Roche/Abbvie's Venclexta Outshines Agios IDH Inhibition In AML At ASH
Executive Summary
Clinicians weigh in on updated data presented at ASH in frontline acute myeloid leukemia, but caution that it is difficult to compare across clinical trials.
Venclexta AML Update Well-received
Clinicians described the updated Venclexta data at the ASH meeting as robust. In the M14-358 study, the rate of complete response plus complete response with at least partial blood count recovery (CR+CRh) was 67% for Venclexta with azacitidine and 71% for Venclexta with decitabine, another hypomethylating agent.In a second study presented at the meeting – M14-387 – the CR/CRi rate for Venclexta/LDAC was 54% and 21% of patients (17/82) achieved MRD-negativity. The CR/CRi rate for those with IDH mutations was 25%.
Phase III studies testing Venclexta with azacitidine or LDAC in previously untreated AML patients who are ineligible for intensive chemotherapy are ongoing.
Patients who are older and not able to undergo intensive chemotherapy can now achieve the benefits of a high remission rate through Venclexta combinations, Hayslip said.
But the story for venetoclax and the BCL-2 target more generally in AML is just beginning, and there is a push to expand the patient groups who can benefit, he said.
"These studies are about Venclexta plus low-intensity [chemotherapy] treatment, but if Venclexta can do this for patients who can't receive more intensive therapies, what can it do for patients who are younger and fitter?" the exec asked.
Cleveland Clinic AML specialist Aaron Gerds said that the presentation of updated data at the meeting adds to the robustness of the Venclexta narrative as it evolves and noted that a lot of doctors are comfortable with the drug as they have already used it in chronic lymphocytic leukemia (CLL). However, he added the caveat that single-arm studies can be misleading and that robust results can dissipate later in a randomized trial.
Peter Emanuel, director of oncology services at CHI St. Vincent at Little Rock, said that in his view venetoclax is the most exciting among the new drugs right now for AML due to broader applicability, versus applicability in particular subsets.
Pressure On Agios Shares
The robust performance of the Venclexta combination, particularly in patients with IDH1/2 mutations, exceeding the results for the IDH2 inhibitor Idhifa as a single agent in frontline AML, as well as safety concerns, put pressure on Agios shares, Leerink Swann analyst Andrew Berns said in a Dec. 3 note.
Agios' stock price fell 13.66% on Dec. 3 to a close of $56.81 and closed down another 4.86% on Dec. 4 at $54.05.
Idhifa and Tibsovo both were approved with a boxed warning for IDH-differentiation syndrome, a condition caused by the rapid proliferation and differentiation of myeloid cells that can be fatal if not treated.
On Nov. 29, the FDA issued a safety communication about differentiation syndrome associated with Idhifa urging greater monitoring and aggressive management of the condition, and the agency also presented a safety meta-analysis drawing attention to the adverse event at the ASH meeting.
Both Gerds and Emanuel told Scrip said that they did not see the risk as a barrier to use and that it may be managed by experienced prescribers. Gerds, who chairs the communications committee at ASH, said a learning curve can be expected with new drugs.
However, Leerink's Berens saw the FDA's safety presentation and efficacy data for Idhifa as monotherapy as part of the Leukemia & Lymphoma Society "Beat AML" umbrella development program for targeted drugs in newly diagnosed AML as negative. The objective response rate in 27 patients treated with Idhifa was 44%, the LLS reported at the meeting. (Also see "AML Master Protocol For Precision Medicine Developed By Nonprofit And US FDA" - Pink Sheet, 21 Dec, 2016.)
Berens said that some doctors at the meeting had the impression that the IDH inhibitors – in particular Idhifa – have diminished activity compared with Venclexta. However, the analyst also said that the Idhifa monotherapy data presented at the meeting "do not represent an accurate assessment of the IDH inhibitor development plan and opportunity."
While Berens sees Venclexta as a significant competitor, he saw two other studies reported by Agios – Tibsovo as a monotherapy in frontline patients not eligible for other therapies and Idhifa or Tibsovo with "7+3" frontline chemotherapy induction – as more relevant for the company.
The monotherapy study tested Tibsovo in a subset of 34 patients (out of a total Phase I study population of 258) who had IDH1 mutant newly diagnosed AML (primary and secondary) and were ineligible for standard treatment.
In the subset, the drug demonstrated a CR+CRh rate of 42.4% and an objective response rate of 57.6%.
Agios CEO David Schenkein pointed out in an interview that these patients were very sick with very limited options. Half had previously had azacitidine as a treatment for myelodysplasia and would not be eligible to have it again as a repeat treatment in combination with venetoclax.
Safety was consistent with prior reports. The rate of IDH-differentiation syndrome of any grade was 17.6% and cases were managed with corticosteroids and diuretics, Agios reported. No permanent treatment discontinuations or deaths were reported.
These data will be submitted as part of Agios' planned FDA filing in IDH-mutated frontline AML next month.
In the combination study, patients received Tibsovo or Idhifa with standard induction and consolidation chemotherapy plus maintenance treatment in newly diagnosed AML (primary and secondary) with IDH1 or IDH2 mutations. In this study, 60 got Tibsovo and 93 got Idhifa.
For those on Tibsovo, the ORR was 80% for efficacy-evaluable patients. In a subset of those who had complete responses, elimination of MRD was achieved in 17%.
The rate of Grade 3+ IDH-differentiation syndrome was 3%.
For Idhifa, the overall best response rate was 72% in efficacy-evaluable patients. The rate of Grade 3+ IDH-differentiation syndrome was 1%.
Agios and Celgene are planning to start the Phase III, randomized-controlled HOVON 150 AML/AMLSG 29-18 study of Tibsovo or Idifa in 1,000 newly diagnosed IDH-mutated AML patients eligible for intensive chemotherapy by the end of the year. The study will test the IDH inhibitors in combination with 7+3 chemotherapy induction and consolidation chemotherapy followed by maintenance treatment for up to two years.
Gerds cautioned against comparing Venclexta with the IDH inhibitors. Venclexta targets the BCL-2 pathway whereas the IDH inhibitors are targeting particular mutations. Also, the studies did not include a direct comparator and results may change when a direct comparator is added and/or when trials get larger.
Comparing the data for Venclexta with IDH inhibitors is not just like comparing apples vs. oranges, but "apples vs. elephants," Gerds told Scrip.
Emanuel said that more data is needed to know whether Venclexta or an IDH inhibitor should be used upfront, but that it would make more scientific sense that if a patient has a genetic abnormality to go first to a drug that targets that specific abnormality.
Schenkein said that his company showed compelling data for Tibsovo and Idhifa with azacitidine in newly diagnosed AML at the American Society of Clinical Oncology (ASCO) meeting this year that were similar to what has been seen with Venclexta.
But he added that he doesn't view Venclexta as competition. In treatment of older patients, none of the drugs are curative at this time, he noted.
"The reality is that patients are going to need all of these medicines," Schenkein said.
MD Anderson is running a Phase I/II study testing the combination of Tibsovo with Venclexta in IDH1-mutated hematologic malignancies.
Agios is also planning to test Tibsovo in combination with an inhibitor of FLT3 mutations.