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European Society for Medical Oncology Congress 2021: Precision Oncology Data Roundup

At the European Society for Medical Oncology Congress held from Sept. 16 to 22, pharmaceutical companies, diagnostics firms, and researchers presented data on drugs targeting various tumor alterations and biomarker tests that identified best responders to treatment. Below is a roundup of some of the data presented at the meeting.

Bayer's Vitrakvi

Bayer presented updated analysis showcasing the broad efficacy of its TRK inhibitor larotrectinib (Vitrakvi), which is approved in the US and Europe as a treatment for refractory solid tumors harboring an NTRK fusion. In one subgroup analysis, researchers presented longer follow-up data on 130 evaluable patients with 20 different non-central nervous system tumors with NTRK fusions, which showed an overall response rate of 67 percent and a 12 percent complete response rate; the median duration of response was 49.3 months at a median follow-up of 23.2 months.  

Among 15 patients who had central nervous system metastasis, the overall response rate was 73 percent. Seventeen patients experienced grade 3 or 4 treatment-related adverse events, but there were no new safety signals. "The long-term data for Vitrakvi continue to support consistent responses and similar safety profile seen with the addition of new patients and with longer follow-up," Scott Fields, senior VP and head of oncology development at Bayer's pharmaceutical division, said in a statement. "These findings reinforce the importance of precision oncology medicines as a meaningful advancement in cancer care."

Oncxerna's Xerna TME Panel

Oncxerna Therapeutics presented data from a cohort of its ONCG100 study showing that its phosphatidylserine inhibitor bavituximab can improve immunotherapy response in patients with immunologically "cold tumors" and that its  Xerna TME Panel — a test that uses an RNA expression-based algorithm to characterize the tumor microenvironment — could identify gastric cancer patients who are likely to benefit from bavituximab and the anti-PD-1 drug pembrolizumab (Merck's Keytruda).

Out of 17 patients with advanced gastric or gastroesophageal junction cancer in the Phase II trial with a PD-L1 expression combined positive score of less than 1, three responded to the combination, while five out of 40 patients with a PD-L1 expression combined positive score of at least 1 responded. Similarly, 14 percent of 43 patients with microsatellite stable disease responded to the bavituximab-pembrolizumab combination. Oncxerna said in a statement that these data suggest that bavituximab can sensitize patients who don't typically respond well to checkpoint inhibition to single-agent immunotherapy.

In the study, patients who received a high immune score from the Xerna TME test were more likely to benefit from the combination. The objective response rate in 32 patients deemed biomarker-positive by the Xerna TME Panel was 22 percent, while out of 25 biomarker-negative patients, only 4 percent responded. Biomarker-positive patients who had low PD-L1 expression and microsatellite stable tumors also had higher objective responses on bavituximab-pembrolizumab. 

Carrick Therapeutics' Samuraciclib

Carrick Therapeutics presented data showing its CDK7 inhibitor samuraciclib plus fulvestrant shrank tumors in patients with advanced or metastatic HR-positive, HER2-negative breast cancer who were previously treated with CDK4/6 inhibitors. Among 24 evaluable patients enrolled in the Phase IIa study, 17 (71 percent) had tumor shrinkage. Two patients achieved a partial response and 13 patients reached stable disease. The median progression-free survival was 16 weeks among all patients. Progression-free survival was twice as long, 32 weeks, among patients without a TP53 mutation.

Based on this initial data, Carrick will advance the treatment into a randomized Phase IIb study in this same patient population. That trial will include patients with both non-measurable disease and those with visceral disease. The second stage of the study will also stratify patients according to TP53 mutation status. "This success aligns with the known biological function of TP53 since its activation has been shown to sensitize cancer cells to CDK7 inhibition," Stuart McIntosh, chief medical officer at Carrick, said in a statement. "Approximately 75 percent of breast cancer patients are TP53 wildtype, and we believe this may be an important potential biomarker for future studies."

Allarity Therapeutics' Dovitinib-DRP

Allarity Therapeutics presented data further validating the ability of its gene expression-based companion diagnostic, Dovitinib-DRP, to identify renal cell carcinoma (RCC) patients likely to derive greater survival benefit with dovitinib compared to sorafenib (Bayer's Nexavar).

The data come from a retrospective analysis that Allarity performed on a previously conducted Phase III clinical trial of dovitinib versus sorafenib. When Allarity selected RCC patients in the trial using the Dovitinib-DRP companion diagnostic, those with a DRP score above 50 percent experienced a median overall survival of 15 months with dovitinib versus 11.2 months with sorafenib. Among patients with DRP scores above 67 percent, moreover, the median survival with dovitinib was 20.6 months. 

This data come on the heels of the US Food and Drug Administration accepting Allarity's premarket approval application for the Dovitinib-DRP in July. Allarity plans to file a new drug application for dovitinib with the agency during Q4 2021 and hopes that it will be able to resuscitate the once-failed agent licensed from Novartis, contingent on approval of the drug and companion diagnostic. 

Innovent Biologics' Pemigatinib

Innovent Biologics reported that in the Phase II FIGHT-202 trial being conducted in China, the FGFR inhibitor pemigatinib shrank tumors in 50 percent of evaluable patients with FGFR2 fusion-positive cholangiocarcinoma. As of a Jan. 29 cutoff date, 15 out of 30 evaluable patients responded to pemigatinib after failing prior systemic therapy. At a median follow-up of 5.13 months, 13 patients were still responding on therapy and the median duration of survival was not reached. The disease control rate was 100 percent, but progression-free survival data were immature. 

A safety analysis, involving 34 patients, showed hyperphosphatemia, xerostomia, and alopecia were among common treatment-related adverse events. Three patients had serious adverse events including rectal polyps, abnormal liver function, and bile duct infection. 

The first-line treatment for advanced cholangiocarcinoma is gemcitabine with cisplatin, which in studies have yielded a 26 percent objective response rate and a median overall survival of 11.7 months. "There is an urgent need [for] drugs that can vastly change the landscape of treatment for intrahepatic cholangiocarcinoma," principal investigator of the trial Jian Zhou from Fudan University Zhongshan Hospital said in a statement.

AstraZeneca, Daiichi Sankyo's Enhertu

Daiichi Sankyo and AstraZeneca showed that metastatic, HER2-positive gastric cancer patients in North America and Europe respond as Asian patients do to their antibody-drug conjugate trastuzumab deruxtecan (Enhertu) in the second-line setting. In the Phase II DESTINY-Gastric-02 trial involving 79 trastuzumab deruxtecan-treated patients with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) cancer, 38 percent had a confirmed overall response, three patients had complete responses, and 27 had partial responses. At a median follow-up of 5.7 months, the median duration of response was 8.1 months and median progression-free survival was 5.5 months. 

Based on data from the earlier DESTINY-Gastric01 trial, regulators in Israel, Japan, and the US approved trastuzumab deruxtecan for advanced HER2-positive gastric or GEJ cancer patients after a trastuzumab-based regimen. However, that study enrolled patients from Japan and South Korea. The DESTINY-Gastric-02 trial reinforced the activity of the antibody-drug conjugate in HER2-positive gastric cancer patients in Western countries.

Merck's Keytruda

In a final analysis from the Phase III KEYNOTE-355, Merck said that the combination of pembrolizumab (Keytruda) and chemotherapy reduced the risk of death by 27 percent compared to chemo alone in patients with PD-L1-positive (combined positive score of at least 10) metastatic triple-negative breast cancer. Median overall survival was 23 months in the pembrolizumab-chemo arm compared to 16.1 months in the chemo-only arm. The overall survival advantage was consistent among pembrolizumab-treated patients regardless of whether they received paclitaxel, nab-paclitaxel, or gemcitabine/carboplatin as their chemotherapy. There wasn't a statistically significant difference in overall survival between treatment arms when the PD-L1 expression threshold was lowered to include patients with a combined positive score of at least 1. 

The progression-free survival advantage with pembrolizumab and chemo previously seen in Keynote-355 supported the regimen's approval in the US and in Japan as a first-line treatment of patients with PD-L1-positive metastatic TNBC. The European Medicines Agency's Committee for Medicinal Products for Human Use has also recommended approval of this indication.  

Novartis' Kisqali

In the Phase III MONALEESA-2 trial, post-menopausal women with advanced, hormone receptor (HR)-positive, HER2-negative breast cancer lived longer on the combination of Novatis' CDK4/6 inhibitor ribociclib (Kisqali) and the aromatase inhibitor letrozole compared to those just on letrozole. After a median follow-up of six-and-a-half years, patients on ribociclib-letrozole lived a year longer than patients receiving only letrozole, with a median overall survival of 63.9 months versus 51.4 months, respectively. In the US and Europe, ribociclib is available as an initial endocrine-based therapy for postmenopausal women with HR-positive, HER2-negative advanced breast cancer in combination with an aromatase inhibitor. 

Other studies have demonstrated that ribociclib plus endocrine therapy extends lives in this subset of breast cancer patients. The latest data from MONALEESA-2 adds to that evidence and "represent the longest reported median survival from a randomized trial in HR-positive/HER2-negative advanced breast cancer," Gabriel Hortobagyi, a professor of medicine at the MD Anderson Cancer Center, said in a statement announcing the results.

AstraZeneca, Daiichi Sankyo's Dato-DXd

In a sub-analysis within the Phase I TROPION-PanTumor01 trial, Daiichi Sankyo and AstraZeneca reported that advanced non-small cell lung cancer patients with various actionable genomic alterations responded to its investigational antibody-drug conjugate datopotamab deruxtecan, called Dato-DXd for short. In 34 evaluable NSCLC patients with actionable genomic alterations, the objective response rate was 35 percent as assessed by independent reviewers. At a median follow-up of 13.4 months, the median duration of response was 9.5 months. Patients with EGFR exon19 deletions and L858R mutations responded to Dato-DXd even after treatment with osimertinib (AstraZeneca's Tagrisso). 

Most patients had EGFR mutations in this cohort, but patients also harbored ALK, ROS1, and RET fusions, and Dato-DXd demonstrated activity in patients with other tumor alterations as well. This Phase I analysis provides preliminary evidence of Dato-DXd's activity in patients with certain genomic alterations, Gilles Gallant, senior VP and global head of oncology R&D at Daiichi Sankyo, said in a statement. These early findings will be further evaluated in the 150-patient Phase II TROPION-Lung05 trial.

Janssen's Balversa

In the Phase Ib/II NORSE trial, Janssen compared the activity of its investigational anti-PD-1 therapy cetrelimab combined with its FGFR inhibitor erdafitinib (Balversa) against just erdafitinib in advanced urothelial cancer patients with FGFR2/3 alterations who are ineligible for cisplatin or other standard-of-care treatments. The investigator-assessed objective response rate in 19 patients on the combination regimen was 68 percent, while 33 percent of 18 patients on erdafitinib monotherapy responded. The disease control rate was 90 percent on cetrelimab-erdafitinib and 100 percent on just erdafitinib. 

In 2019, the US Food and Drug Administration granted accelerated approval to erdafitinib as a treatment for patients with metastatic urothelial cancer with FGFR3 and FGFR2 genetic alterations, who have progressed on platinum-containing chemotherapy. "As we learn more about the genetic factors that impact treatment outcomes, we are exploring new treatment approaches that may help patients with specific mutations, including FGFR alterations and fusions," Thomas Powles, director of Barts Cancer Institute in London and the principal investigator of the NORSE trial, said in a statement. "With this combination of erdafitinib and cetrelimab, we aim to change the tumor microenvironment to make it more receptive to PD-1 intervention."  

Novartis' 177Lu-PSMA-617 Radioligand Therapy

Novartis reported that in the Phase III VISION trial, metastatic, prostate-specific membrane antigen (PSMA)-positive castration-resistant prostate cancer (mCRPC) patients on its investigational radioligand therapy with standard-of-care treatments reported better health-related quality-of-life symptoms compared to those on just standard-of-care therapy. Patients on its radioligand therapy reported a 54 percent reduction from baseline in the risk of worsening health-related quality-of-life parameters, compared to those on the comparator arm. 177Lu-PSMA-617 plus standard of care also reduced the risk of worsening pain from baseline by 55 percent compared to the standard of care.

At the American Society of Clinical Oncology's annual meeting in June, Novartis reported that patients receiving 177Lu-PSMA-617 with standard-of-care therapy had a median overall survival of 15.3 months compared to 11.3 months for patients only on the standard of care. Median radiographic progression-free survival was 8.7 months in the 177Lu-PSMA-617 arm and 3.4 months in the comparator arm.