Minimal residual disease in Myeloma: Application for clinical care and new drug registration

The development of novel agents has transformed the treatment paradigm for multiple myeloma, with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow–based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in patients with multiple myeloma. Complementary liquid biopsy–based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid–based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real-world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory multiple myeloma, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in multiple myeloma is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes

Minimal residual disease in Myeloma: Application for clinical care and new drug registration

The development of novel agents has transformed the treatment paradigm for multiple myeloma, with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow–based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in patients with multiple myeloma. Complementary liquid biopsy–based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid–based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real-world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory multiple myeloma, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in multiple myeloma is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes

Association between Prior Malignancy Exclusion Criteria and Age Disparities in Cancer Clinical Trials

Prior malignancy exclusion criteria (PMEC) are often utilized in cancer clinical trials; however, the incidence of PMEC and the association of PMEC with trial participant age disparities remain poorly understood. This study aimed to identify age disparities in oncologic randomized clinical trials as a result of PMEC. Using a comprehensive collection of modern phase III cancer clinical trials obtained via ClinicalTrials.gov, we assessed the incidence and covariates associated with trials excluding patients with prior cancers within 5+ years from registration (PMEC-5). Using the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database, we further sought to determine the correlation between PMEC-5 and age disparities. PMEC-5 were used in 41% of all trials, with higher PMEC-5 utilization among industry-supported trials as well as trials evaluating a targeted therapy. Comparing trial patient median ages with population-matched median ages by disease site and time-period, we assessed the association between PMEC-5 and age disparities among trial participants. PMEC-5 were independently associated with heightened age disparities, which further worsened with longer exclusionary timeframes. Together, PMEC likely contribute to age disparities, suggesting that eligibility criteria modernization through narrower PMEC timeframes may work toward reducing such disparities in cancer clinical trial enrollment

High Plus Low Dose Radiation Strategy in Combination with TIGIT and PD1 Blockade to Promote Systemic Antitumor Responses

Tumors deploy various immune-evasion mechanisms that create a suppressive environment and render effector T-cells exhausted and inactive. Therefore, a rational utilization of checkpoint inhibitors may alleviate exhaustion and may partially restore antitumor functions. However, in high-tumor-burden models, the checkpoint blockade fails to maintain optimal efficacy, and other interventions are necessary to overcome the inhibitory tumor stroma. One such strategy is the use of radiotherapy to reset the tumor microenvironment and maximize systemic antitumor outcomes. In this study, we propose the use of anti-PD1 and anti-TIGIT checkpoint inhibitors in conjunction with our novel RadScopal technique to battle highly metastatic lung adenocarcinoma tumors, bilaterally established in 129Sv/Ev mice, to mimic high-tumor-burden settings. The RadScopal approach is comprised of high-dose radiation directed at primary tumors with low-dose radiation delivered to secondary tumors to improve the outcomes of systemic immunotherapy. Indeed, the triple therapy with RadScopal + anti-TIGIT + anti-PD1 was able to prolong the survival of treated mice and halted the growth of both primary and secondary tumors. Lung metastasis counts were also significantly reduced. In addition, the low-dose radiation component reduced TIGIT receptor (PVR) expression by tumor-associated macrophages and dendritic cells in secondary tumors. Finally, low-dose radiation within triple therapy decreased the percentages of TIGIT+ exhausted T-cells and TIGIT+ regulatory T-cells. Together, our translational approach provides a new treatment alternative for cases refractory to other checkpoints and may bring immunotherapy into a new realm of systemic disease control

Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials

Background: Radiotherapy might augment systemic antitumoral responses to immunotherapy. In the PEMBRO-RT (phase 2) and MDACC (phase 1/2) trials, patients with metastatic non-small-cell lung cancer were randomly allocated immunotherapy (pembrolizumab) with or without radiotherapy. When the trials were analysed individually, a potential benefit was noted in the combination treatment arm. However, owing to the small sample size of each trial, differences in response rates and outcomes were not statistically significant but remained clinically notable. We therefore did a pooled analysis to infer whether radiotherapy improves responses to immunotherapy in patients with metastatic non-small-cell lung cancer. Methods: Inclusion criteria for the PEMBRO-RT and MDACC trials were patients (aged ≥18 years) with metastatic non-small-cell lung cancer and at least one unirradiated lesion to monitor for out-of-field response. In the PEMBRO-RT trial, patients had previously received chemotherapy, whereas in the MDACC trial, patients could be either previously treated or newly diagnosed. Patients in both trials were immunotherapy-naive. In the PEMBRO-RT trial, patients were randomly assigned (1:1) and stratified by smoking status (<10 vs ≥10 pack-years). In the MDACC trial, patients were entered into one of two cohorts based on radiotherapy schedule feasibility and randomly assigned (1:1). Because of the nature of the intervention in the combination treatment arm, blinding to radiotherapy was not feasible in either trial. Pembrolizumab was administered intravenously (200 mg every 3 weeks) with or without radiotherapy in both trials. In the PEMBRO-RT trial, the first dose of pembrolizumab was given sequentially less than 1 week after the last dose of radiotherapy (24 Gy in three fractions), whereas in the MDACC trial, pembrolizumab was given concurrently with the first dose of radiotherapy (50 Gy in four fractions or 45 Gy in 15 fractions). Only unirradiated lesions were measured for response. The endpoints for this pooled analysis were best out-of-field (abscopal) response rate (ARR), best abscopal disease control rate (ACR), ARR at 12 weeks, ACR at 12 weeks, progression-free survival, and overall survival. The intention-to-treat populations from both trials were included in analyses. The PEMBRO-RT trial (NCT02492568) and the MDACC trial (NCT02444741) are registered with ClinicalTrials.gov. Findings: Overall, 148 patients were included in the pooled analysis, 76 of whom had been assigned pembrolizumab and 72 who had been assigned pembrolizumab plus radiotherapy. Median follow-up for all patients was 33 months (IQR 32·4–33·6). 124 (84%) of 148 patients had non-squamous histological features and 111 (75%) had previously received chemotherapy. Baseline variables did not differ between treatment groups, including PD-L1 status and metastatic disease volume. The most frequently irradiated sites were lung metastases (28 of 72 [39%]), intrathoracic lymph nodes (15 of 72 [21%]), and lung primary disease (12 of 72 [17%]). Best ARR was 19·7% (15 of 76) with pembrolizumab versus 41·7% (30 of 72) with pembrolizumab plus radiotherapy (odds ratio [OR] 2·96, 95% CI 1·42–6·20; p=0·0039), and best ACR was 43·4% (33 of 76) with pembrolizumab versus 65·3% (47 of 72) with pembrolizumab plus radiotherapy (2·51, 1·28–4·91; p=0·0071). Median progression-free survival was 4·4 months (IQR 2·9–5·9) with pembrolizumab alone versus 9·0 months (6·8–11·2) with pembrolizumab plus radiotherapy (hazard ratio [HR] 0·67, 95% CI 0·45–0·99; p=0·045), and median overall survival was 8·7 months (6·4–11·0) with pembrolizumab versus 19·2 months (14·6–23·8) with pembrolizumab plus radiotherapy (0·67, 0·54–0·84; p=0·0004). No new safety concerns were noted in the pooled analysis. Interpretation: Adding radiotherapy to pembrolizumab immunotherapy significantly increased responses and outcomes in patients with metastatic non-small-cell lung cancer. These results warrant validation in a randomised phase 3 trial. Funding: Merck Sharp & Dohme

Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations

Somatic mutations in the isocitrate dehydrogenase 2 gene (IDH2) contribute to the pathogenesis of acute myeloid leukaemia (AML) through the production of the oncometabolite 2-hydroxyglutarate (2HG)(1-8). Enasidenib (AG-221) is an allosteric inhibitor that binds to the IDH2 dimer interface and blocks the production of 2HG by IDH2 mutants(9,10). In a phase I/II clinical trial, enasidenib inhibited the production of 2HG and induced clinical responses in relapsed or refractory IDH2-mutant AML(11). Here we describe two patients with IDH2-mutant AML who had a clinical response to enasidenib followed by clinical resistance, disease progression, and a recurrent increase in circulating levels of 2HG. We show that therapeutic resistance is associated with the emergence of second-site IDH2 mutations in trans, such that the resistance mutations occurred in the IDH2 allele without the neomorphic R140Q mutation. The in trans mutations occurred at glutamine 316 (Q316E) and isoleucine 319 (I319M), which are at the interface where enasidenib binds to the IDH2 dimer. The expression of either of these mutant the expression of the Q316E or I319M mutation together with the R140Q mutation in trans allowed 2HG production that was resistant to inhibition by enasidenib. Biochemical studies predicted that resistance to allosteric IDH inhibitors could also occur via IDH dimer-interface mutations in cis, which was confirmed in a patient with acquired resistance to the IDH1 inhibitor ivosidenib (AG-120). Our observations uncover a mechanism of acquired resistance to a targeted therapy and underscore the importance of 2HG production in the pathogenesis of IDH-mutant malignancies

Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study

Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708

Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study

Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708