Date: 2018-10-06
Type of
information: Presentation of results at a congress
phase: 1-2
Announcement: presentation of results at the 88th Annual Meeting of the American Thyroid Association
Company: Loxo Oncology (USA - CT)
Product: LOXO-292
Action
mechanism:
- RET inhibitor/kinase inhibitor. LOXO-292 is an oral and selective investigational RET inhibitor. RET fusions have been identified in approximately 2% of non-small cell lung cancer, 10-20% of papillary thyroid cancer, and a subset of colon and other cancers. RET point mutations account for approximately 60% of medullary thyroid cancer. Both RET fusion and select RET mutated cancers are primarily dependent on this single activated kinase for their proliferation and survival. This dependency, often referred to as “oncogene addiction,” renders such tumors highly susceptible to small molecule inhibitors targeting RET. LOXO-292 was designed to inhibit native RET signaling as well as anticipated acquired resistance mechanisms that could otherwise limit the activity of this therapeutic approach.
Disease: RET-fusion non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC) and other tumors with increased RET activity
Therapeutic
area: Cancer - Oncology
Country: USA
Trial
details:
- LIBRETTO-001 ((LOXO-292 Investigated to Block RET-altered Tumors) is a Phase 1/2 trial of LOXO-292 in advanced cancer patients who primarily have activating RET alterations. LIBRETTO-001 contains a Phase 1 dose escalation phase and a Phase 2 dose expansion phase. The dose escalation phase follows a “3+3” design. LOXO-292 is dosed orally in 28-day cycles. As dose cohorts are cleared, additional patients can enroll in these cleared cohorts. Intra-patient dose escalation is also permitted as dose cohorts are cleared. The primary endpoint of the trial is the determination of the maximum tolerated dose (MTD) or recommended dose for further study. Secondary endpoints include safety, overall response rate (by RECIST 1.1) and duration of response. The dose expansion phase is designed to further characterize the overall response rate, durability of response, and safety of LOXO-292 in predefined groups of patients with activating RET alterations.
- In this study LOXO-292 was administered orally to patients with advanced solid tumors, including RET-fusion non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC) and other tumors with increased RET activity.
- In the expansion phase, five cohorts are planned to allow for the characterization of preliminary activity of LOXO-292 in the following genetically-defined populations:
- – 1) RET-fusion lung cancer patients with prior RET inhibitor experience;
- – 2) RET-fusion lung cancer patients with no prior RET inhibitor experience;
- – 3) RET-mutant medullary thyroid cancer patients with prior RET inhibitor experience;
- – 4) RET-mutant medullary thyroid cancer patients with no prior RET inhibitor experience; and
- – 5) other RET-altered solid tumors.
- Loxo Oncology anticipates that approximately 15 patients will be enrolled to each of the expansion cohorts. (NCT03157128)
Latest
news:
- • On October 6, 2018, Loxo Oncology announced updated interim clinical data for LOXO-292 from the global Phase 1/2 LIBRETTO-001 trial in patients with RET-mutant medullary thyroid cancer (MTC) and RET fusion-positive thyroid cancer who were initially included in the LOXO-292 presentation at the 2018 ASCO Annual Meeting. In these 38 patients, approximately 3.5 months of additional patient follow-up were available, as were first follow-up scans for the nine patients most recently enrolled. Sixteen of 17 (94%) responding RET-mutant MTC patients remained on therapy, with median follow-up of 8.4 months. Seven of seven (100%) responding RET fusion-positive thyroid cancer patients remained on therapy, with median follow-up of 8.5 months. Inclusion of new restaging data for the most recently enrolled patients resulted in a 59% overall response rate (56% confirmed overall response rate) in the presented subset of RET-mutant MTC patients, and a 78% confirmed overall response rate in the presented subset of RET fusion-positive thyroid cancer patients. These data have been presented at the 88th Annual Meeting of the American Thyroid Association .
- Key Data Presented: The data presented were based on a July 19, 2018 data cut-off date and included the 29 patients with RET-mutant MTC and the nine patients with RET fusion-positive thyroid cancer who were initially included in the LOXO-292 presentation at the 2018 ASCO Annual Meeting.
- Patients were heavily pretreated, having received a median of three prior systemic treatment regimens. Of the patients with RET-mutant MTC, 79% had previously received cabozantinib or vandetanib and 45% had received prior treatment with both agents. Of the patients with RET fusion-positive thyroid cancer, 78% had previously received radioactive iodine and 78% had previously received sorafenib or lenvatinib.
- With 3.5 months of additional follow-up since the 2018 ASCO Annual Meeting presentation, LOXO-292 demonstrated encouraging, early evidence of durable activity. Sixteen of 17 (94%) responding RET-mutant MTC patients remained on therapy and in response (median follow-up of 7.6 months for all 29 patients; median follow-up of 8.4 months for responding patients). Seven of seven (100%) responding RET fusion-positive thyroid remained on therapy and in response (median follow-up of 7.6 months for all nine patients; median follow-up of 8.5 months for responding patients). The longest treated patient was the first RET-mutant MTC patient enrolled, who had been on therapy for more than 13 months as of the data cut-off date.
- The new data cutoff date allowed for the inclusion of first follow-up scans for nine patients (seven with RET-mutant MTC and two with RET fusion-positive thyroid cancer) who had not had any post-baseline response assessment as of the ASCO presentation. Of 29 patients with RET-mutant MTC, 17 demonstrated an objective response by RECIST 1.1 (two complete responses and 15 partial responses, including two patients with unconfirmed partial responses awaiting confirmatory response assessments) and seven additional patients demonstrated evidence of tumor regression (-12% to -26%). The overall response rate was 59% (17/29) (95% CI: 39%-77%) and the confirmed overall response rate was 56% (15/27) (95% CI: 35%-75%). Included in this analysis are two patients with non-measurable disease at baseline (1 confirmed complete response, 1 stable disease). Of nine patients with RET fusion-positive thyroid cancer, seven demonstrated an objective response by RECIST 1.1 (all partial responses) and one additional patient demonstrated evidence of tumor regression (-21%). The confirmed overall response rate was 78% (7/9) (95% CI: 40%-97%). Included in the analysis is one patient with non-measurable disease at baseline (stable disease). Response assessments were performed by the local clinical trial sites.
- Anti-tumor activity was observed regardless of RET mutation, RET fusion partner, and prior multikinase inhibitor treatment. One patient, with RET fusion-positive thyroid cancer, had RECIST target lesions in the central nervous system (CNS) and exhibited an intracranial partial response by RECIST 1.1, pending confirmation.
- Of the 82 patients in the safety analysis, most treatment-emergent adverse events were Grade 1 in severity and judged by the investigator as not related to LOXO-292. The treatment-emergent adverse events observed in =10% of patients, regardless of relationship to LOXO-292, were diarrhea (15% Grade 1, 7% Grade 2, 1% Grade 3), fatigue (9% Grade 1, 13% Grade 2, 0% =Grade 3), dry mouth (21% Grade 1, 0% =Grade 2), constipation (17% Grade 1, 2% Grade 2, 0% =Grade 3), hypomagnesemia (12% Grade 1, 1% Grade 2, 0% =Grade 3), cough (11% Grade 1, 1% Grade 2, 0% =Grade 3), headache (10% Grade 1, 1% Grade 2, 1% Grade 3) and nausea (9% Grade 1, 4% Grade 2, 0% =Grade 3). Four patients experienced adverse events =Grade 3 that were attributed to LOXO-292 (all Grade 3): tumor lysis syndrome, increased ALT/AST, diarrhea, and thrombocytopenia. All resolved with dose interruption. 160mg BID has been advanced as the Phase 2 dose, with dose exploration at 200mg BID ongoing to further characterize LOXO-292 safety and efficacy.• On September 25, 2018, Loxo Oncology announced updated interim clinical data for LOXO-292 from the global Phase 1/2 LIBRETTO-001 trial in patients with RET fusion-positive non-small cell lung cancer (NSCLC) who were initially included in the LOXO-292 presentation at the 2018 ASCO Annual Meeting. In these 38 patients, approximately 3.5 months of additional patient follow-up were available, as were first follow-up scans for the eight patients most recently enrolled. Twenty-five of 26 (96%) responding patients remained on therapy, with median follow-up of 9.5 months. Inclusion of new restaging data for the most recently enrolled patients resulted in a 68% confirmed overall response rate in the presented subset. These data have been presented at the 2018 IASLC 19th World Conference on Lung Cancer in Toronto (abstract 13922).
- The data presented were based on a July 19, 2018 data cut-off date and included the 38 patients with RET fusion-positive NSCLC who were initially included in the LOXO-292 presentation at the 2018 ASCO Annual Meeting.
- Patients were heavily pretreated, having received a median of three prior systemic treatment regimens. Thirty-nine percent had received both prior platinum-based chemotherapy and an anti-PD-1 or anti-PD-L1 therapy.
- With 3.5 months of additional follow-up since the 2018 ASCO Annual Meeting presentation, LOXO-292 demonstrated encouraging, early evidence of durable activity, with 25 of 26 (96%) responding RET fusion-positive NSCLC patients remaining on therapy and 24 of 26 (92%) remaining in response (median follow-up of 8.5 months for all 38 patients; median follow-up of 9.5 months for responding patients). The longest responding patient on therapy was the first RET fusion-positive NSCLC patient enrolled, who had been on therapy for more than 14 months as of the data cut-off date.
- The new data cutoff date allowed for the inclusion of first follow-up scans for eight patients who had not had any post-baseline response assessment as of the ASCO presentation. Of 38 patients with RET fusion-positive NSCLC, 26 demonstrated an objective response by RECIST 1.1 (all partial responses, including one patient with an unconfirmed partial response awaiting a confirmatory response assessment) and six additional patients demonstrated evidence of tumor regression (-3% to -29%). The overall response rate was 68% (26/38) (95% CI: 51%-83%) and the confirmed overall response rate was 68% (25/37) (95% CI: 50%-82%). Response assessments were performed by the local clinical trial sites.
- Anti-tumor activity was observed regardless of RET fusion partner (including KIF5B) and prior treatment, including chemotherapy, immunotherapy and multikinase inhibitors. Four patients had RECIST target lesions in the central nervous system (CNS) and all four exhibited confirmed intracranial responses by RECIST 1.1 (one complete response, three partial responses).
- Of the 82 patients in the safety analysis, most treatment-emergent adverse events were Grade 1 in severity and judged by the investigator as not related to LOXO-292. The treatment-emergent adverse events observed in =10% of patients, regardless of relationship to LOXO-292, were diarrhea (15% Grade 1, 7% Grade 2, 1% Grade 3), fatigue (9% Grade 1, 13% Grade 2, 0% =Grade 3), dry mouth (21% Grade 1, 0% =Grade 2), constipation (17% Grade 1, 2% Grade 2, 0% =Grade 3), hypomagnesemia (12% Grade 1, 1% Grade 2, 0% =Grade 3), cough (11% Grade 1, 1% Grade 2, 0% =Grade 3), headache (10% Grade 1, 1% Grade 2, 1% Grade 3) and nausea (9% Grade 1, 4% Grade 2, 0% =Grade 3). Four patients experienced adverse events =Grade 3 that were attributed to LOXO-292 (all Grade 3): tumor lysis syndrome, increased ALT/AST, diarrhea, and thrombocytopenia. All resolved with dose interruption. 160mg BID has been advanced as the Phase 2 dose, with dose exploration at 200mg BID ongoing to further characterize LOXO-292 safety and efficacy.• On June 2, 2018, Loxo Oncology announced interim clinical data from the LOXO-292 global Phase 1 LIBRETTO-001 dose escalation trial. LOXO-292 is an investigational, highly potent and selective RET inhibitor. These data have been presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.
- Key Data Presented at ASCO: The data presented at ASCO were based on an April 2, 2018 data cut-off date. Eighty-two total patients had been enrolled to eight dose escalation cohorts: 20 mg QD (n=6), 20 mg BID (n=10), 40 mg BID (n=16), 60 mg BID (n=10), 80 mg BID (n=18), 120 mg BID (n=4), 160 mg BID (n=12) and 240 mg BID (n=6). RET alterations were identified by local laboratories either in tumor or plasma and included the following primary diagnoses:
- 38 patients with RET fusion-positive non-small cell lung cancer (NSCLC) (21 with prior MKI treatment, 17 without)
- 9 patients with RET fusion-positive thyroid cancer (8 with prior MKI treatment, 1 without)
- 2 patients with RET fusion-positive pancreatic cancer (1 with prior MKI treatment, 1 without)
- 29 patients with RET-mutated medullary thyroid cancer (MTC) (23 with prior MKI treatment, 6 without)
- 4 patients with no known activating RET alterations
In addition to many patients with prior MKI treatment, 46% of patients had received prior chemotherapy and 24% had received prior immunotherapy (47% of those with NSCLC). Pharmacokinetic analyses during the dose escalation demonstrated dose-dependent increases in LOXO-292 exposure with increasing dose. Starting at the 40 mg BID dose and the 80 mg BID dose, respectively, LOXO-292 delivered sustained >IC90 RET fusion and >IC90 RET M918T-mutant target coverage, based on cell-based potencies.
The data presented at ASCO, summarized below, are based on response assessments performed by each respective clinical trial site (local, investigator-assessed radiology).
|
RET Fusion-Positive Cancers |
RET-
Mutated
MTC
|
No Known
Activating
RET Alteration
|
|
All |
NSCLC |
Other1 |
| Enrolled |
49 |
38 |
11 |
29 |
4 |
| Eligible for response evaluation2 |
39 |
30 |
9 |
22 |
3 |
| Overall response rate
(95% CI)3 |
77%
(61%-89%) |
77%
(58%-90%) |
78%
(40%-97%) |
45%
(24%-68%) |
0%
(0%-71%) |
| Confirmed overall response rate3,4 |
74% |
74% |
71% |
33% |
0% |
| CR |
-- |
-- |
-- |
1 |
-- |
| uCR5 |
-- |
-- |
-- |
1 |
-- |
| PR |
25 |
20 |
5 |
5 |
-- |
| uPR5 |
5 |
3 |
2 |
3 |
-- |
| SD |
6 |
4 |
2 |
9 |
2 |
| PD |
-- |
-- |
-- |
2 |
1 |
| Not evaluable6 |
3 |
3 |
-- |
1 |
-- |
1. Patients eligible for response evaluation include thyroid cancer (n=7), pancreatic cancer (n=2).
2. Excludes patients recently enrolled that remain on treatment, but have not had a first post-baseline response assessment.
3. Response status per RECIST 1.1. Overall response rate = CR+uCR+PR+uPR. Overall response rate, Confirmed overall response rate: all RET fusion-positive (30/39, 25/34), RET fusion-positive NSCLC (23/30, 20/27), RET fusion-positive other (7/9, 5/7), RET-mutant MTC (10/22, 6/18).
4. Excludes patients with unconfirmed CR/PR pending confirmation at time of data cut-off.
5. Unconfirmed responses in patients that remain on treatment awaiting a confirmatory response assessment.
6. Patients that discontinued treatment prior to a first post-baseline response assessment.
- Anti-tumor activity was observed regardless of RET fusion partner (including KIF5B), RET mutation (including M918T and V804M gatekeeper mutations), and prior MKI treatment. Twelve patients with RET fusion cancers had central nervous system (CNS) metastases at enrollment and all remained on study without progression. Three of these patients had RECIST target lesions in the CNS, and all three exhibited intracranial partial responses. In patients with RET-mutant MTC, LOXO-292 treatment resulted in significant reductions in the serum tumor markers calcitonin and carcinoembryonic antigen (CEA).
- As of the data cutoff, LOXO-292 demonstrated early evidence of durable activity, with 90% of RET fusion-positive cancer patients and 93% of RET-mutant MTC patients remaining on therapy. All responding patients across all tumor types remained on therapy. The longest responding patient on therapy was the first RET fusion-positive NSCLC patient enrolled, who had been on therapy for more than ten months as of the data cut-off date.
- Most treatment-emergent adverse events were Grade 1 in severity. The treatment-emergent adverse events observed in ?10% of patients, regardless of relationship to LOXO-292, were fatigue (12% Grade 1, 7% Grade 2, 0% ?Grade 3), diarrhea (10% Grade 1, 6% Grade 2, 0% ?Grade 3), constipation (13% Grade 1, 1% Grade 2, 0% ?Grade 3), dry mouth (12% Grade 1, 0% ?Grade 2), nausea (9% Grade 1, 4% Grade 2, 0% ?Grade 3), and dyspnea (7% Grade 1, 2% Grade 2, 1% ?Grade 3). Only two adverse events ?Grade 3 were attributed to LOXO-292 (Grade 3 tumor lysis syndrome, Grade 3 increased ALT). An MTD had not been reached. At the 240 mg BID dose level, one dose limiting toxicity (DLT) was reported (aforementioned Grade 3 tumor lysis syndrome).
- • On May 10, 2017, Loxo Oncology announced that the first patient has been enrolled in the Phase 1 clinical trial of LOXO-292, an investigational, highly potent and selective RET inhibitor
Is
general: Yes
