On the horizon of translational research

  • Elena Garralda
Targeted Therapy Translational Research
On Target

Elena Garralda

Vall d' Hebron Institute of Oncology, Barcelona, Spain
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Tumour agnostic targeted agents and ‘smarter’ dynamic designs are two major areas of interest leading to more patient-centric approaches in cancer care

In oncology, we are continuing to witness how disruptive study designs and genomically enriched trial strategies are dancing to the beat of precision oncology through the advent of master protocol trials, including basket and umbrella studies, that are progressively reshaping the landscape of drug development in oncology.

Similarly, N-of-1 trial methodology, while challenging, represents an upcoming contender as we shift from traditional treatment-centric models to dynamic patient-centric approaches toward expediting cancer drug development and extending the promise of personalised medicine to an increasing number of our patients.

Targeting HER2 across multiple tumour types

Interim results of the ongoing phase II DESTINY-PanTumor-02 trial, recently presented by lead author Funda Meric-Bernstam at the University of Texas MD Anderson Cancer Center in Houston, showed that HER2-targeted antibody drug conjugate (ADC) trastuzumab deruxtecan achieved encouraging clinical activity and long-lasting responses in a variety of tumour types.

This international open-label basket trial is the first to take a tumour-type agnostic approach for ADC therapy. Including 267 patients with HER2-expressing (by IHC) locally advanced or metastatic cervical, endometrial, ovarian, biliary tract, pancreatic and bladder cancers, as well as other tumours, the investigators evaluated the anti-tumour activity of trastuzumab deruxtecan.

The investigators reported an objective response rate (ORR) of 61.3% with a median duration of response (DOR) of 22.1 months in patients with the highest levels of HER2 expression. Across all patients, who had received a median of two prior lines of therapy, the ORR was 37.1% with a median DOR of 11.8 months. An ORR of more than 30% was observed in all cancer types with the exception of biliary tract (22%) and pancreatic cancers (4%).

The safety profile of trastuzumab deruxtecan was consistent with previous clinical trials, with grade 3 or higher treatment-related adverse events occurring in 38.6% of all patients, the most common being nausea, fatigue and cytopenias ILD was reported in 18 pts (6.7%).

The strong anti-tumour activity and durable responses shown in multiple tumour types, most notably in the gynaecological cancer cohorts and in those patients expressing higher levels of HER2 expression, point to the promise of this ADC as a new treatment avenue for patients with advanced and HER2-positive cancers to more effectively tackle these hard-to-treat tumours.

We eagerly await data on progression-free survival and overall survival analysis with further follow-up that should establish the practice-changing nature of this important study.

Tumour agnostic FGFR-directed therapy

Primary analysis results of the ongoing open-label, single-arm tumour-agnostic Phase II RAGNAR trial, led by Shubham Pant at the University of Texas MD Anderson Cancer Center in Houston, have shown the efficacy of targeted therapy with the selective pan-FGFR tyrosine kinase inhibitor erdafitinib in heavily pre-treated patients with advanced FGFR-altered solid tumours across 16 different cancer types.

This trial enrolled 217 adult and paediatric patients with FGFR-mutated advanced solid tumours (excluding urothelial cancer) who all had disease progression after at least one prior systemic therapy, with no alternative treatment options. Including patients with central nervous system tumours, gastrointestinal, gynaecologic, lung cancers, and other rare tumours, this study represents the largest tumour-agnostic trial of FGFR-directed therapy to date.

Among these patients, data showed an overall response rate (ORR) of 29.5%, including six complete responses and 58 partial responses. The ORR was comparable across FGFR1-3 mutations and fusions.

The investigators reported a disease control rate of 73.7% and a clinical benefit rate of 45.6%, including an ORR of 56% in patients with pancreatic cancer and 52% in cholangiocarcinoma. Treatment-emergent side effects were observed in all but one patient, and 70% of study participants experienced grade 3 or higher adverse events. The safety profile was consistent with the known side effects observed in previous trials.

These encouraging data suggest that targeted therapy with erdafitinib could ultimately open up a new, and much needed avenue for the treatment of patients with advanced FGFR-mutated solid cancers, across multiple tumour types.

A change to come for phase I combination trials

The first-in-human, phase I dose-escalation study led by Alexander E. Drilon at the Memorial Sloan Kettering Cancer Center and the Weill Cornell Medical College of Medicine in New York, evaluated the efficacy of the novel allosteric SHP2 inhibitor PF-07284892 as a single agent and in combination with different targeted therapies in patients with advanced oncogene-driven solid tumours that progressed on prior targeted treatment.

Adopting a patient-centric approach, the unique design of this adaptive two-part trial enabled patients with progressive disease after dose-escalation PF-07284892 monotherapy (part 1) to continue on trial in the combination dose-escalation part (2). Patients then received therapy with this novel agent plus a specific molecularly guided therapy (lorlatinib, encorafenib plus cetuximab or binimetinib), based on the individual genomic profile of each patient.

Preliminary results showed that PF-07284892 was generally well tolerated alone and in combination with targeted therapies, and the study’s design facilitated combination therapy rescue of disease progression on PF-07284892 monotherapy. With combined therapy, partial responses were observed in 3 treatment-refractory patients, and stable disease was observed in 6 patients with drug-resistant disease. Worthy of note, all patients had previously progressed to the same or similar targeted therapy in the past.

As I discussed in a viewpoint article (Cancer Discov. 2023 Jun 3;OF1-OF3) accompanying a simultaneous publication in the same issue (Cancer Discov. 2023 Jun 3;OF1-OF13), results pave the way for optimized dose-escalation clinical trial design to include a first-in-human dose-defining part for a single agent targeted therapy, followed by combined personalized therapy matched to individual genomic profiles.

Moving forward, the disruptive nature of this study will no doubt contribute to the implementation of patient-centric personalized approaches in the design and methodology of phase I trials. These ‘smarter’ dynamic designs should help to accelerate our collective efforts aimed at identifying the optimal treatment for the right patient, at the right time, and overcome certain limitations of traditional randomised approaches.

Challenging current treatment paradigms

Likewise, current research efforts focus on exploring kinder treatment strategies that could minimize treatment-related toxicity and harmful side effects while maintaining therapeutic gains.

Treatment de-escalation in selected populations of patients across tumour types aims at improving the quality of life and wellbeing of patients. As an example, results of primary outcome analysis from the phase III randomized, investigator-initiated, nationwide SONIA study presented by lead investigator Gabe S. Sonke of the Netherlands Cancer Institute in Amsterdam, challenge the recommended use of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors as first-line therapy in patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer.

This pragmatic trial evaluated the efficacy, safety and cost-effectiveness of CDK4/6i added to either first-or second-line endocrine therapy (ET) in 1,050 treatment-naïve patients enrolled in the study. Data showed that there was no significant difference in time to progression on second-line therapy or overall survival with first- versus second-line treatment with CDK4/6i and ET.

Favouring deferred use until the second-line setting, results revealed that first-line administration extended the time on CDK4/6i by 16.5 months, increased the incidence of grade 3/4 toxicity by 42%, and led to significantly higher drug costs due to the longer treatment time. This last point is particularly relevant in relation to promoting sustainable and equitable healthcare in oncology.

Since this trial was initiated in 2017, newer treatment options in both the first and second-line settings have emerged. Despite this consideration, the SONIA trial underscores the importance of identifying those patients who would most likely benefit from endocrine monotherapy to potentially stave off the additional toxicity of a CDK4/6i, and demonstrates proof of concept of a self-funded trial.

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