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ESMO 2019 Precision Oncology Highlights

NEW YORK – The European Society of Medical Oncology Congress took place in Barcelona from Sept. 27 to Oct. 1. Below is a collection of the biomarker- and genomic testing-driven precision oncology research presented at the meeting.

In the Phase II FIGHT-202 trial, involving Incyte's FGFR inhibitor pemigatinib, 36 percent of 107 previously treated, locally advanced cholangiocarcinoma patients with FGFR2 fusions or rearrangements saw their tumors shrink. At a median follow up of 15 months, patients had a median progression-free survival of 6.9 months. Preliminary median overall survival was 21.1 months, but these data aren't mature, and patients will be followed further.  

Cholangiocarcinoma is a rare form of bile duct cancer and patients with advanced disease lack first-line treatment options beyond chemotherapy. FGFR2 fusions or rearrangements mostly occur in intrahepatic cholangiocarcinoma and show up in 10 percent to 16 percent of patients.

The data presented at the meeting was from cohort A of the FIGHT-202 study. Cohort B includes advanced cholangiocarcinoma patients with other FGF or FGFR alterations, and cohort C includes patients with no FGF or FGFR alterations.

The safety analysis, involving 146 patients, demonstrated that pemigatinib was generally well tolerated, with 12 percent of patients experiencing Grade 3 or higher hypophosphatemia, though none of these patients needed dose reductions or discontinued the study. Incyte said in a statement that it will submit a New Drug Application in this indication with the US Food and Drug Administration before year end.

Researchers conducted a three-year follow-up analysis in the Phase III CheckMate-238 study, comparing the adjuvant use of nivolumab (Bristol-Myers Squibb's Opdivo) against ipilimumab (BMS' Yervoy) in 906 stage III/IV melanoma patients who are at increased risk of recurrence after surgical resection. In this study, 58 percent of patients on nivolumab didn't experience recurrence after three years, compared to 45 percent of those on ipilimumab. At 36 months, 66 percent of nivolumab-treated patients experienced distant-metastasis-free survival, compared to 58 percent on Yervoy.

While researchers considered treatment efficacy according to biomarker status, the improved outcomes with nivolumab were seen in patients regardless of whether they had a BRAF mutation or higher PD-L1 expression. Researchers reported no new safety concerns over the longer follow-up period.

BMS and Ono Pharmaceutical reported data from the Phase III ATTRACTION-3 trial comparing nivolumab against chemotherapy (docetaxel or paclitaxel) in patients with advanced esophageal squamous cell cancer who are not responding to fluoropyrimidine and platinum drugs. In the study, patients receiving nivolumab had a 23 percent reduction in the risk of death and lived on average 2.5 months longer than those on chemo. At one year and at 18 months, 47 percent and 31 percent patients on nivolumab were alive, respectively, compared to 34 percent and 21 percent of patients on the standard-of-care arm. The survival advantage with nivolumab was seen regardless of patients' PD-L1 expression status.  

Objective response rates were comparable between the two arms (19 percent on nivolumab versus 22 percent on chemo), and there was no meaningful difference in progression-free survival, according to a statement from the companies. However, duration of response was significantly higher for those on the immunotherapy, at 6.9 months, compared to 3.9 months in the chemo arm. Patients also reported improved quality of life on nivolumab, according to an exploratory analysis.

Guardant Health and the National Cancer Center Hospital East in Japan presented data from the prospective Phase II TRIUMPH trial showing that metastatic colorectal cancer patients with HER2 amplifications as detected by the Guardant360 liquid biopsy test benefited from guideline-recommended HER2-targeted combination treatment.

An interim analysis showed that 33.3 percent of metastatic CRC patients with HER2 amplification by Guardant360, who were also RAS wild type and refractory to EGFR inhibitors, saw their tumors shrink after receiving HER2 targeted drugs, trastuzumab and pertuzumab (Genentech's Herceptin and Perjeta). When researchers excluded patients who had resistance markers as detected by Guardant360, the objective response rate was 45.5 percent.

The overall median progression-free survival in the study was four months and the median duration of response was 4.2 months. Patients with HER2-amplified tumors who also had mutations in KRAS, NRAS, PIK3CA, or HER2 as gauged by Guardant360 fared worse in terms of response and progression-free survival, compared to those who lacked mutations in these genes.

Currently, advanced CRC patients aren't tested for HER2 amplifications unless they are undergoing tissue-based next-generation sequencing, but invasive biopsies are often not possible for many late-stage patients. Liquid biopsies can fill a need in this regard.

"The results of the TRIUMPH study strongly suggested that circulating tumor DNA analysis can equally identify patients with HER2-amplified metastatic CRC who benefit from the dual HER2-targeted therapy as the tissue analysis," principal investigator Yoshiaki Nakamura from the National Cancer Center Hospital East said in a statement.

Internal validation data from the Circulating Cell-free Genome Atlas (CCGA) study showed that Grail's blood-based targeted methylation assay can detect more than 20 cancer types across different stages, accurately identify the site of cancer in the body, and have a low false positive rate.

The test demonstrated a specificity of 99.4 percent for detecting early- and late-stage cancers.  The overall sensitivity of the assay for detecting more than 20 kinds of cancers was 54.7 percent, and 75.8 percent for detecting 14 prespecified cancers that account for around two-thirds of cancer deaths in the US.

Researchers led by Dana-Farber Cancer Institute's Geoffrey Oxnard reported that the assay's sensitivity for detecting lung cancer was 71.6 percent; however, the detection rate was lower in early-stage disease, but better for squamous cell carcinomas versus adenocarcinoma. The test's sensitivity for detecting breast cancer was 33.2 percent, but was also negatively affected by early-stage disease and hormone receptor-positive status.

The targeted methylation assay was able to assign a tissue of origin to 97 percent of samples, and 89 percent of the calls were correct. Independent validation data for this assay will be presented at a future meeting, Oxnard said, noting that the findings thus far support the continued development of the targeted methylation test for the detection of multiple cancers.

Preliminary results from Ayala Pharmaceuticals' ongoing Phase II ACCURACY study suggested that its investigational drug, AL101, may be efficacious and safe in patients with recurrent/metastatic adenoid cystic carcinoma (ACC) who have Notch activating mutations. ACC impacts 1,300 patients a year in the US, and there is no standard treatment. Patients with Notch mutations have an aggressive form of the disease.

In the study so far 38 patients have been screened and 27 have received a dose of the Notch inhibitor AL101. As of August 31, 18 of the 27 patients receiving the drug had a minimum of one pre-dosing and one post-dosing radiological evaluation. The preliminary data shows a 22 percent response rate and 61 percent disease control rate. AL101 was well tolerated, and though diarrhea was one of the most common adverse events (as seen with other Notch inhibitors), the vast majority of incidents were not serious.

In an updated pooled analysis involving 121 adult and pediatric patients with a variety of solid cancers characterized by TRK fusions, larotrectinib (Bayer/Eli Lilly's Vitrakvi) had an overall response rate of 79 percent. Of the patients who responded, 16 percent saw their tumors completely disappear and and 63 percent had a partial response. In a dozen patients with brain metastases, the overall response rate was 75 percent.

Median progression free survival was 28.3 months, median overall survival was 44.4 months, and 88 percent of patients were alive one year after starting treatment.

NTRK fusions are exceedingly rare in solid tumors. According to Lilly and Bayer, the latest data brings the total number of evaluable patients with TRK fusions who have received larotrectinib to 153, making it the largest dataset on a TRK inhibitor to date. 

The FDA granted accelerated approval to larotrectinib last year for the treatment of adult and pediatric patients with solid tumors characterized by an NTRK gene fusion and without an acquired resistance mutation. Continued market availability of the drug relies on post-marketing data that supports the evidence used for its expedited approval. 

Researchers from Genentech and Foundation Medicine reported that the blood-based next-generation sequencing test, FoundationOne Liquid, was able to identify ALK rearrangements in non-small cell lung cancer patients, indicating their ability to potentially benefit from the ALK inhibitor alectinib (Alecensa).

In the Phase II/III Blood First Assay Screening Trial (BFAST), Genentech and Foundation have partnered to prospectively evaluate whether the use of blood-based next-generation sequencing can detect gene fusions in non-small cell lung cancer patients and whether the results can inform treatment, doing away with the need for tissue-based testing.

FoundationOne Liquid detects the four classes of genomic alterations, microsatellite instability, and specific fusions, including fusions in ALK in circulating tumor DNA from a blood sample. In BFAST, 87.4 percent of advanced NSCLC patients that the blood test identified as having an ALK fusion saw their tumors shrink on alectinib. The responses seen in this study are in line with the Phase III ALEX study involving the same drug, which identified patients with ALK fusions using tissue testing.

Independent reviewers reported an overall response rate of 92 percent in BFAST. Median progression-free survival and duration of response was not reached after more than a year follow up.

"Validated and comprehensive liquid biopsy tests are critical to help physicians find the best possible treatment approach for patients with advanced cancer and for whom tissue testing isn't feasible," Brian Alexander, Foundation's chief medical officer, said in a statement. "Identifying ALK fusions can be particularly challenging and these data demonstrate that FoundationOne Liquid can accurately predict which patients can respond to therapy."

Results from a Phase Ib study of Imugene's anti-cancer vaccine HER-Vaxx showed that three patients with metastatic, HER2 overexpressing gastric cancer, who received the optimal dose (50 micrograms) of the drug, saw their tumors shrink. 

HER-Vaxx is a B-cell peptide cancer vaccine that Imugene is developing to treat cancers that overexpress the HER-2/neu receptor. Preclinical studies, and now this Phase Ib data, demonstrated that the immunotherapy can stimulate polyclonal antibody responses to HER2/neu proteins.  

Researchers reported exploratory outcomes data from 11 evaluable patients who were divided into three dose-specific cohorts, 10, 30, and 50 micrograms. In the first cohort, one patient had a complete response, and two had stable disease. In the second cohort, two had partial responses, two had stable disease, and one patient progressed. In the third cohort, in which patients received the highest dose, all three patients experienced partial responses. 

Across the three cohorts, in five of the 11 evaluable patients, tumor reduction was associated with high HER2-specific antibody levels upon vaccination with HER-Vaxx, which suggests that the drug may effectively inhibit cancer cell growth by blocking HER2 phosphorylation. 

Imugene earlier this year started an open label Phase II study of HER-Vaxx involving 68 patients with HER2 overexpressing, metastatic gastric cancer, and hopes to complete the trial next year.