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Background: The cobas HPV Test (“cobas”; Roche Molecular Systems) detects HPV16 and HPV18 individually, and a pool of 12 other high-risk (HR) HPV types. The test is approved for (i) atypical squamous cells of undetermined significance (ASC-US) triage to determine need for colposcopy, (ii) combined screening with cytology (“cotesting”), and (iii) primary HPV screening. Methods: To assess the possible value of HPV16/18 typing, >17,000 specimens from a longitudinal cohort study of initially HPV-positive women (HC2, Qiagen) were retested with cobas. To study accuracy, cobas genotyping results were compared with those of an established method, the Linear Array HPV Genotyping Test (LA, Roche Molecular Systems). Clinical value of the typing strategy was evaluated by linking the cobas results (supplemented by other available typing results) to 3-year cumulative risks of CIN3+. Results: Grouped hierarchically (HPV16, else HPV18, else other HR types, else negative), the κ statistic for agreement between cobas and LA was 0.86 [95% confidence interval (CI), 0.86–0.87]. In all three scenarios, HPV16-positive women were at much higher 3-year risk of CIN3+ than HPV16-negative women: women ages 21 and older with ASC-US (14.5%; 95% CI, 13.5%–15.5% vs. 3.5%; 95% CI, 3.3–3.6); women ages 30 years and older that were HPV-positive cytology-negative (10.3%; 95% CI, 9.6–11.1 vs. 2.3%; 95% CI, 2.2–2.4); and all women 25 years and older that were HPV-positive (18.5%; 95% CI, 17.8–19.2 vs. 4.3%; 95% CI, 4.2–4.4). Conclusion: The cobas and LA results show excellent agreement. The data support HPV16 typing. Impact: HPV16 typing is useful in the management of HPV-positive/cytology-negative women in cotesting, of all HPV-positive women in primary HPV testing, and perhaps in the management of HPV-positive women with ASC-US. Cancer Epidemiol Biomarkers Prev; 24(9); 1304–10. ©2015 AACR. See related commentary by Del Mistro, p. 1302

The effective management of women with human papillomavirus (HPV)-positive, cytology-negative results is critical to the introduction of HPV testing into cervical screening. HPV typing has been recommended for colposcopy triage, but it is not clear which combinations of high-risk HPV types provide clinically useful information. This study included 18,810 women with Hybrid Capture 2 (HC2)-positive, cytology-negative results and who were age ≥30 years from Kaiser Permanente Northern California. The median follow-up was 475 days (interquartile range [IQR], 0 to 1,077 days; maximum, 2,217 days). The baseline specimens from 482 cases of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) and 3,517 random HC2-positive noncases were genotyped using 2 PCR-based methods. Using the case-control sampling fractions, the 3-year cumulative risks of CIN3+ were calculated for each individual high-risk HPV type. The 3-year cumulative risk of CIN3+ among all women with HC2-positive, cytology-negative results was 4.6%. HPV16 status conferred the greatest type-specific risk stratification; women with HC2-positive/HPV16-positive results had a 10.6% risk of CIN3+, while women with HC-2 positive/HPV16-negative results had a much lower risk of 2.4%. The next most informative HPV types and their risks in HPV-positive women were HPV33 (5.9%) and HPV18 (5.9%). With regard to the etiologic fraction, 20 of 71 cases of cervical adenocarcinoma in situ (AIS) and adenocarcinoma in the cohort were positive for HPV18. HPV16 genotyping provides risk stratification useful for guiding clinical management; the risk among HPV16-positive women clearly exceeds the U.S. consensus risk threshold for immediate colposcopy referral. HPV18 is of particular interest because of its association with difficult-to-detect glandular lesions. There is a less clear clinical value of distinguishing the other high-risk HPV types.

Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining ≥ 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P = .049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial.

e23196 Background: Enzymatic degradation of hyaluronan (HA) by PEGylated recombinant human hyaluronidase PH20 (PEGPH20) induces a remodeling of the tumor microenvironment that impacts tumor behavior and response to therapy. Ventana Medical Systems, Inc., (VMSI) and Halozyme Therapeutics co-developed the VENTANA HA RxDx Assay and a scoring method to evaluate HA in solid tumors to potentially predict which patients might better respond to the addition of PEGPH20 to cancer treatments. Methods: Using Halozyme’s novel recombinant HA binding probe altered to include a rabbit Fc region, VMSI developed a highly specific and sensitive affinity histochemistry assay that binds to HA in tissues. Histological features and staining patterns of 106 samples from Halozyme’s 109-202 Phase 2 study of PEGPH20 combined with nab-paclitaxel plus gemcitabine (AG) vs. AG alone in patients with previously untreated stage IV pancreatic ductal adenocarcinoma (PDA) with clinical outcome data were analyzed to develop a scoring method evaluating HA accumulation. Results: A novel scoring algorithm focused solely on the extracellular matrix (ECM) was developed. An ECM HA staining ≥ 50% of the entire tumor surface at any intensity defines an HA-High PDA. We recommend that a 0.05 cm x 0.2 cm uninterrupted fragment of tumor cells and associated stroma obtained using needle gauges of 16 to 20 G as the minimally required amount of tissue to assess HA in PDA. Based on verification studies performed by VMSI, including an inter-reader precision study with a 94% agreement rate, VMSI scoring method proved to be trainable, reproducible, and transferable to pathologists, supporting an IDE approval for selecting patients in the Phase 3 HALO 109-301 study. Conclusions: Performance of the VENTANA HA RxDx Assay, a robust affinity histochemical assay, has been successfully verified in PDA. Two Halozyme clinical studies in PDA (Phase 2 HALO 109-202 Stage 2 & ongoing Phase 3 HALO 109-301) are expected to validate the VMSI HA scoring method in selecting patients who might better respond to the addition of PEGPH20 to cancer treatments. Current Phase 1/2 studies are exploring the utility of the VENTANA HA RxDx Assay and the pantumor potential of PEGPH20.

4008 Background: Hyaluronan (HA) accumulation in the tumor microenvironment produces elevated tumor pressure, vascular compression, and reduced drug delivery. PEGPH20 degrades HA, increasing the access and therapeutic index of anticancer agents. Methods: In Stage 1 of this phase II study, pts with untreated mPDA were randomized 1:1 to PAG (P; 3 µg/kg IV 2x/wk x 3 wks in C1, then 1x/wk x 3 wks in C2+, plus AG) vs AG every 28 days. An imbalance in thromboembolic (TE) events in the PAG arm led to a clinical hold (~40% of pts discontinued PEGPH20), exclusion of pts at high risk for TE events and enoxaparin prophylaxis in both study arms. In Stage 2, randomization was 2:1 to PAG vs AG. Tumor HA was tested using a novel assay (VENTANA HA RxDx). Primary endpoints were PFS (evaluable pts) and TE event rate (Stage 2). Secondary endpoints were PFS by HA level and ORR. Results: 279 pts were randomized; 231 are evaluable for efficacy. Of 246 pts with HA data, 84 (34%) were HA-High. As of December 16, 2016, the primary PFS endpoint was statistically significant for PAG vs AG (HR 0.73, 95% CI 0.53-1.00; p = 0.048) (Table). PFS in HA-High pts was also statistically significant in the PAG vs AG arm (HR 0.51; 95% CI 0.26-1.00; p = 0.048). ORR in HA-High pts was 46% (PAG) vs 34% (AG). Overall survival in HA-High pts (exploratory) was 11.5 months (mo) (PAG) and 8.5 mo (AG) (HR 0.96, 95% CI 0.57-1.61). TE events were similar (PAG 14% vs AG 10%) following enoxaparin initiation. All grade treatment-related AE included peripheral edema (PAG 63% vs AG 26%), muscle spasms (56% vs 3%), neutropenia (34% vs 19%), and myalgia (26% vs 7%). Conclusions: Randomized Phase II study met both primary endpoints (PFS and TE event rate), with the largest improvement in the secondary endpoint of PFS in HA-High pts. These data support HA as a potential predictive biomarker for patient selection of PEGPH20, currently investigated in the ongoing global Phase III HALO 301 study with PFS and OS as co-primary endpoints. Clinical trial information: NCT01839487. [Table: see text]

e15749Background: Ventana Medical Systems, Inc. is developing in collaboration with Halozyme Therapeutics an affinity histochemical companion diagnostic to aid in selecting patients with pancreatic...

4104Background: Poor outcome in pancreatic ductal adenocarcinoma (PDA) is associated partly with stromal hyaluronan (HA) accumulation, which compromises chemotherapy perfusion. PEGPH20 (PEGylated r...