Showing papers by "Richard Pazdur published in 2022"

Association of Radiation Therapy With Risk of Adverse Events in Patients Receiving Immunotherapy: A Pooled Analysis of Trials in the US Food and Drug Administration Database.

Abstract: Importance Immune checkpoint inhibitors (ICIs) and radiation therapy (RT) are widely used to treat various cancers, but little data are available to guide clinicians on ICI use sequentially with RT. Objective To assess whether there is an increased risk of serious adverse events (AEs) associated with RT given within 90 days prior to an ICI. Design, Setting, and Participants Individual patient data were pooled from 68 prospective trials of ICIs submitted in initial or supplemental licensing applications in the US Food and Drug Administration (FDA) databases through December 2019. Two cohorts were generated: (1) patients who received RT within the 90 days prior to beginning ICI therapy and (2) those who did not receive RT within the 90 days prior to beginning ICI therapy, and AE frequencies were determined. A 1:1 propensity score-matched analysis was performed. Interventions All patients received an ICI (atezolizumab, avelumab, cemiplimab, durvalumab, ipilimumab, nivolumab, or pembrolizumab); 1733 received RT within the 90 days prior to starting ICI therapy, and 13 956 did not. Main Outcomes and Measures The primary outcome was frequency and severity of AEs. Incidence of AEs was compared descriptively between participants who did vs did not receive RT in the propensity score-matched set. Because all analyses are exploratory (ie, not preplanned and no alpha allocated), assessment for statistical significance of the differences between groups was not considered appropriate. Results A total of 25 469 patients were identified; 8634 were excluded because they lacked comparators who had received RT (n = 976), did not receive an ICI (n = 4949), received RT outside of the target window (n = 2338), or had missing data in 1 or more variables used in the propensity analysis (n = 371), leaving 16 835 patients included in the analysis. The majority were younger than 65 years (9447 [56.1%]), male (10 459 [62.1%]), and White (13 422 [79.7%]). Patients receiving RT had generally similar rates of AEs overall to those patients who did not receive RT. The average absolute difference in rates across the AEs was 1.2%, and the difference ranged from 0% for neurologic AEs to 8% for fatigue. No difference in grade 3 to 4 AEs was observed between the 2 groups (absolute difference ranged from 0.01% to 2%). These findings persisted after propensity score matching. Conclusions and Relevance In this pooled analysis, administration of an ICI within 90 days following RT did not appear to be associated with an increased risk of serious AEs. Thus, it would appear to be safe to administer an ICI within 90 days of receiving RT. These findings should be confirmed in future prospective trials.

The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint.

Abstract: On April 21, 2022, the Oncologic Drugs Advisory Committee of the US Food and Drug Administration (FDA) will discuss class-wide safety findings observed with PI3K inhibitors in haematological malignancies. Dysregulated PI3K signalling promotes the survival and proliferation of malignant lymphocytes and is the rationale for therapeutic targeting of PI3K isoforms in haematological malignancies. Four PI3K inhibitors have received approval for indications involving relapsed or refractory indolent non-Hodgkin lymphoma or chronic lymphocytic leukaemia: idelalisib (Gilead Sciences), copanlisib (Bayer HealthCare Pharmaceuticals), duvelisib (Secura Bio), and umbralisib (TG Therapeutics; table). These inhibitors each inhibit the PI3Kδ isoform and some also inhibit other isoforms. Alpelisib, a PI3Kα-specific inhibitor approved in breast cancer and PIK3CA-related overgrowth spectrum, is not included in this Comment. Although the four PI3K inhibitors have shown durable overall response rates or improvements in progression-free survival, or both, they have also shown substantial toxicity. TableStatus of FDA-approved PI3K inhibitors for haematological malignancies Initial approval information* Indications are extracted; approval endpoints are from the US Prescribing Information on initial approval date. Post-approval trials Outcome Idelalisib (PI3Kδ inhibitor) Regular approval 2014: relapsed chronic lymphocytic leukaemia in combination with rituximab † Rituximab alone would be considered appropriate therapy due to comorbidities. based on a RCT of idelalisib plus rituximab vs placebo plus rituximab in relapsed chronic lymphocytic leukaemia: progression-free survival HR 0·18 (95% CI 0·10–0·31), overall survival immature 2016: three RCTs halted in chronic lymphocytic leukaemia or indolent non-Hodgkin lymphoma for increased deaths and serious toxic side-effects: idelalisib with bendamustine plus rituximab vs placebo plus bendamustine plus rituximab in untreated chronic lymphocytic leukaemia; idelalisib plus rituximab vs placebo plus rituximab in relapsed or refractory indolent non-Hodgkin lymphoma; idelalisib with bendamustine plus rituximab vs placebo with bendamustine plus rituximab in relapsed or refractory indolent non-Hodgkin lymphoma. Pooled analysis, idelalisib groups vs control: deaths 7·4% vs 3·5%, overall survival HR 2·29 (95% CI 1·26–4·18) 1 Gilead SciencesImportant drug warning: decreased overall survival and increased risk of serious infections in patients receiving Zydelig (idelalisib). http://cllsociety.org/docs/Zydelig%20Safety%20Update.pdfDate: March, 2016 Date accessed: February 16, 2022 Google Scholar Warning and limitations of use added to prescribing information (2016, 2018) Accelerated approval 2014: relapsed follicular lymphoma and small lymphocytic lymphoma after ≥2 systemic therapies based on single-arm trial: follicular lymphoma: overall response rate 54% (95% CI 42–66), duration of response median not reached; small lymphocytic lymphoma: overall response rate 58% (95% CI 37–77), duration of response median 11·9 months Required post-marketing trial: slow accrual to trial evaluating idelalisib dosage in relapsed or refractory follicular lymphoma Voluntary withdrawal of follicular lymphoma and small lymphocytic lymphoma indications (2022) Copanlisib (PI3Kα and PI3Kδ inhibitor) Accelerated approval 2017: relapsed follicular lymphoma after ≥2 systemic therapies based on single-arm trial: overall response rate 59% (95% CI 49–68), duration of response median 12·2 months CHRONOS-3: RCT of copanlisib plus rituximab vs placebo plus rituximab in relapsed indolent non-Hodgkin lymphoma: 2 Matasar MJ Capra M Özcan M et al. Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2021; 22: 678-689 Summary Full Text Full Text PDF PubMed Scopus (17) Google Scholar progression-free survival HR 0·52 (95% CI 0·39–0·69), interim overall survival HR 1·07 (95% CI 0·63–1·82) Voluntary withdrawal of NDA based on CHRONOS-3 Duvelisib (PI3Kδ and PI3Kγ inhibitor) Regular approval 2018: relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma after ≥2 therapies based on a RCT of duvelisib vs ofatumumab in relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma: progression-free survival HR 0·52 (95% CI 0·39–0·69), overall survival immature Final analysis, duvelisib vs ofatumumab: overall survival HR 1·11 (95% CI 0·80–1·53) 3 Secura BioCorrection of drug information: updated overall survival data for Copiktra (duvelisib) in patients with relapsed/refractory (R/R) chronic lymphatic leukemia (CLL) and small lymphocytic lymphoma (SLL). https://copiktrahcp.com/notice-to-hcps/Date: March 18, 2022 Date accessed: March 18, 2022 Google Scholar Under FDA review Accelerated approval 2018: relapsed or refractory follicular lymphoma after ≥2 systemic therapies based on single-arm trial: overall response rate 42% (95% CI 31–54), 43% of responses were ongoing at ≥6 months and 17% at ≥12 months Required post-marketing trial: RCT was not initiated for commercial reasons Voluntary withdrawal of follicular lymphoma indication (2021) Umbralisib (PI3Kδ and CK1ɛ inhibitor) Accelerated approval 2021: relapsed or refractory follicular lymphoma after ≥3 systemic therapies and relapsed or refractory marginal zone lymphoma after ≥1 anti-CD20-based regimen based on single-arm trial: follicular lymphoma: overall response rate 43% (95% CI 34–52), duration of response median 11·1 months; marginal zone lymphoma: overall response rate 49% (95% CI 37–62), duration of response median not reached UNITY-CLL: RCT of umbralisib plus ublituximab vs obinutuzumab plus chlorambucil in untreated and relapsed or refractory chronic lymphocytic leukaemia: progression-free survival HR 0·55 (95% CI 0·41–0·72); 4 Gribben JG Jurczak W Jacobs RW et al. Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 Unity-CLL study. Blood. 2020; 136 (abstr).: 37-39 Crossref Google Scholar interim overall survival HR 1·23 5 TG TherapeuticsPress release: TG Therapeutics provides regulatory update. https://ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-provides-regulatory-updateDate: Nov 30, 2021 Date accessed: March 7, 2022 Google Scholar ‡ Overall survival data reflect later data cutoff; 95% CI was not available publicly. Planned for discussion by ODAC, April 22, 2022 FDA=US Food and Drug Administration. HR=hazard ratio. NDA=new drug application. ODAC=Oncologic Drugs Advisory Committee. RCT=randomised controlled trial. * Indications are extracted; approval endpoints are from the US Prescribing Information on initial approval date. † Rituximab alone would be considered appropriate therapy due to comorbidities. ‡ Overall survival data reflect later data cutoff; 95% CI was not available publicly. Open table in a new tab FDA=US Food and Drug Administration. HR=hazard ratio. NDA=new drug application. ODAC=Oncologic Drugs Advisory Committee. RCT=randomised controlled trial. PI3K inhibitors in haematological malignanciesWe read the Comment in The Lancet Oncology by Nicholas Richardson and colleagues1 on PI3K inhibitors in patients with haematological malignancies with great interest. However, we are writing to correct two inaccuracies with respect to the discussion of copanlisib. Full-Text PDF PI3K inhibitors in haematological malignanciesPI3K signalling regulates several cellular activities, including growth and apoptosis.1 Therefore, inhibition of PI3K presented an intriguing and novel therapeutic avenue to treat several haematological malignancies, such as chronic lymphocytic leukaemia, follicular lymphoma, and marginal zone lymphoma. Given the paucity of novel treatments for these malignancies in the relapsed and refractory settings, there was considerable interest when the first PI3K inhibitor, idelalisib, was approved in 2014. Full-Text PDF PI3K inhibitors in haematological malignanciesWe are writing in response to the Comment by Nicholas Richardson and colleagues1 from the US Food and Drug Administration, which discussed the use of PI3K inhibitors in haematological malignancies. As investigators who have treated many patients with PI3K inhibitors, beginning with the phase 1 study of idelalisib in 2010, we can attest to the transformative and life-saving nature of these therapies. Many of the patients whom we have treated with PI3K inhibitors have derived great benefit for 5 years or more while on therapy. Full-Text PDF

Outcomes of anti–PD-(L)1 therapy with or without chemotherapy (chemo) for first-line (1L) treatment of advanced non–small cell lung cancer (NSCLC) with PD-L1 score ≥ 50%: FDA pooled analysis.

Abstract: 9000 Background: FDA-approved 1L treatment options for patients with PD-L1-high advanced NSCLC (PD-L1 score ≥50%) include IO ± chemo (± anti-angiogenics) but it is unclear if chemo substantially improves efficacy outcomes when added to IO in this patient population. Methods: Data was pooled from 12 randomized controlled trials that investigated anti-PD-(L)1 regimens ± chemo for the 1L treatment of patients with advanced NSCLC. PD-L1 score was defined as the proportion of tumor cells stained by the assay and analysis was conducted for patients with tumor PD-L1 score ≥50%. OS, PFS, and ORR were compared between chemo-IO and IO alone via a pooled analysis. Median survival times were estimated using Kaplan-Meier methods. Hazard ratios were estimated using Cox proportional hazards models stratified by trial; odds ratios were estimated using a logistic regression model with trial as a covariate. All analyses were adjusted for age, sex, race, ECOG, histology and smoking status. Results: A total of 3,189 patients with NSCLC and PD-L1 score ≥50% were identified for this analysis. Baseline characteristics were: 38% ages 65-74 years and 11% ages ≥75 years; 69% male; 80% White; 66% ECOG ≥1; and 89% former/current smokers. Median OS in the pooled chemo-IO ( N=455) and IO-only ( N=1,298) arms was 25.0 vs 20.9 months (HR 0.82; 95% CI: 0.62, 1.08); median PFS was 9.6 vs 7.1 months, respectively (HR 0.69; 95% CI: 0.55, 0.87). ORR was higher with chemo-IO than with IO alone (61% vs 43%; Odds ratio 1.2, 95% CI: 1.1, 1.3). Conclusions: This exploratory, hypothesis-generating pooled analysis suggests that most subgroups of patients with advanced NSCLC with PD-L1 score ≥50% receiving FDA-approved chemo-IO regimens may have OS and PFS outcomes that are comparable with or better than IO-only regimens. Patients ≥75 years of age receiving chemo-IO may not have improved outcomes over IO. These results support shared decision-making that balances potential benefits and risks of adding chemo to IO regimens based on patient factors that may impact tolerability. [Table: see text]

FDA Approval Summary: Belzutifan for von Hippel-Lindau disease associated tumors.

Abstract: On August 13, 2021, the United States Food and Drug Administration (FDA) approved belzutifan (WELIREG, Merck), a first-in-class hypoxia-inducible factor (HIF) inhibitor for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. The FDA granted approval based on the clinically meaningful effects on overall response rate (ORR) observed in patients enrolled in Study MK-6482-004. All 61 patients had VHL-associated RCC; some also had CNS hemangioblastomas and/or pNET. For VHL disease associated RCC, ORR was 49% (95% CI: 36 to 62), median duration of response (DoR) was not reached, 56% of responders had DoR ≥12 months, and median time to response was 8 months. Twenty-four patients had measurable CNS hemangioblastomas with an ORR of 63% (95% CI: 41 to 81) and 12 patients had measurable pNET with an ORR of 83% (95% CI: 52 to 98). For these tumors, median DoR was not reached, with 73% and 50% of patients having response durations ≥12 months for CNS hemangioblastomas and pNET, respectively. The most common adverse reactions, including laboratory abnormalities, reported in ≥20% were anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Belzutifan can render some hormonal contraceptives ineffective and can cause embryo-fetal harm during pregnancy. This article summarizes the data and the FDA thought process supporting traditional approval of belzutifan for this indication.

FDA Approval Summary: Abemaciclib With Endocrine Therapy for High-Risk Early Breast Cancer

Abstract: PURPOSE The US Food and Drug Administration approved abemaciclib in combination with endocrine therapy (ET) for the adjuvant treatment of adult patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative, node-positive, early breast cancer (EBC) at high risk of recurrence and a Ki-67 score ≥ 20%. PATIENTS AND METHODS The approval was based on monarchE, a phase III, open-label, 2-cohort, multicenter trial of patients with EBC randomly assigned to receive abemaciclib plus ET (n = 2,808) or ET alone (n = 2,829). Abemaciclib was given at 150 mg orally twice daily for 2 years. RESULTS Invasive disease-free survival (IDFS) in the intent-to-treat population was statistically significant at the second IDFS interim analysis (IA; March 2020; hazard ratio [HR; 95% CI], 0.747 [0.598 to 0.932]; P = .0096); however, only 12.5% of patients had completed adjuvant therapy, and the HR for overall survival (OS) was > 1. A prespecified, controlled analysis of IDFS in patients with Ki-67 ≥ 20% in cohort 1 was statistically significant at the final IDFS analysis (July 2020; HR [95% CI], 0.643 [0.475 to 0.872]; P = .0042). At the first OS IA (April 2021), the majority of patients had completed adjuvant therapy, IDFS remained consistent, and potential detriment in OS was not observed for this subgroup (HR [95% CI], 0.767 [0.511 to 1.152]). The HR for OS in the intent-to-treat population at OS IA remained > 1 (HR [95% CI], 1.091 [0.818 to 1.455]). More patients in the abemaciclib plus ET arm experienced treatment emergent adverse events (all grades 98.4% v 88.8%, grade 3 ≥ 49.7% v 16.3%). CONCLUSION The approval of abemaciclib in adjuvant EBC was limited to patients with high risk of recurrence and Ki-67 ≥ 20%, given their favorable benefit:risk with a statistically significant IDFS advantage and no observed detriment on survival.

FDA Approval Summary: Pembrolizumab, Atezolizumab, and Cemiplimab-rwlc as single agents for first-line treatment of advanced/metastatic PD-L1 high NSCLC.

Abstract: FDA's approval of cemiplimab-rwlc on February 22, 2021 follows prior approvals of pembrolizumab and atezolizumab for similar indications - as first-line treatment for patients with programmed death ligand-1 (PD-L1)-high advanced non-small cell lung cancer (NSCLC). Approvals of these anti-PD-(L)-1 agents were supported by statistically significant and clinically meaningful improvements in overall survival (OS) in international, multi-center, active-controlled randomized trials. In KEYNOTE-024, the OS hazard ratio (HR) was 0.60 (95% [CI]: 0.41, 0.89; p=0.005) favoring pembrolizumab over platinum-doublet chemotherapy. In IMpower110, the OS HR was 0.59 (95% CI: 0.40, 0.89; p=0.0106) favoring atezolizumab over platinum-doublet chemotherapy. In Study 1624, the OS HR was 0.68 (95% CI: 0.53, 0.87; p=0.0022) favoring cemiplimab-rwlc over platinum-doublet chemotherapy. The PFS effect sizes for these anti-PD-(L)-1 antibodies were also comparable across their respective registrational trials, and their safety profiles were consistent with the anti-PD-(L)-1 class adverse event profile. The consistent survival benefits and manageable toxicity profiles of these single agent anti-PD-(L)-1 antibodies have established them as important treatment options in the PD-L1 high NSCLC treatment landscape. FDA approvals of these anti-PD-(L)-1 antibodies, based on their favorable benefit-risk profiles, present effective chemotherapy-free therapeutic options for patients with advanced PD-L1 high NSCLC in the United States.

FDA approval summary: Crizotinib for pediatric and young adult patients with relapsed or refractory systemic anaplastic large cell lymphoma

Abstract: In January 2021, the U.S. Food and Drug Administration (FDA) approved crizotinib for pediatric patients 1 year and older and young adults with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). This is the first approval for pediatric sALCL. Approval was based on a single‐arm trial of crizotinib monotherapy that included 26 patients, aged 1–20 years, with previously treated sALCL. Efficacy was based on centrally assessed objective response rate (88%) and duration of response. Herein, we highlight unique aspects of the regulatory review, including extension of the indication to young adults, postmarketing safety, and dose optimization strategies.

Outcomes of first-line immune checkpoint inhibitors with or without chemotherapy according to KRAS mutational status and PD-L1 expression in patients with advanced NSCLC: FDA pooled analysis.

Abstract: 9001 Background: While existing data suggest a detriment of immune checkpoint inhibitors (ICI) in other targetable mutations in non-small cell lung cancer (NSCLC), limited retrospective analyses suggest patients with Kirsten rat sarcoma oncogene ( KRAS)-mutated NSCLC benefit from ICI in the front-line (1L). To better define this benefit, pooled data from 12 registrational clinical trials investigating 1L ICI with or without chemotherapy (chemo) in patients with documented KRAS status (mutant or wildtype) was evaluated for efficacy of ICI+chemo, ICI alone, and chemo alone. Methods: Pooled data was evaluated for objective response rate (ORR) and overall survival (OS) by KRAS status (mutant, G12C, or wildtype). ORR and 95% confidence intervals (CI) were estimated using Clopper-Pearson method; median OS was estimated using Kaplan-Meier methods. Subgroup analyses were performed using Cox model stratified by KRAS status and PD-L1 status (Positive (combined positive score (CPS) ≥1), Negative (CPS<1), High (CPS≥50), Low (CPS<50)). Results: KRAS mutational status was reported in 1430 patients (61% wildtype, 39% mutated). KRAS G12C was reported in 11% of patients with a KRAS mutation (157/555). Demographics were similar between KRAS mutated, G12C, and wildtype patients. Amongst all patients, 60% were male, 89% white, 60% positive PD-L1, 67% former or current smokers. Table 1 shows outcomes of chemo+ICI, ICI alone, and chemo alone in each population. Conclusions: This retrospective, pooled analysis suggests that patients with KRAS-mutated NSCLC benefit from 1L chemo-ICI similarly to those with KRAS wild-type NSCLC, and should receive combination therapy upfront. Patients with KRAS-mutated NSCLC derived the greatest benefit from the combination of chemo-ICI as compared to ICI or chemo alone. The small number of patients with documented KRAS G12C mutation limits interpretation of the data for this subgroup. Clinical trials investigating targeted therapies for KRAS-mutated NSCLC in the 1L should include a chemo-ICI comparator arm. [Table: see text]

Importing oncology trials from China: a bridge over troubled waters?

Abstract: On Feb 10, 2022, the US Food and Drug Administration's Oncologic Drugs Advisory Committee will convene to discuss ORIENT-11, a clinical trial comparing chemotherapy plus sintilimab, an anti-PD-1 monoclonal antibody and member of the checkpoint inhibitor class, with chemotherapy alone as an initial treatment for metastatic non-small-cell lung cancer (NSCLC). 1 Roth LK Federal Register Vol. 86, No. 236. https://www.govinfo.gov/content/pkg/FR-2021-12-13/pdf/2021-26923.pdfDate: Dec 13, 2021 Date accessed: January 28, 2022 Google Scholar Done exclusively in China, the trial's design, patient population, and statistical analysis closely resembles landmark NSCLC trials that established checkpoint inhibitors as part of initial treatment regimens several years ago. 2 Yang Y Wang Z Fang J et al. Efficacy and safety of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC: a randomized, double-blind, phase 3 study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol. 2020; 15: 1636-1646 Google Scholar Rather than an isolated case, this application reflects an increasing number of oncology development programmes based solely or predominantly on clinical data from China, with at least 25 applications from China in drug development phases, planned to be submitted, or currently under review. 3 Beaver JA Pazdur R The wild west of checkpoint inhibitor development. N Engl J Med. 2021; (published online Dec 15.)https://doi.org/10.1056/NEJMp2116863 Google Scholar

Accelerated Approval Is Not Conditional Approval: Insights From International Expedited Approval Programs.

Abstract: Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue

FDA Approval Summary: Revised Indication and Dosing Regimen for Ponatinib Based on the Results of the OPTIC Trial.

Abstract: On December 18, 2020, US Food and Drug Administration (FDA) approved a supplemental application for ponatinib extending the indication in patients with chronic-phase chronic myeloid leukemia (CP-CML) to patients with resistance or intolerance of at least 2 prior kinase inhibitors. Ponatinib was initially approved in December 2012 but was briefly voluntarily withdrawn due to serious safety concerns including the risk of arterial occlusive events (AOE). It returned to the market in December 2013 with an indication limited to patients with T315I mutation or for whom no other tyrosine kinase inhibitor (TKI) therapy was indicated with revised warnings and precautions. A post-marketing requirement was issued to identify the optimal safe and effective dose for CP-CML. Thus, the OPTIC trial was performed, which randomized patients to 1 of 3 doses, 45 mg, 30 mg, or 15 mg, with a dose reduction to 15 mg on achievement of MR2 (BCR-ABLIS ≤1%). Patients enrolled were treated with at least 2 prior TKIs or had a T315I mutation. Patients with a history of clinically significant, uncontrolled, or active cardiovascular disease were excluded. Efficacy was established on an interim analysis based on the rate of MR2 at 12 months in the modified intent-to-treat population of 261 patients, with 88, 86, and 87 patients in the 45, 30, and 15 mg cohorts, respectively. With a median follow-up of 28 months, the rate of achievement of MR2 at 12 months was 42%, 28%, and 24% in the respective cohorts. The safety profile was consistent with that observed in prior evaluations of ponatinib with notable adverse reactions including pancreatitis, hypertension, hyperlipidemia, liver dysfunction, and AOE. Of patients treated at the 45/15 mg dose, AOEs were seen in 13%, with a higher rate being observed in patients age 65 or older compared to younger patients. A readjudication of AOEs seen on the prior pivotal phase 2 study resulted in a rate of 26%. Overall, the results supported a modification of the recommended dose for patients with CP-CML to 45 mg until the achievement of MR2 followed by a reduction to 15 mg. The expansion of the indication to patients with exposure to 2 prior TKIs was approved given data showing that ponatinib could be successfully used for the treatment of this population with appropriate monitoring and screening for risk factors.

Reimagining patient-centric cancer clinical trials: a multi-stakeholder international coalition

Abstract: The Bloomberg New Economy International Cancer Coalition brings together academia, industry, government, patient advocacy and policy think tanks to leverage technology and collaboration to improve patient access to clinical trials and to harmonize regulations aiming to accelerate cancer cures and prevention worldwide in the post-pandemic era.

FDA approval summary: decitabine and cedazuridine tablets for myelodysplastic syndromes.

Abstract: On July 7, 2020, the Food and Drug Administration approved Inqovi (Otsuka Pharmaceutical Co.), an oral fixed dose combination tablet comprising 35 mg decitabine, a hypomethylating agent, and 100 mg cedazuridine, a cytidine deaminase inhibitor (abbreviated DEC-C) for treatment of adult patients with myelodysplastic syndromes (MDS). Evidence of effectiveness of DEC-C was established in Phase 3 ASTX727-02 (N=133) in adults with MDS. The study involved a 2-sequence crossover comparing DEC-C and intravenous (IV) decitabine 20 mg/m2 once daily for the first 5 days of each 28-day cycle in the first 2 cycles. From Cycle 3 onwards, patients received DEC-C. Five-day cumulative area under the curve (5-d AUC) of decitabine for DEC-C was similar to that of IV decitabine with geometric mean ratio 0.99 (90% confidence interval: 0.93, 1.06). Clinical benefit was supported by Study ASTX727-02 and the similarly designed Phase 2 Study ASTX727-01-B (n=80), with complete remission (CR) of 21% and 18% and median duration of CR 7.5 and 8.7 months, respectively. Adverse reactions were consistent with IV decitabine. Post-marketing assessments were issued to address the effect of cedazuridine on QT prolongation, food effect, moderate and severe hepatic impairment, and severe renal impairment on the pharmacokinetics and safety of DEC-C.

FDA Approval Summary: Belantamab Mafodotin for Patients with Relapsed or Refractory Multiple Myeloma.

Abstract: On August 5, 2020, the Food and Drug Administration granted accelerated approval to belantamab mafodotin-blmf (BLENREP; GlaxoSmithKline) for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. Substantial evidence of effectiveness was obtained from the phase 2, multicenter DREAMM-2 trial. Patients received belantamab mafodotin 2.5 mg/kg or 3.4 mg/kg intravenously once every 3 weeks until disease progression or unacceptable toxicity. The trial demonstrated an overall response rate of 31% in the 2.5 mg/kg cohort and 34% in the 3.4 mg/kg cohort. Keratopathy was the most frequent adverse event, occurring in 71% and 77% of patients, respectively. Other ocular toxicities included changes in visual acuity, blurred vision, and dry eye. The U.S. prescribing information for belantamab mafodotin includes a boxed warning for ocular toxicity, and belantamab mafodotin is available only through a restricted program under a Risk Evaluation and Mitigation Strategy. This article summarizes the data and the FDA review process supporting accelerated approval of belantamab mafodotin 2.5 mg/kg intravenously once every 3 weeks. This approval may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Approvals in 2021: dangling Accelerated Approvals, drug dosing, new approvals and beyond

Abstract: In 2021, policy areas of focus for FDA Oncology included the Accelerated Approval programme, expanding eligibility criteria, dose optimization and patient-reported outcomes. The FDA continued to be active with approvals of both new drugs and supplementary applications, including three new chimeric antigen receptor T cell products, two antibody–drug conjugates and several new targeted agents.

Impact of an evolving regulatory landscape on skin cancer drug development in the U.S.

Abstract: BACKGROUND There has been a rapid proliferation of FDA-approved medications with labeled indications for skin cancer over the last decade, with particular growth over the last 5 years. OBJECTIVE We aimed to evaluate the impact of an evolving U.S. regulatory framework on drug development programs to better understand current trends and regulatory considerations when adjudicating drug approvals for patients with skin cancer. METHODS We reviewed publicly-available regulatory documents of all systemic medications with a labeled indication for skin cancer. RESULTS We identified 130 FDA approvals that resulted in a unique indication, usage, formulation, or dosage change in skin cancer since 1949. LIMITATIONS Publicly available data from the mid-to-late 20th century is limited. CONCLUSIONS The therapeutic landscape in skin cancer has changed greatly since the first approval in 1949. In concert, regulatory medicine has also evolved over the last 70 years with the aim of ensuring safe and effective medicines for a diverse array of patients.

FDA Approval Summary: Ivosidenib for the treatment of patients with advanced unresectable or metastatic, chemotherapy refractory cholangiocarcinoma with an IDH1 mutation.

Abstract: On August 25, 2021, the FDA approved ivosidenib for the treatment of adult patients with unresectable locally advanced or metastatic hepatocellular isocitrate-dehydrogenase-1 (IDH1) mutated cholangiocarcinoma (CCA) as detected by an FDA-approved test with disease progression after 1-2 prior lines of systemic therapy for advanced disease. The approval was based on data from Study AG120-C-005 (ClarIDHy), a double-blind placebo-controlled trial which randomly allocated (2:1) patients to receive either ivosidenib or placebo. Independently-assessed progression free survival (PFS) was the primary endpoint. With a median follow up of 6.9 months, the hazard ratio for PFS was 0.37 (95% confidence interval 0.25, 0.54, p< 0.0001). Overall survival (OS) was the key secondary endpoint. At the final analysis of OS, with 70.5% patients in the placebo arm receiving ivosidenib post disease progression, a non-statistically significant improvement in the ivosidenib arm with a HR = 0.79 (95% CI: 0.56, 1.12) and median OS of 10.3 months (95% CI 7.8, 12.4) and 7.5 months (95% CI 4.8, 11.1) in the ivosidenib and placebo arms respectively were reported. Adverse reactions occurring in >20% of patients receiving ivosidenib were fatigue/asthenia, nausea, diarrhea, abdominal pain, ascites, vomiting, cough, and decreased appetite. Adverse reactions occurring in >20% of patients receiving placebo were fatigue/asthenia, nausea, abdominal pain, and vomiting. This is the first approval for the subset of patients with CCA harboring an IDH1 mutation.

FDA Approval Summary: lutetium Lu 177 vipivotide tetraxetan for patients with metastatic castration-resistant prostate cancer.

Abstract: On March 23, 2022, the United States Food and Drug Administration (FDA) approved Pluvicto (lutetium Lu 177 vipivotide tetraxetan, also known as 177Lu-PSMA-617) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The recommended 177Lu-PSMA-617 dose is 7.4 gigabecquerels (GBq; 200 mCi) intravenously every 6 weeks for up to 6 doses, or until disease progression or unacceptable toxicity. The FDA granted traditional approval based on VISION (NCT03511664), which was a randomized (2:1), multicenter, open-label trial that assessed the efficacy and safety of 177Lu-PSMA-617 plus best standard of care (BSoC) (n=551) or BSoC alone (n=280) in men with progressive, PSMA-positive mCRPC. Patients were required to have received ≥1 androgen receptor pathway inhibitor, and 1 or 2 prior taxane-based chemotherapy regimens. There was a statistically significant and clinically meaningful improvement in overall survival (OS) with a median OS of 15.3 months in the 177Lu-PSMA-617 plus BSoC arm and 11.3 months in the BSoC arm, respectively (Hazard ratio: 0.62, 95% CI: 0.52, 0.74, p<0.001). The most common adverse reactions (≥20%) occurring at a higher incidence in patients receiving 177Lu-PSMA-617 were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥30% of patients receiving 177Lu-PSMA-617 were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium. This article summarizes the FDA review of data supporting traditional approval of 177Lu-PSMA-617 for this indication.

FDA Approval Summary: Cabozantinib for Differentiated Thyroid Cancer.

Abstract: On September 17, 2021, the U.S. Food and Drug Administration (FDA) approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine (RAI)-refractory or ineligible. This is the first approval for patients with RAI-refractory locally advanced or metastatic DTC who have progressed following prior therapy and the first approval in pediatric patients with DTC. The approval was based on data from COSMIC-311 (Study XL184-311, NCT03690388), an international, randomized, double-blind trial in which patients with locally advanced or metastatic RAI-refractory DTC that progressed during or following treatment with at least one VEGFR-targeting tyrosine kinase inhibitor (TKI) were treated with either cabozantinib 60 mg orally once daily (N=170) or placebo with best supportive care (N=88). The primary efficacy outcome measures were progression-free survival (PFS) and overall response rate (ORR) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. The median PFS was 11.0 months (95% CI: 7.4, 13.8) in the cabozantinib arm compared to 1.9 months (95% CI 1.9, 3.7) in the control arm, with a hazard ratio (HR) of 0.22 (95% CI: 0.15, 0.31). The endpoint of ORR was not met. No new safety signals were identified with the exception of hypocalcemia which was added as a warning in the product labeling.

Use of Single-Arm Trials for US Food and Drug Administration Drug Approval in Oncology, 2002-2021.

Abstract: Importance Single-arm trials have allowed for transformative therapies to be made available to patients expeditiously. However, using single-arm trials to support drug approval presents several challenges that must be carefully considered. Observations Between January 1, 2002, and December 31, 2021, the US Food and Drug Administration granted 176 new malignant hematology and oncology indications based on single-arm trials, including 116 accelerated approvals (AAs) and 60 traditional approvals. Overall, 87 approvals (49%) were for new molecular entities or original biologics and 89 (51%) were supplemental indications. Response rate (RR) was the most common end point used to support approval in these single-arm trials (173 of 176 [98%]). Of the 116 AAs based on single-arm trials, 45 (38%) fulfilled their postmarketing requirement to verify clinical benefit, 61 (52%) are pending verification of benefit, and 10 (9%) were withdrawn from the market as of December 31, 2021. Most (56 of 61 [92%]) AAs based on single-arm trials pending verification of benefit occurred during the previous 5 years and have ongoing confirmatory trials as of December 2021. Conclusions and Relevance Single-arm trials have been a common development strategy to support regulatory approval as early-stage expansion cohorts with promising durable RRs have become more prevalent. In the appropriate context, single-arm trials using durable RRs can allow patients expedited access to novel therapies and will continue to serve a role in advancing drug development in oncology. However, single-arm trials have a smaller noncomparative safety data set, inability to use time-to-event end points, and other limitations that require careful consideration within the context of the disease and available therapies. The randomized clinical trial remains the preferred approach in clinical investigation.

FDA Approval Summary: Belumosudil for Adult and Pediatric Patients 12 Years and Older with Chronic GVHD After Two or More Prior Lines of Systemic Therapy.

Abstract: On July 16, 2021, the Food and Drug Administration approved belumosudil, a kinase inhibitor, for adult and pediatric patients 12 years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy. Approval was based on the results of Study KD025-213, which included 65 patients with chronic GVHD treated with belumosudil 200 mg daily in an open-label, single-arm cohort. Efficacy was determined by the overall response rate (ORR) through Cycle 7 Day 1, which included complete response (CR) or partial response (PR) according to the 2014 NIH consensus criteria, and durability of response. The ORR through Cycle 7 Day 1 was 75% (95% CI: 63, 85); 6% of patients achieved a CR, and 69% achieved a PR. The median duration of response was 1.9 months (95% CI: 1.2, 2.9), and 62% (95% CI: 46, 74) of responding patients remained alive without new systemic therapy for at least 12 months from response. The common adverse reactions were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, phosphate decreased, gamma glutamyl transferase increased, lymphocytes decreased, and hypertension. Additional study is warranted to confirm safety with long-term use.

Improving Dose-Optimization Processes Used in Oncology Drug Development to Minimize Toxicity and Maximize Benefit to Patients.

Abstract: This review highlights strategies to integrate dose optimization into premarketing drug development and discusses the underlying statistical principles. Poor dose optimization can have negative consequences for patients, most commonly because of toxicity, including poor quality of life, reduced effectiveness because of inability of patients to stay on current therapy or receive subsequent therapy because of toxicities, and difficulty in developing combination regimens. We reviewed US Food and Drug Administration initial approvals (2019-2021) of small molecules and antibody-drug conjugates for oncologic indications to determine the proportion with a recommended dosage at the maximum tolerated dose or the maximal administered dose, to characterize the use of randomized evaluations of multiple dosages in dose selection, to describe the frequency of dose modifications at the recommended dosage, and to identify case examples that highlight key principles for premarket dose optimization during drug development. Herein, we highlight major principles for dose optimization and review examples of recent US Food and Drug Administration approvals that illustrate how investigation of dose- and exposure-response relationships and use of randomized dose trials can support dose optimization. Although there has been some progress, dose optimization through randomized dose evaluation in oncology trials is not routinely conducted. Dose optimization is essential to ensure that patients receive therapies which maximize efficacy while minimizing toxicity.

Development of Tissue-Agnostic Treatments for Patients with Cancer

Abstract: In 2017 the FDA (US Food and Drug Administration) approved pembrolizumab, a programmed death 1 (PD-1) inhibitor, for the treatment of unresectable or metastatic, microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) solid tumors, regardless of tumor site or histology. This represented the first approval based on the identification of a biomarker and independent of tumor site. Although this approach may intuitively appear rational, tissue-agnostic drug development can be complicated by tumor-specific resistance mechanisms or other factors that can alter a drug's effect. Inherent with the tissue-agnostic approach is the fact that there may be residual uncertainty concerning a drug's effect in unstudied tumor types (e.g., at the time of approval). However, this approach may be the only available mechanism to support approval and provide access to a drug that is indicated for the treatment of patients with certain rare biomarker-positive cancers.

Association of progression-free survival and overall response rate with overall survival in first-line randomized trials of immune checkpoint inhibitor–based regimens for metastatic non–small cell lung cancer (NSCLC): An FDA pooled analysis.

Abstract: 9029 Background: Overall Survival (OS) has represented the endpoint of choice to support approvals of Immune Checkpoint Inhibitors (ICIs) in first-line metastatic NSCLC. Despite continued interest in the use of earlier clinical endpoints as true surrogates for OS in this setting, the correlation of Progression-Free Survival (PFS) and Overall Response Rate (ORR) with OS remain an area of active investigation. We conducted a patient-level and trial-level pooled analysis of first-line randomized trials of ICI-based regimens to assess correlations of early clinical endpoints of PFS and ORR with OS in first-line metastatic NSCLC. Methods: The analysis included randomized trials comparing ICI-based regimens (anti-PD-(L)1 with or without anti-CTLA4 antibodies, with or without platinum-based chemotherapy) to platinum-based chemotherapy alone for the first-line treatment of patients with metastatic NSCLC that were submitted to the U.S. Food and Drug Administration between July 2016 to March 2021 to support a marketing application. Patient-level associations were estimated using Spearman (rs) correlation coefficients for PFS and OS, and Cox Proportional Hazards models in RECIST response-based subgroups for ORR and OS. At the trial level, associations were estimated using R2 coefficients from weighted linear regression models, using the log of hazard-ratio (HRs) for PFS and OS and log-odds ratio for ORR. Results: The pooled analysis included 13 trials enrolling 9,285 patients total. Seven trials compared ICIs combined with chemotherapy vs chemotherapy; 6 trials compared ICIs alone vs chemotherapy. Among all patients, the distribution of PD-L1 expression was 31%, 66%, and 32% for PD-L1 <1%, ≥1%, and ≥50%, respectively. The table shows the correlation coefficients for PFS and OS, and ORR and OS at the patient and trial levels. At the patient level, the OS HR comparing ICI-based regimens to chemotherapy was 0.54 (95% CI: 0.48, 0.61) for RECIST responders and 0.96 (95% CI: 0.90, 1.02) for non-responders. Conclusions: This pooled analysis did not indicate a strong correlation between endpoints of PFS and ORR with OS at the patient and trial levels in first-line randomized trials of ICI-based regimens for metastatic NSCLC, potentially because of use of subsequent therapies, cross-over to ICIs, and continuation of ICIs beyond progression. Future research will explore the correlation of alternative endpoints with OS, such as time to treatment discontinuation. Our analysis supports the continued importance of OS as an endpoint for first-line NSCLC trials of ICI-based regimens.[Table: see text]

FDA Approval Summary: Mobocertinib for Metastatic Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations.

Abstract: On September 15, 2021, the U.S. Food and Drug Administration (FDA) granted accelerated approval to mobocertinib (Exkivity, Takeda Pharmaceuticals USA, Inc.) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. The approval was based on data from Study AP32788-15-101 (NCT02716116), an international, non-randomized, multi-cohort clinical trial which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. The overall response rate (ORR) in 114 patients whose disease had progressed on or after platinum-based chemotherapy was 28% (95% CI: 20%, 37%) with a median duration of response of 17.5 months (95% CI: 7.4, 20.3). The most common adverse reactions (>20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. Product labeling includes a Boxed Warning for QTc prolongation and Torsades de Pointes. This is the first approval of an oral targeted therapy for patients with advanced EGFR exon 20 insertion mutation-positive NSCLC.

FDA Approval Summary: Pemigatinib for Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with FGFR2 fusion or other rearrangement.

Abstract: On April 17, 2020, the Food and Drug Administration granted accelerated approval to pemigatinib (PEMAZYRE, Incyte Corporation) for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test. Approval was based on FIGHT-202 (NCT02924376), a multicenter open-label single-arm trial. Efficacy was based on 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma whose disease had progressed on or after at least one prior therapy and had an FGFR2 gene fusion or rearrangement. Patients received pemigatinib, 13.5 mg orally, once daily for 14 consecutive days, followed by 7 days off therapy. Safety was based on a total of 466 patients, 146 of whom had cholangiocarcinoma and received the recommended dose). Efficacy endpoints were overall response rate (ORR) and duration of response (DOR) determined by an independent review committee using RECIST 1.1. ORR was 36% (95% CI: 27%, 45%). Median DOR was 9.1 months. The most common adverse reactions were hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin. Ocular toxicity and hyperphosphatemia are important risks of pemigatinib. The recommended dose is 13.5 mg orally once daily for 14 consecutive days followed by 7 days off therapy in 21-day cycles. FDA also approved the FoundationOne® CDX (Foundation Medicine, Inc.) as a companion diagnostic for patient selection.