response of 12 months. Subsequent resistance was associated with new genomic amplifications and deletions. Given the lack of options for patients with ACC, our data suggest that this approach may prove useful for identifying novel therapeutic candidates.

6069 Background: Locally advanced Human Papillomavirus (HPV) + oropharyngeal carcinoma (OPC) has a significantly better response, locoregional control and survival compared to non HPVOPC. Standard-dose chemoradiotherapy (sdCRT) results in significant side effects, leading to acute and life-threatening late morbidity. We studied whether reduced dose chemoradiation (rdCRT) after induction chemotherapy (IC) resulted in equivalent progression-free survival (PFS) compared to sdCRT + IC with decreased late morbidity. Methods: Patients with locally advanced OPC and < 20 pack years (py) smoking history were tested for p16 and then HPV by type-specific PCR. After 3 cycles of docetaxel, cisplatin and fluorouracil (TPF) IC all HPV+/p16+ subjects underwent clinical and radiographic evaluation. Clinical responders were randomized to either sdCRT (70Gy) or rdCRT (56Gy) with weekly carboplatin (AUC 1.5) at a 1:2 ratio. The primary endpoint was 2 year PFS; the secondary endpoint was 2 year overall survival (OS). Toxicity, late morbidity and swallowing were monitored. Results: 23 patients were enrolled and 20 randomized, 8 to sdCRT and 12 to rdCRT; 2 were HPV- and 1 refused further therapy after IC and were not randomized. Median age was 56.5 yrs (range 36-78); 30% were African-American, 10% were Hispanic, 5% were female; 16 were HPV 16+ and 4 were other high risk (HR) variants; 60% never smoked, 25% were < 10 py, and 15% were 10-20 py; 70% had high risk features: T4, N2c, or N3. Clinical response to TPF was 100%; 70% had a clinical complete response. As of February 1, patients have been followed for a median of 37.5 months (range 21.7 – 49.5). 2 year PFS/OS for sdCRT and rdCRT are 87.5% vs 83.3% (log-rank test p = 0.85), respectively. All 3 failures were local or regional and 2 of 3 occurred in non HPV16 HR variants. Conclusions: HPV+ OPC patients who received rdCRT after TPF IC had similar PFS/OS compared to those receiving sdCRT. These results uphold the potential clinical benefit of radiation dose reduction as a treatment option with comparable survival to the standard radiation dose. A Phase III trial comparing IC plus rdCRT to sdCRT alone or with IC is warranted in this population. Non-HPV16 HR variants may have a worse outcome. Clinical trial information: NCT01706939.

6058 Background: HPVOPC has a significantly better prognosis and survival than HPV negative cancer resulting in overtreatment with significant acute and late toxicities and mortality. Radiation therapy is the single greatest determinant of toxicity. Studies to support reduction of radiation dose are a high priority. IC improves local regional control, reduces distant metastases, and may support radiotherapy de-escalation. Patients with T4, ECE, and N2c disease have poorer local regional control (LRC) and a higher rate of distant metastases (DM) and may be suitable for this option. Methods: Data was combined for the experimental arm of a previously reported Phase 3 trial (12 subjects, NCT01706939) and a continuation Phase 2 trial (20 subjects, NCT02945631). After informed consent subjects who were PCR+ HPVOPC, smoked < 20 py, and were LA or functionally unresectable were treated with Taxotere, cisplatin and reduced 5-fluorouracil (mTPF) for 3 cycles and then assessed for response. Responders were treated with 5600 cGy and weekly carboplatin, and then followed for LRC, DM, PFS, OAS and toxicity. Data was analyzed as of 2/1/21. 85% LRC at 3 years was considered non inferior to standard of care chemoradiotherapy. An acceptable end point was predetermined to be 80% PFS and 85% LRC at 3 years in this LA population. Results: 32 subjects were entered and included in the analysis, all responded to IC and had RDCRT. 2 patients with non-HPV16 subtypes were initially entered, treated with IC, responded, and then were taken off study and excluded from the analysis due to non-HPV 16 subtype. They were treated with 7000 cGy and are alive and well. Poor risk factors (ECE, T4, N2c, Non-HPV16 subtype) were present in 72% of 32 subjects; 22 (69%) never smoked. At data cutoff with a median follow up of 50m (21-95m), 28/32 (87.5%) have LRC, 1/32 DM (3.1%), OS is 28/32 (87.5%) and PFS is 27/32 (84.4%). All 5 patients who recurred did so in the first 12m (median 8m); all had 1 or more poor risk factors and 1 is alive with disease 42m post recurrence. 2 year LRC, PFS and OS are 87.4% [95% CI: 69.8%, 95.1%], 84.4% [95% CI: 66.5%, 93.2%] and 90.6% [95% CI: 73.7%, 96.9%] respectively. There was no therapy-related mortality, generally rapid recovery from CRT and minimal long term consequences (to be reported). Conclusions: Induction with mTPF followed by RDCRT resulted in excellent LRC, PFS and OS in patients with LA HPV OPC and significant risk factors. These results compare favorably to standard of care and other dose de-escalation trials in high and low risk categories. This treatment paradigm is highly effective in a LA, high risk HPVOPC patients and is a reasonable treatment option to be compared to other de-escalation treatment plans in Phase 3 trials for this higher risk population. Clinical trial information: NCT02945631, NCT01706939.