Efficacy and safety of selpercatinib in RET fusion-positive cancers other than lung or thyroid cancers
Prof Vivek Subbiah - MD Anderson Cancer Center, Houston, USA
On behalf of my co-investigators it is my pleasure and honour to present the initial results of the efficacy and safety of selpercatinib, a highly selective and potent RET inhibitor, in patients with RET fusion-positive cancers other than lung or thyroid cancers. The RET proto-oncogene is generally activated by two mechanisms: the RET fusions or mutations. RET fusions occur predominantly in 2% of lung cancers and 10-20% of thyroid cancers and in low frequency in an increasing number of diverse cancers like pancreatic cancer, salivary gland cancer and colorectal cancer. The therapeutic relevance of RET fusions occurring outside of lung and thyroid cancers has not been very well established.
As previously described, multi-kinase inhibitors have had very limited clinical activity in patients with RET driven cancers. Selpercatinib is a first in class, highly selective and potent, CNS active RET kinase inhibitor. Again, selpercatinib is highly selective for RET with minimal activity against other kinases. Selpercatinib in preclinical models and in clinical models also showed anti-tumour activity in the central nervous system, initially based on preclinical data and subsequently observed clinically in the ongoing LIBRETTO-001 clinical trial.
As previously published, selpercatinib has demonstrated marked and durable activity in non-small cell lung cancer, regardless of the RET fusion partner, with an objective response rate of 64% in a heavily pre-treated population and an objective response rate as high as 85% in patients who were treatment naïve. The median duration of response in lung cancer was 17.5 months in patients who were heavily pre-treated and not reached in patients with non-small cell lung cancer who were treatment naïve. Similarly, patients with RET fusion-positive thyroid cancer derived clinical benefit from selpercatinib across a variety of histologies with an objective response rate of 79% in patients who were previously treated and an objective response rate of 100% in the treatment naïve population.
Selpercatinib has received approval in multiple countries, including the United States and Europe, for the treatment of RET fusion-positive lung as well as RET driven thyroid cancers.
This LIBRETTO-001 trial was conducted in two parts – a phase I dose escalation and a phase II dose expansion part across 16 countries and 89 sites. The trial included multiple cohorts, including patients with RET mutant cancers who are not being presented here. A total of 441 patients with RET fusions were enrolled in the LIBRETTO-001 trial as of the data cut-off of March 19th. Here we discuss the 38 patients who had a RET fusion-positive cancer, excluding those with lung or thyroid as the data from these patients has been previously published. The efficacy evaluable population here consists of 32 patients who had enrolled on or before September 19th, long enough to allow a six month follow-up after the first dose of selpercatinib.
What are the eligibility criteria for this clinical trial? Patients were required at least to be 12 years of age with a diagnosis of advanced or metastatic solid tumour and an ECOG performance status of 0-2. The primary endpoint of the study was an objective response rate by RECIST version 1.1. Secondary endpoints included duration of response, progression free survival and safety, among others.
I would like to present the selpercatinib safety and efficacy as determined by investigator assessment in patients with non-lung and non-thyroid RET fusion-positive cancers. Here, 62% of the patients had treatment refractory GI cancers with very limited therapy options. The patients had received a median of two prior therapies with over a third of patients having received three or more prior lines of treatment. The majority of patients received prior chemotherapy while a few patients received prior multi-kinase inhibitors or anti-PD-1 or PD-L1 therapy. The most common fusion partner identified in this subset was NCOA4.
The waterfall plot we showed highlights the activity of selpercatinib in patients with RET fusion-positive non-lung and non-thyroid cancers from the LIBRETTO-001 study. The objective response rate per investigator assessment was 47% and included two complete responses. The waterfall plot showed only patients who had a measurable disease, therefore three patients that included a patient with xanthogranuloma who achieved a complete response are not included because they had only non-target lesions or did not have a baseline target lesion measurement.
Also, tumour response was observed across the spectrum of RET fusion partners. Also we showcase the swimmer plot that illustrates a rapid and durable anti-tumour activity of selpercatinib in the patient population with a median time to response of just under two months. Almost half of the patients remain on treatment with a current median time on treatment of 11 months.
The safety profile of these 38 patients was consistent with previous reports in the overall safety population as shown in the presentation. In the cohort reported the most frequent emergent adverse events of any grade included liver enzymes, dry mouth and hypertension. Most importantly, no patients in this cohort discontinued treatment due to a treatment related adverse event.
In the talk I shared three specific cases who benefitted from selpercatinib. The first one is a patient with a 31-year-old female with metastatic pancreatic ductal adenocarcinoma. Prior therapies included FOLFIRINOX and FOLFIRI. Genetic profiling revealed the tumour harbouring RET fusion that was microsatellite stable and KRAS BRAF wild type. The patient was enrolled on the LIBRETTO-001 trial. The patient’s disease demonstrated partial response to selpercatinib after four cycles with 38% shrinkage which continues to decrease over time to 50% tumour shrinkage at 40 cycles. Selpercatinib was well tolerated with manageable low-grade AEs. As of February 2021 the patient still continues on selpercatinib with an ongoing response of 37 months.
The second case was a case of a Japanese female from Japan who was diagnosed with ER HER2 negative stage 4 breast cancer, this time harbouring a CCD6-RET fusion with no co-occurring alterations identified. After enrolling on the selpercatinib treatment the prior therapies that included Tamoxifen and goserelin and which were discontinued due to disease progression, the patient enrolled on the selpercatinib treatment and the patient experienced a complete response just after three months on selpercatinib. The patient continues on clinical therapy although the patient’s cancer progressed because the investigators felt an assessment of ongoing clinical benefit.
The third case I shared was a case of a 36-year-old white man with metastatic xanthogranuloma with no organ involvement. The NGS testing revealed no other co-occurring alterations but NCOA4-RET fusion. Twelve weeks after the patient began therapy with selpercatinib the marked improvement of disfiguring lesions was seen. After seven months of selpercatinib treatment a complete response was observed.
In summary, RET fusions in tumours other than non-small cell lung cancer and thyroid cancer are uncommon but potentially actionable. Selpercatinib demonstrates promising activity across a variety of non-lung and non-thyroid RET fusion-positive advanced solid tumours including difficult to treat, treatment refractory GI malignancies. The objective response rate by investigator assessment in this heavily pre-treated population was 47% and this included complete responses. Efficacy was observed across cancer types and a spectrum of fusion partners. Overall, selpercatinib was well tolerated with a safety profile consistent with what has been previously reported with no new safety signals identified.
This analysis reiterates the importance of a broad-based comprehensive genomic profiling to identify actionable oncogenic drivers that include RET fusions. The safety and efficacy of selpercatinib continues to be explored in the ongoing LIBRETTO-001 trial which is still enrolling patients with RET fusion-positive non-lung cancers.
I would like to thank the motivated patients and their family members and caregivers of the LIBRETTO-001 trial. I would also like to thank all the global investigators across all the 89 sites and their support staff for their ongoing commitment to the clinical trial. Thank you.