Background

Selinexor is a first-in-class oral selective inhibitor of nuclear export that is approved in the US for treatment of patients with relapsed multiple myeloma, and has demonstrated anti-cancer activity in patients with other haematological and solid tumor malignancies.

Methods

Diagnostic, demographic and baseline laboratory data from 1,936 cancer patients treated with selinexor on 13 clinical trials were used to predict tolerability (measured by days on selinexor) and best overall response. An integrated machine learning model averaging neural networks, random forests, logistic regression, and gradient boosting was used. To distinguish between predictive markers for selinexor and general prognostic markers, patients enrolled on the BOSTON study treated with selinexor, dexamethasone, and bortezomib (SVd), were compared to patients on the control arm (Vd).

Results

A combined machine learning model for predicting response that tested over 70 variables among selinexor treated patients achieved an area under the receiver operating characteristic curve of 0.674. Lower lactate dehydrogenase (LDH), higher hematocrit (HCT) and higher hemoglobin (HGB) were found to have the strongest associations with positive response. In a separate analysis of selinexor tolerability, higher HGB, lower LDH and higher HCT were also the three strongest predictors of longer time on study. When applying these models to the BOSTON study, variable correlations with treatment duration were stronger and more consistent with data from other trials for patients on the SVd arm compared to those on the Vd arm, indicating specificity for predicting tolerance to selinexor (Table). Table: 89P

Comparison of single variable correlations with time on study between two arms of the BOSTON study

Conclusions

Lower LDH and higher HCT/HGB may be useful for predicting patients who will respond safely and favorably to selinexor. Our combined models using common lab values that can easily be assessed may help in identifying patients most likely to derive clinical benefit from selinexor treatment.

Legal entity responsible for the study

Karyopharm Therapeutic Inc.

Funding

Karyopharm Therapeutic Inc.

Disclosure

Y. Artstein: Full/Part-time employment: Karyopharm Therapeutics. C. Walker: Shareholder/Stockholder/Stock options, Full/Part-time employment: Karyopharm Therapeutics. F. Yang: Shareholder/Stockholder/Stock options, Full/Part-time employment: Karyopharm Therapeutics. D. Van Domelen: Shareholder/Stockholder/Stock options, Full/Part-time employment: Karyopharm Therapeutics. D. Borochov: Shareholder/Stockholder/Stock options, Full/Part-time employment: Karyopharm Therapeutics. I. Mercier: Shareholder/Stockholder/Stock options, Full/Part-time employment: Karyopharm Therapeutics. J. Shah: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Karyopharm Therapeutics. S. Shacham: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment, Officer/Board of Directors: Karyopharm Therapeutics. Y. Landesman: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment, Officer/Board of Directors: Karyopharm Therapeutics. S. Tang: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment, Officer/Board of Directors: Karyopharm Therapeutics. E. Shacham: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Karyopharm Therapeutics.

Background

Selinexor, a first-in-class, novel oral selective inhibitor of nuclear export which inhibits the Exportin-1 (XPO1) or chromosomal region maintenance 1 (CRM1), had demonstrated synergistic activity with many chemotherapies and conferred antitumor efficacy in multiple cancers in in vivo studies.

Methods

This was an open label, single-center, multi-arm phase Ib study utilizing a "3 + 3” design and a "basket type” expansion. Selinexor with topotecan was employed as one of the 13 parallel arms. Patients with advanced or metastatic solid tumours who were unresponsive or had relapsed following prior systemic therapy or where the addition of selinexor to standard chemotherapy deemed appropriate and acceptable, were eligible.

Results

Fourteen patients with the median age of 60 (range, 21 – 68 years) were treated, and the most common cancer types were gynecological cancers; including ovarian (n=5), endometrial (n=2), and 1 each with fallopian tube and vaginal cancers. All 14 patients had at least one treatment emergent adverse events (TEAE) and 13 patients were evaluable for response. The most prevalent TEAE were followings; anemia (85%), fatigue (78%), thrombocytopenia (71%), hyperglycemia (71%), hyponatremia (64%), nausea (64%), fatigue (61%), hypomagnesemia (57%), and vomiting (57%). The commonest grade ≥ 3 TEAE were hyponatremia (28%), anemia (21%), neutropenia (21%), thrombocytopenia (21%) and leukopenia (14%). Two patients dosed at selinexor 60mg had dose limiting toxicities. One patient had grade 3 nausea and vomiting where other experienced grade 4 neutropenia and thrombocytopenia. A patient with endometrial cancer achieved partial response (7.7%) and treatment to failure (TTF) was 48 weeks whereas six patients (46.1%) had stable disease contributing the clinical benefit rate of 53.8%. TTF ranged from 3 to 74 weeks.

Conclusions

Our study showed that once weekly selinexor in combination with topotecan was viable and showed clinical activity with substantial objective responses and the recommend phase II dose of selinexor was 60 mg once weekly in combination with IV topotecan. Future studies are warranted of once weekly oral selinexor in combiation with once weekly oral topotecan.

Clinical trial identification

NCT02419495.

Legal entity responsible for the study

The authors.

Funding

Karyopharm.

Disclosure

All authors have declared no conflicts of interest.

Background

Selinexor is a first-in-class novel, oral potent selective inhibitor of nuclear export which blocks the transport protein called Exportin-1. Carboplatin+ Taxol (CT) is one of the standard chemotherapy regimens used in various tumour types. Preclinical models have suggested that selinexor and CT exerts antitumor activity in multiple malignancies.

Methods

This was an open label, single-center, multi-arm phase Ib study utilizing a “3 + 3” design and a “basket type” expansion. CT + selinexor was employed as one of the 13 parallel arms. Patients with advanced or metastatic solid tumours who were unresponsive or had relapsed following prior systemic therapy or where the addition of selinexor to standard chemotherapy deemed appropriate and acceptable, were eligible.

Results

Of 13 patients treated, 12 patients were evaluable for response. The most common cancers were breast (n=4), esophageal (n=2), ovarian (n=2) and non-small cell lung cancers (n=2). All 13 patients had at least one treatment-emergent adverse events (TEAE) and the commonest TEAE were anemia (84%), neutropenia (84%), leukopenia (84%), thrombocytopenia (84%), fatigue (61%), elevated AST or ALT (61%), nausea (53%), hypomagnesemia (53%), and peripheral motor or sensory neuropathy (53%). The most prevalent grade ≥ 3 TEAE were neutropenia (69%), thrombocytopenia (53%), leukopenia (46%), and anemia (15%). One patient at 60mg once weekly had experienced DLT with grade 4 neutropenia lasting >7 days. Partial response was noted in 4 patients (33.3%) in patients with esophageal (n=2), 1 patient each with breast and ovarian cancer. Five patients (41.7%) achieved stable disease and the clinical benefit rate was 75%. Majority of patients (84%), including 3 patients who had PR, had prior exposure to carboplatin and/ or paclitaxel. Treatment time to failure (TTF) ranged from 10 to 148 weeks and TTF for patients with PR was from 18 to 23 weeks.

Conclusions

Oral selinexor can be safely combined with CT and the RP2D was 60 mg once weekly in combination with CT. The combination conferred appreciable clinical activity with durable objective responses which should further be explored in tumour types for which CT is used as standard of care.

Clinical trial identification

NCT02419495.

Legal entity responsible for the study

The authors.

Funding

Karyopharm.

Disclosure

All authors have declared no conflicts of interest.

Background

Selinexor is a first-in-class novel, oral potent selective inhibitor of nuclear export, which inhibits the transport protein Exportin-1. Preclinical models have suggested that SEL in combination with checkpoint inhibitor (CPI) would enhance the ability to inhibit the proliferation and survival of tumor cells.

Methods

This open label, single center phase IB combination therapy study in metastatic/locally advanced cancers enrolled either treatment naïve (t/n) pts or pts who relapsed on prior therapies (r/p). The addition of SEL to multiple standard chemotherapy and CPI regimens was tested in parallel, with ARM L using PEM (200g IV q3 weeks) in combination with SEL (starting dose 60mg PO BIW). For this melanoma (MM) cohort, we used recommended phase II dose (RP2D) data obtained from the dose escalation. Primary objective was to establish the safety and tolerability of SEL/PEM. Secondary endpoints included response rate (RR) and progression free survival (PFS).

Results

25 pts MM (13 male) have enrolled, including 6 pts with uveal MM, with a median age of 65.8 years (range 31.4-83). The majority of patients (n=17) had no prior systemic therapies for MM, but 5 pts had +/>3 lines of prior therapy. Most common SEL or PEM related AEs included nausea (68%), vomiting (52%), and anemia (48%). Three pts discontinued therapy due to AE. At a median follow up of 4.8 months (range 0.1-14.0) three pts achieved a CR (13%), 6 achieved a PR (26%) and 10 (43%) had stable disease (SD). Specifically, the overall RR in non-uveal t/n pts, 54% achieved either a CR (23%) or PR (31%). None of the uveal MM responded (5 pts SD). The median PFS for the entire cohort has not been reached and the 6-month PFS rate was 0.65 (95% CI: 0.46, 0.91). The 9-month PFS rate was 0.57 (95% CI: 0.37, 0.87). The median overall survival (OS) has not been reached, and the 6 months OS rate of 0.81 (95% CI: 0.63, 1). 22/25 pts are still alive.

Conclusions

The RP2D dose was Selinexor 60 mg po BIW and q 3 week PEM in patients with MM. Treatment with SEL/PEM is well-tolerated and shows significant clinical activity with a ORR of 54% compared to historical ORR of 30% with single agent PEM in t/n pts compared to historic single agent PEM. The combination warrants further evaluation.

Clinical trial identification

NCT02419495.

Legal entity responsible for the study

University of Texas MD Anderson Cancer Center.

Funding

Karyopharm Therapeutics, Inc.

Disclosure

All authors have declared no conflicts of interest.

Background

Single-agent belantamab mafodotin (belamaf; GSK2857916), a first-in-class antibody-drug conjugate targeting B-cell maturation antigen, demonstrated deep and durable responses in heavily pretreated patients with RRMM in DREAMM-2 (NCT03525678) primary and post hoc analyses.

Methods

DREAMM-2 patients had ≥3 prior lines of therapy, were refractory to an immunomodulatory agent and a proteasome inhibitor, with anti-CD38 antibody exposure. Systematic searches for trials in a similar patient population to DREAMM-2 identified only STORM Part 2 (selinexor plus low-dose dexamethasone [sel+dex]; NCT02336815) for comparative analyses. MAIC were performed on populations receiving belamaf (2.5 mg/kg; n=97) versus sel+dex (sel 80 mg + dex 20 mg; n=123), matching for clinically validated effect modifiers and prognostic factors. Incidences of any grade and Grade 3–4 adverse events (AEs) among Grade 3–4 AEs affecting ≥5% of either trial population were compared. MAIC efficacy analyses are reported separately.

Results

Belamaf had lower risk (p<0.05) for frequent (≥25%) any-grade/Grade 3–4 thrombocytopenia, anaemia, neutropenia, fatigue, hyponatremia, and decreased appetite, and any-grade nausea and diarrhoea; (Table). Risk for any-grade/Grade 3–4 lymphopenia and hyperglycaemia, and any-grade leukopenia, pneumonia, hypokalaemia, and mental status changes was higher with belamaf than sel+dex. Keratopathy was reported in DREAMM-2 but not STORM Part 2. Hypercalcemia risk was higher with belamaf. Table: 901P

MAIC of frequent (≥25%) AEs

Conclusions

MAIC of single-agent belamaf showed high efficacy and a favourable safety profile versus sel+dex for haematologic/non-haematologic AEs reported in compared studies.

Clinical trial identification

DREAMM-2: NCT03525678; STORM: NCT02336815.

Editorial acknowledgement

Editorial assistance was provided by Muchaala Yeboah, PhD, of Fishawack Indicia Ltd and funded by GlaxoSmithKline.

Legal entity responsible for the study

Study funded by GlaxoSmithKline.

Funding

Study funded by GlaxoSmithKline 207147. Drug linker technology licensed from Seattle Genetics; Monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.

Disclosure

A. Suvannasankha: Advisory/Consultancy: GlaxoSmithKline, Janssen, and Karyopharm Therapeutics; Research grant/Funding (self): GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and Celgene; Travel/Accommodation/Expenses: GlaxoSmithKline and Janssen. T. Prawitz, V. Kapetanakis, G. Sarri, R. Hughes, F. Wang, C. Hogea, S. Allen Ferrante, B. Gutierrez, B. Gorsh, J. Willson: Research grant/Funding (self): employee of Evidera which received research funding from GlaxoSmithKline. R. Popat: Honoraria (self), Honoraria (institution): Janssen, Takeda, Celgene, and GlaxoSmithKline; Advisory/Consultancy: Takeda, AbbVie, GlaxoSmithKline, and Celgene; Research grant/Funding (self): Takeda; Travel/Accommodation/Expenses: Janssen, Takeda, and GlaxoSmithKline.