Photo: Mrinal Gounder, MD
The search for better treatments for advanced chordoma just took another step forward: Data from a Phase 1 clinical trial testing a new experimental drug called ERAS-601 alone and in combination with cetuximab were presented at ASCO, the world’s largest annual oncology conference. Of the 13 chordoma participants who enrolled on the trial, 1 patient achieved a partial response by RECIST criteria (meaning the tumor shrank by at least 30%) and 11 patients experienced stable disease, 10 of whom had some tumor shrinkage (though less than the 30% needed to meet RECIST criteria). Of these patients, 11 received the drug combination, and ERAS-601 alone was given to two chordoma patients during the dose escalation phase of the trial, one of whom experienced stable disease. The investigators report that the drugs were reasonably safe and tolerable for all participants.
“The activity we've seen in this trial is promising and warrants further clinical evaluation in chordoma patients,” says Mrinal Gounder, MD, medical oncologist at Memorial Sloan Kettering Cancer Center and Chordoma Foundation Medical Advisory Board Member, who presented the results at ASCO. “In particular, we need to continue following these patients to understand how durable their clinical benefit is, and to better understand the efficacy of SHP2 inhibitor monotherapy in chordoma patients,” he says.
ERAS-601, which is being developed by the company Erasca, Inc., works by inhibiting SHP2 (pronounced “ship-two”), a target that regulates multiple cancer-driving processes. Cetuximab, the other drug tested in this trial, works by inhibiting epidermal growth factor receptor (EGFR), a target that is also showing potential in treating chordoma. The combined use of SHP2 inhibitors and EGFR-targeting drugs is supported by scientific rationale and has shown promise against some other tumor types.
SHP2 was identified as a potential therapeutic target for chordoma through our partnership with the Schreiber Lab at the Broad Institute of MIT and Harvard. Once that team identified SHP2 as a key vulnerability in chordoma, we quickly evaluated SHP2 inhibitors in preclinical experiments directed through Chordoma Foundation Labs, finding strong anti-tumor activity — in fact, SHP2 inhibitors appeared to be among the most effective therapies we’ve tested preclinically. The data were then reviewed by our Medical Advisory Board, who endorsed evaluation of SHP2 inhibitors in chordoma patients. Their endorsement sparked intensive efforts to engage with companies developing SHP2 inhibitors and to enroll chordoma patients on associated Phase 1 trials.
“This is an exciting example of the rapid translation of discoveries from the lab to patients made possible via Chordoma Foundation Labs, our research partners, and expert chordoma oncologists on our Medical Advisory Board. Together, we can quickly identify therapies that could meaningfully extend the lives of patients with advanced-stage chordoma, and increase the chances that companies will include them in clinical trials,” says Dan Freed, PhD, Chief Scientific Officer at the Chordoma Foundation.
While this trial is no longer enrolling chordoma patients, its results highlight the potential of SHP2 inhibitors to treat advanced chordoma. Further research is needed to understand the efficacy of SHP2 inhibitors alone to tease out whether the effects observed in this trial are due to SHP2 inhibition, cetuximab, or a synergy between the two. Meanwhile, a cetuximab clinical trial we’re supporting is currently enrolling patients at MD Anderson Cancer Center. Our Patient Navigators are available to answer questions about clinical trial participation, and a full list of clinical trials testing drugs endorsed by our Medical Advisory Board is available here.
Multiple effective drugs and drug combinations will probably be necessary in order for all advanced-stage chordoma patients to benefit from drug therapy, and we still have much to learn about applying these treatments in a personalized manner. To advance this goal, we’re supporting numerous projects with the aim of identifying additional chordoma treatment opportunities, and working in Chordoma Foundation Labs to uncover mechanisms of sensitivity and resistance to promising drugs.
We’re grateful to everyone who made this trial possible: Erasca, the investigators who helped enroll chordoma patients, the patients who participated, and our donors — in this case, Team Mac and the Roye family in particular — whose generosity is helping bring about new chordoma treatment options.