Oncology Drug Research Articles

Dose optimization and exposure-response analyses to support optimal dose of ABBV-400, a novel C-met–targeting antibody drug conjugate, in patients with metastatic colorectal cancer (mCRC).

3030 Background: ABBV-400 is an antibody drug conjugate (ADC) consisting of a c-Met targeting antibody conjugated to a potent inhibitor of topoisomerase 1 (Top1) payload. ABBV-400 has shown encouraging activity and demonstrated tolerability of dosages up to 3.0 mg/kg Q3W as monotherapy in patients with advanced solid tumors in an ongoing phase 1 study (1). Dosage optimization is a critical aspect of oncology drug development and FDA Project Optimus has focused on reformulating the dosage selection paradigm for oncology products. The phase 1 study included a dose optimization phase in mCRC patients in which 3 doses were evaluated (1.6, 2.4 and 3.0 mg/kg Q3W) to determine the optimal dose for further development. Herein, exposure-response analyses are reported to determine optimal monotherapy dose in mCRC patients. Methods: Data across a range of doses (1.6 – 6.0 mg/kg Q3W) from the phase 1 study (NCT05029882) were used. Population pharmacokinetics (PK) and exposure-response (E-R) analyses were conducted to characterize ABBV-400 conjugate and unconjugated payload PK and the relationship between exposures and efficacy (objective response rate [ORR]) and safety (Grade (Gr) ≥ 3 neutropenia, anemia and thrombocytopenia) endpoints. Relative dose intensity (RDI) analysis was performed. Results: ABBV-400 conjugate and payload PK were adequately described by a combined multi-analyte population PK model with first order kinetics (n=204). ABBV-400 conjugate average concentration was a better predictor of response and showed that higher exposure correlated with higher probability of response (n=122 CRC, ORR, p < 0.05) and safety events (n=204, Gr ≥ 3 neutropenia, anemia and thrombocytopenia, p < 0.001). Dose intensity analyses showed greater number of dose reductions for 3 mg/kg Q3W with effective (actual) dose received of 2.6 mg/kg Q3W in mCRC patients. E-R analyses for safety and efficacy and dose intensity analyses in mCRC 3L+ patients indicate that both 2.4 and 3.0 mg/kg doses provided meaningful efficacy (ORR); while the 3.0 mg/kg dose may provide higher response rates, the 2.4 mg/kg Q3W dosing regimen provides an optimal balance of safety and efficacy compared to 3.0 mg/kg Q3W. Conclusions: Population PK, E-R for efficacy and safety and RDI analyses and totality of clinical data supported the selection of 2.4 mg/kg Q3W as optimal ABBV-400 monotherapy dose for further study in mCRC patients. 1. Sharma M, et al. ASCO 2023. Abstract 3015. Clinical trial information: NCT05029882 .

Oncology Drug Approvals Under Health Canada’s Notice of Compliance With Conditions Policy: A Retrospective Cohort Analysis

Health Canada’s Notice of Compliance with conditions (NOC/c) policy provides expedited access to promising new therapies for serious conditions. This retrospective cohort analysis sought to examine the use of the NOC/c policy for oncology drugs, to determine whether confirmatory studies are aligned with the approved indication, and to assess the impact of the NOC/c policy by quantifying the number of oncology drugs approved under this policy that become the standard of care treatment for their respective indications. The findings suggest that Health Canada’s NOC/c policy has been successful in providing expedited access to promising new therapies. However, ensuring that confirmatory trials are under way at the time of NOC/c issuance may provide assurance that studies addressing the uncertainty associated with NOC/c will not be unnecessarily prolonged. The inclusion of real-world evidence (RWE) as part of confirmatory evidence may help fill gaps.

Viewpoint: Reflections on an Analysis of Health Canada’s NOC/c Policy for Oncology Drug Approvals

This project provided an opportunity to examine the data and nuances of oncology submissions processed under Health Canada’s Notice of Compliance With Conditions (NOC/c) policy. While Health Canada's transparency mechanisms typically focus on individual submissions, our examination across all submissions over time provided us with a comprehensive resource. This allowed us not only to observe the extent to which confirmatory studies align with approved indications, but also to understand the impact of our decisions under the NOC/c policy. Looking ahead, this study underscores the importance of maintaining mechanisms for reviewing promising new medications and emphasizes the significance of confirmatory trials. Real-world evidence may play an important role in supplementing confirmatory studies and providing additional support for the use of these products.

Tipifarnib physiologically-based pharmacokinetic modeling to assess drug-drug interaction, organ impairment, and biopharmaceutics in healthy subjects and cancer patients.

A physiologically-based pharmacokinetic (PBPK) model for tipifarnib, which included mechanistic absorption, was built and verified by integrating invitro data and several clinical data in healthy subjects and cancer patients. The final PBPK model was able to recover the clinically observed single and multiple-dose plasma concentrations of tipifarnib in healthy subjects and cancer patients under several dosing conditions, such as co-administration with a strong CYP3A4 inhibitor and inducer, an acid-reducing agent (proton pump inhibitor and H2 receptor antagonist), and with a high-fat meal. In addition, the model was able to accurately predict the effect of mild or moderate hepatic impairment on tipifarnib exposure. The appropriately verified model was applied to prospectively simulate the liability of tipifarnib as a victim of CYP3A4 enzyme-based drug-drug interactions (DDIs) with a moderate inhibitor and inducer as well as tipifarnib as a perpetrator of DDIs with sensitive substrates of CYP3A4, CYP2B6, CYP2D6, CYP2C9, and CYP2C19 in healthy subjects and cancer patients. The effect of a high-fat meal, acid-reducing agent, and formulation change at the therapeutic dose was simulated. Finally, the model was used to predict the effect of mild, moderate, or severe hepatic, and renal impairment on tipifarnib PK. This multipronged approach of combining the available clinical data with PBPK modeling-guided dosing recommendations for tipifarnib under several conditions. This example showcases the totality of the data approach to gain a more thorough understanding of clinical pharmacology and biopharmaceutic properties of oncology drugs in development.

Implementing a closed system drug transfer device to enable nurses to prepare monoclonal antibody treatment.

Efforts to increase capacity for oncology treatment in the author's Chemotherapy Day Unit, while allowing staff to treat more patients and offer more flexibility to patients, increased strain on the Aseptic Pharmacy at the author's Trust. Therefore, the possibility of nurse-led drug preparation was explored. Nurse-led monoclonal antibody (MAb) preparation was piloted to investigate whether a reduction in reliance on Aseptic Pharmacy could co-exist with maintaining optimal treatment capacity. The effectiveness of a closed system transfer device (CSTD) to protect nurses against drug exposure was also explored. A risk assessment for MAbs considered for nurse-led preparation was created, alongside a procedure for the safe handling of systemic anti-cancer therapy (SACT) with the use of a CSTD. The pilot resulted in an 89% reduction in the time patients had to wait for MAbs to be prepared. Seven oncology drugs were included in the new procedure without increasing the risk of exposure for nurses. The pilot successfully reduced demand on Aseptic Pharmacy while enabling efficient capacity use on the Chemotherapy Day Unit. The use of the CSTD minimised the risk of nurse exposure to SACT.

Cancer Treatment Before and After Physician-Pharmacy Integration

Integration of pharmacies with physician practices, also known as medically integrated dispensing, is increasing in oncology. However, little is known about how this integration affects drug use, expenditures, medication adherence, or time to treatment initiation. To examine the association of physician-pharmacy integration with oral oncology drug expenditures, use, and patient-centered measures. This cohort study used claims data from a large commercial insurer in the US to analyze changes in outcome measures among patients treated by pharmacy-integrating vs nonintegrating community oncologists in 14 states between January 1, 2011, and December 31, 2019. Commercially insured patients were aged 18 to 64 years with 1 of the following advanced-stage diagnoses: breast cancer, colorectal cancer, kidney cancer, lung cancer, melanoma, or prostate cancer. Data analysis was conducted from May 2023 to March 2024. Treatment by a pharmacy-integrating oncologist, ascertained by the presence of an on-site pharmacy or nonpharmacy dispensing site. Oral, intravenous (IV), total, and out-of-pocket drug expenditures for a 6-month episode of care; share of patients prescribed oral drugs; days' supply of oral drugs; medication adherence measured by proportion of days covered; and time to treatment initiation. The association between an oncologist's pharmacy integration and each outcome of interest was estimated using the difference-in-differences estimator. Between 2012 and 2019, 3159 oncologists (745 females [27.1%], 2002 males [72.9%]) treated 23 968 patients (66.4% female; 53.4% aged 55-64 years). Of the 3159 oncologists, 578 (18.3%) worked in practices that integrated with pharmacies (with a low rate in 2011 of 0% and a high rate in 2019 of 31.5%). In the full sample (including all cancer sites), after physician-pharmacy integration, no significant changes were found in oral drug expenditures, IV drug expenditures, or total drug expenditures. There was, however, an increase in days' supply of oral drugs (5.96 days; 95% CI, 0.64-11.28 days; P = .001). There were no significant changes in out-of-pocket expenditures, medication adherence, or time to treatment initiation of oral drugs. In the breast cancer sample, there was an increase in oral drug expenditures ($244; 95% CI, $41-$446; P = .02) and a decrease in IV drug expenditures (-$4187; 95% CI, -$8293 to -$80; P = .05). Results of this cohort study indicated that the integration of oncology practices with pharmacies was not associated with significant changes in expenditures or clear patient-centered benefits.

Charcot Neuro-Osteoarthropathy With Superimposed Osteomyelitis in a Nondiabetic Patient, as a Consequence of Cancer Chemotherapy: A MR-Monitored Case Report.

Charcot neuro-osteoarthropathy (CNO) is a manifestation of peripheral neuropathy as a chronic complication of diabetes mellitus but, less frequently, can be associated to other conditions such as alcoholism or neurotoxic therapies. An increasingly emerging cause of CNO is the use of oncological drugs which can cause neuropathic damage. The use of these therapies dramatically increased in recent years. CNO leads to a progressive degeneration of the foot's joints and to bone destruction and resorption which ends in deformities. These alterations in the foot's anatomy determine a high risk of ulceration, infection, and osteomyelitis. The superimposition of osteomyelitis on CNO increases the risk of major amputation, already high in patients suffering either from only CNO or osteomyelitis alone. We report the case of a 61-year old nondiabetic woman affected by CNO as a consequence of antiblastic therapy for breast cancer and the subsequent overlap of osteomyelitis, confirmed by magnetic resonance imaging. This case underlines how it is necessary to consider CNO as a possible complication of antiblastic therapy in the view of the severe consequences of missing its diagnosis.

Abstract B011: Predictable successes: drug additivity explains the efficacy of combination therapies for metastatic urothelial cancer

Abstract Objective: Combination drug regimens have changed the treatment landscape of metastatic urothelial cancer (mUC) and other cancers and are integrated into routine clinical practice. Combination drug regimens may impact cancer outcomes via three major pharmacologic principles: less-than-additive, additive, or more-than-additive efficacy (i.e., synergy). Despite the profound implications of these types of interactions on future drug and biomarker development, as well as on treatment sequencing, these principles have been underexplored in contemporary clinical trials. Here we analyze recent phase 3 trials in locally advanced or metastatic UC to assess whether progression-free survival (PFS) distributions of combination therapies with immune checkpoint inhibitors (ICIs) are lesser than, greater than, or equal to the additive effect expected based on single-agent efficacies. Methods: We analyzed phase 3 trials in locally advanced or metastatic UC including EV302, CheckMate 901, KEYNOTE-361, DANUBE, and IMvigor130. When one monotherapy was not included as an arm in the phase 3 trial, we utilized monotherapy PFS distributions from trials in patients with metastatic UC including EV103, KEYNOTE-045, CheckMate 275, and HCRN-GU17-294. The expected additive effect of a drug combination was calculated by adding the PFS durations of individual drugs, sampled from monotherapy distributions, as recently described for other approved oncology drug combinations (Hwangbo et al, Nature Cancer, 2023). Results: Combination therapies with ICIs were as clinically effective as predicted by additivity, or less so in one case. Specifically, Pembrolizumab plus Enfortumab vedotin (EV302), Nivolumab plus Gemcitabine/Cisplatin (CheckMate 901), Pembrolizumab plus chemotherapy (KEYNOTE-361), and Durvalumab plus Tremelimumab (DANUBE) each exhibited PFS distributions that were statistically indistinguishable from PFS predicted by the additivity model (Cox Proportional Hazards). Atezolizumab plus chemotherapy (IMvigor130) was inferior to additivity. Subgroup analyses by PD-L1 expression and by cisplatin versus carboplatin will be presented. Conclusions: Life-prolonging treatments for mUC have been the result of additive combination therapies, wherein the efficacy of the drug combination is quantitatively explained by the individual efficacies of the component drugs. Additivity in this setting has several potential implications: (1) when a single-agent is principally active in a biomarker-defined subpopulation, the use of that agent in a combination will also principally improve outcomes in that subpopulation; (2) net duration of disease control may be similar between up-front combination and sequential use of the same drugs; assuming that the biology of disease at progression does not preclude the ability to receive subsequent lines of therapy, and (3) future drug development should prioritize combinations based on highly active single agents rather than solely based on hypothesized mechanistic rationale. Citation Format: Noah M. Schlachter, Eric J. Miller, Jonathan F. Anker, Matthew D. Galsky, Adam C. Palmer. Predictable successes: drug additivity explains the efficacy of combination therapies for metastatic urothelial cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B011.

Dose Optimization in Oncology Drug Development: An International Consortium for Innovation and Quality in Pharmaceutical Development White Paper.

The landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug Administration, stands as a groundbreaking endeavor to reform dose selection of oncology drugs, presenting both opportunities and challenges for the field. To address complex dose optimization challenges, an Oncology Dose Optimization IQ Working Group was created to characterize current practices, provide recommendations for improvement, develop a clinical toolkit, and engage Health Authorities. Historically, dose selection for cytotoxic chemotherapeutics has focused on the maximum tolerated dose, a paradigm that is less relevant for targeted therapies and new treatment modalities. A survey conducted by this group gathered insights from member companies regarding industry practices in oncology dose optimization. Given oncology drug development is a complex effort with multidimensional optimization and high failure rates due to lack of clinically relevant efficacy, this Working Group advocates for a case-by-case approach to inform the timing, specific quantitative targets, and strategies for dose optimization, depending on factors such as disease characteristics, patient population, mechanism of action, including associated resistance mechanisms, and therapeutic index. This white paper highlights the evolving nature of oncology dose optimization, the impact of Project Optimus, and the need for a tailored and evidence-based approach to optimize oncology drug dosing regimens effectively.

Oncology drug pricing: potential Medicare savings on cancer-directed and supportive care medications through the Mark Cuban cost plus drug model.

Prescription drug costs within oncology remain a challenge for many patients with cancer. The Mark Cuban Cost Plus Drug Company (MCCPDC) launched in 2022, aiming to provide transparently priced medications at reduced costs. In this study, we sought to describe the potential impact of MCCPDC on Medicare Part-D oncology spending related to cancer-directed (n = 7) and supportive care (n = 26) drugs. We extracted data for drug-specific Part-D claims and spending for 2021. Using 90-count purchases from MCCPDC, we found potential Part-D savings of $857.8 million (91% savings) across the 7 cancer-directed drugs and $28.7 million (67% savings) across 21/26 (5/26 did not demonstrate savings) supportive care drugs. Collectively, our findings support that alternative purchasing models like MCCPDC may promote substantial health care savings.

Design Strategy and Consideration for Oncology Dose-Optimization: An Industry Perspective

The conventional more-is-better dose selection paradigm is often inappropriate for novel molecularly targeted agents. In response, the US Food and Drug Administration (FDA) initiated Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development. Furthermore, the FDA recently also published draft guidance “Optimizing the dosage of human prescription drugs and biological products for the treatment of oncologic diseases guidance for industry,” providing overviews on the rationale, importance, and principles of dose optimization from the regulatory perspective. However, detailed guidance on how to design dose optimization trials is still lacking; it is a key issue faced by drug developers. The article discusses statistical and design strategies of dose optimization in oncology by sharing current industry practice on dose-finding, delineating key statistical components for dose optimization trials, describing available design strategies, and providing recommendations and future directions. This article is a joint work of the Statistical Methods in Oncology Scientific Working Group (Dose-Optimization Workstream) of the American Statistical Association Biopharmaceutical Section.

Abstract PO1-09-09: The journey of HR positive, HER2 negative metastatic breast cancer’s patients: heterogeneities and barriers in Brazilian public health system- a national survey

Abstract Background: Breast cancer is the most common neoplasm in Brazilian women, with high percent of patients diagnosed in advanced stages. Metastatic breast cancer (mBC) is a challenge in the country, where 75% of the population is covered by public health system (Sistema Único de Saúde, SUS). We conducted an on-line survey to describe the journey of human epidermal growth factor receptor 2-negative (HER2-), hormone receptor positive (RH+) mBC patients across public scenario in Brazil. Methods: An on-line survey comprised of 39 to 48 (depending on the kind of some questions, which could open another question in case of affirmative answer) objective questions were sent by e-mail to180 oncologists working in public and private health care system. Questions were focused on assessing wait time for first treatment after admission in the hospital in both systems, availability of oncological drugs within SUS according to essential medicines list by World Health Organization, and presence of palliative and multidisciplinary teams in both systems. Continuous variables were measured by median and mean. The level of statistical significance adopted was 5% with Teste p two-sided. Analyses were performed using SAS statistical software (version 25.0). Results: We had 150 respondents working in SUS and private health system, which fulfilled the inclusion criteria to participate in this survey. The other 30 respondents were excluded from the study because they worked exclusively in SUS or exclusively in the private system, and their answers were not analyzed. Median wait time for surgery was 60 days in the SUS (N=150) and 30 days in the private health system (N=150) e (p < 0,0001). Regardless of chemotherapy provided, median waiting time was 30 and 15 days in the SUS (N=150) and the private health system (N=150), respectively (p < 0,0001). Most oncologists in the SUS (N=125, 83.3%) pointed to endocrine therapy as their first-choice treatment in mBC. Concerning endocrine therapy in the SUS, Gonadotropin-Releasing Hormone Agonist (GnRHa) was available, and it was prescribed by 54 (36.0%) and Fulvestrant for 72 (48.0%) of respondents. Considering chemotherapy, weekly paclitaxel alone or combined with platin were available and they were prescribed by 124 (82.6%) and 109 (72.6%) of oncologists respectively. Vinorelbine was available and it was prescribed according to oncologists’ report by 109 (72.6%) and Pegylated liposomal doxorubicin (PLD) by 38 (25.3%) of oncologists. Oncologists answered agree or strongly agree that they had a multidisciplinary care team in SUS 77,3% (N =116) versus 87,3% (N=131) in the private system (p=0.022). Concerning palliative care 66,09% (N= 99) in the SUS versus 82,0% (N=123) in the private system answered that they agreed or strongly agreed that this service was available (p=0.001). Conclusions: The Brazilian government has continuously improved delivery of services and medicines via the public system (SUS), but there are still significant differences within this system and versus the private sector. Unavailability of endocrine therapy agents as GnRHa and Fulvestrant, and some chemotherapy agents as PLD and Vinorelbine for high percentage of patients, raises the existence of disparities within SUS. Also, longer waiting times for treatment in the SUS, lower availability of support teams such multidisciplinary and palliative care, they point out disparities between SUS and private health systems. The lack of a National Cancer Control Program and low health investment by Brazilian government might explain the difference in cancer patients’ access. Citation Format: Heloísa Resende, Igor Soares, Angélica Renó, Ana Cunha, Vinícius Aguiar, Letícia Tureta, Viviane Pereira. The journey of HR positive, HER2 negative metastatic breast cancer’s patients: heterogeneities and barriers in Brazilian public health system- a national survey [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-09-09.

Validation, adaptation and application of a multi‐criteria decision analysis‐based framework for chemotherapeutic agents in Egypt

AbstractHealth technology assessment is a systematic, transparent, robust, and unbiased assessment of healthcare technology that links evidence and decisions. Healthcare decisions usually require trading‐off, and using a structured approach, such as multi‐criteria decision analysis (MCDA), could improve decision quality. This study aimed to adapt an MCDA‐based framework for oncological drug evaluation in an Egyptian clinical setting to explore the perspectives of different stakeholders. The 10th edition of the Evidence and Value: Impact on decision making framework was translated, validated, adapted, and applied to explore key differences between the priorities of different stakeholders for coverage decisions in the oncology field in Egypt. A direct rating scale or hierarchical point allocation was used to elicit criteria weights. Normalized weights were calculated and compared using the preset cut‐off value of 0.008. Understandability, willingness to use the adopted weighting techniques, and cognitive burden were assessed and compared. Ninety participants completed the criteria‐weighting interview for the adapted tool. The elicited criteria weights differed between the two adopted weighting techniques when comparing stakeholders' priorities using the preset cut‐off (0.008). However, there was no significant difference in the weighting technique understandability, future use willingness, and cognitive burden parameters on categorization by either the weighting technique or stakeholder group. This study provides a specially tailored, straightforward procedure for Egyptian stakeholders to evaluate oncologic drugs in a standardized manner by combining various inputs. It also highlights the main variations across Egyptian stakeholder preferences.

Timeliness of Health Technology Assessments and Price Negotiations for Oncology Drugs in Canada.

To evaluate whether time targets for Canadian Agency for Drugs and Technologies in Health (CADTH) reimbursement reviews and pan-Canadian Pharmaceutical Alliance (pCPA) price negotiations are being achieved for oncology drugs. Recommendations, dates of submission and publication, and indications for oncology medicines issued between January 2014 and December 2023 were recorded from CADTH's reimbursement reports webpage. The date any negotiation began and the date it was completed (successfully or not), or when a decision was made not to pursue negotiation was extracted from the pCPA's webpage. The duration of each CADTH review and pCPA negotiation was calculated, together with time between CADTH's recommendation and start of the pCPA negotiation or a decision not to negotiate. Percentages of reviews completed within CADTH's target and of times taken by the pCPA to decide whether to negotiate and by its price negotiations completed within the relevant targets were calculated. CADTH achieved its 270-days target in 88.2% to 100% of reviews issued between 2015 and 2019 but only in 65.9% to 73.1% of reviews issued in the last three years of the decade. CADTH's "typical timeline" of 180 days was achieved in under 40% of reviews issued in 2015 and not attained in any review in 2021, 2022 or 2023. The pCPA's target of 60 days for deciding whether to negotiate was achieved for all recommendations issued in 2014 but dropped below 40% for the last seven years of the decade; its target of 130 days for negotiations was achieved for over 85% of the recommendations in 2014 but decreased to only 14.3% in 2016 and then gradually increased to 61.5% in 2023. CADTH's "typical timeline" and the pCPA's targets were not met sufficiently to be meaningful. Their processes take too long for cancer drugs.

Assessing patient risk, benefit, and outcomes in drug development: A decade of ramucirumab clinical trials.

This study aims to evaluate published clinical trials of ramucirumab to assess the risk/benefit profile and burden over time for patients. The burden of oncologic drug development on patients paired with increasing clinical trial failure rates emphasizes the need for reform of drug development. Identifying and addressing patterns of excess burden can guide policy, ensure evidence-based protections for trial participants, and improve medical decision-making. On May 25, 2023 a literature search was performed on Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov for clinical trials using ramucirumab as monotherapy or in combination with other interventions for cancer treatment. Authors screened titles and abstracts for potential inclusion in a masked, duplicate fashion. Following data screening, data was extracted in a masked, duplicate fashion. Trials were classified as positive when meeting their primary endpoint and safety, negative or indeterminate. Ramucirumab was initially approved for gastric cancer but has since been tested in 20 cancers outside of its FDA approved indications. In our analysis of ramucirumab trials, there were a total of 10,936 participants and 10,303 adverse events reported. Gains in overall survival and progression-free survival for patients were 1.5 and 1.2 months, respectively. FDA-approved indications have reported more positive outcomes in comparison to off-label indications. We found that FDA-approved indications for ramucirumab had better efficacy outcomes than non-approved indications. However, a concerning number of adverse events were observed across all trials assessed. Participants in ramucirumab randomized controlled trials saw meager gains in overall survival when evaluated against a comparison group. Clinicians should carefully weigh the risks associated with ramucirumab therapy given its toxicity burden and poor survival gains.

Factors Associated with Inclusion of Japan in Phase I Multiregional Clinical Trials in Oncology.

Early inclusion of Japan in the global development program could be a key factor in reducing the drug lag, making participation in phase I multiregional clinical trials (Ph. I MRCTs) an important consideration for oncology drug development in Japan. We aimed to investigate the factors associated with the inclusion of Japan in Ph. I MRCTs in oncology. We compared the trial design, target population, type of primary tested drug, trial conduct profile, and sponsor profile for Ph. I MRCTs with or without Japan conducted by the top 20 companies in more than two countries and started between January 1, 2011, and December 31, 2020. One hundred and ninety-seven Ph. I MRCTs included Japan, and 697 did not. Detailed features of the Ph. I MRCTs in oncology were summarized, and several factors (trial design, target population, trial conduct profile, and sponsor profile) associated with inclusion of Japan in the Ph. I MRCTs were identified. It is important for Japanese subsidiaries within global pharmaceutical companies to closely communicate with the headquarters based on medical practice and unmet needs in Japan to join global development from an early stage. In addition, further efforts to attract emerging biopharmaceutical companies to Japan from the regulatory and/or political perspectives would be needed, thereby preventing drug lag in Japan.

Impact of Early Access Reform on Oncology Innovation in France: Approvals, Patients, and Costs.

An ambitious reform of the early access (EA) process was set up in July 2021 in France, aiming to simplify procedures and accelerate access to innovative drugs. This study analyzes the characteristics of oncology drug approvals through the EA process and its impact on real-life data for oncology patients. The number and characteristics of EA demands concerning oncology drugs submitted to the National Health Authority (HAS, Haute Autorité de Santé) were reviewed until 31 December 2022. A longitudinal retrospective study on patients treated with an EA oncology drug between 1 January 2019 and 31 December 2022 was also performed using the French nationwide claims database (Systeme National des Données de Santé [SNDS]) to assess the impact of the reform on the number of indications and patients, and the costs. Among 110 published decisions, the HAS granted 88 (80%) EA indications within 70 days of assessment on average, including 46 (52%) in oncology (67% in solid tumors and 33% in hematological malignancies). Approved indications were mostly supported by randomized phase III trials (67%), whereas refused EA relied more on non-randomized (57%) trials. Overall survival was the primary endpoint of 28% of EA approvals versus none of denied EAs. In the SNDS data, the annual number of patients with cancer treated with an EA drug increased from 3137 patients in 2019 to 18,341 in 2022 (+ 484%), whereas the number of indications rose from 12 to 62, mainly in oncohematology (n=17), lung (n=12), digestive (n=9) and breast cancer (n=9). Reimbursement costs for EA treatments surged from €42 to €526 million (+ 1159%). The French EA reform contributed to enabling rapid access to innovations in a wide range of indications for oncology patients. However, the findings highlight ongoing challenges in financial sustainability, warranting continued evaluation and adjustments.

Safety of Off-Label Use of Anticancer Drugs in Oncology

Safety of Off-Label Use of Anticancer Drugs in Oncology

Availability and Access to Orphan Drugs for Rare Cancers in Bulgaria: Analysis of Delays and Public Expenditures.

Rare cancers are defined by an annual incidence of fewer than 6 per 100,000. Bearing similarities to rare diseases, they are associated with substantial health inequalities due to diagnostic complexity and delayed access to innovative therapies. This situation is further aggravated in Southeastern European countries like Bulgaria, where limited public resources and expertise underscore the need for additional policy and translational research on rare cancers. This study aimed to explore the availability and access to orphan drugs for rare cancers in Bulgaria for the period of 2020-2023. We cross-compared data from both the European Union and national public sources to evaluate the number of available and accessible orphan drugs for rare cancers, the delay from market authorization to reimbursement, the dynamics of public expenditures, and regional disparities in access across the country. We juxtaposed the main characteristics of oncological and non-oncological orphan drugs as well. Only 15 out of 50 oncological orphan drugs that were authorized by the European Medicine Agency were accessible for rare cancer patients in Bulgaria. The median delay between market authorization and inclusion in the Bulgarian Positive Drug List was 760 days. The total expenditures for all orphan drugs for rare cancers amounted to EUR 74,353,493 from 2020 to 2023. The budgetary impact of this group rose from 0.24% to 3.77% of total public medicinal product expenditures for the study period. Rare cancer patients represent a vulnerable population that often faces limited to no access to treatment. We call for targeted European and national policies to address this major inequality.

Composite event-free-survival as an endpoint in oncology drug evaluation: Review and guidance perspectives from the Haute Autorité de Santé (HAS)

BackgroundThe use of right-censored composite endpoints, such as progression-free survival, has been questioned in haemato-oncology trials due to potential bias in estimated treatment effect. This may impact the accuracy of health technology evaluations. We hypothesized that there is heterogeneity and potential sources of bias in the reporting of composite endpoints to health technology assessment (HTA) bodies. MethodsWe reviewed the submissions for reimbursement of oncology drugs in 2021 and 2022 that used a composite endpoint in the pivotal trial, after appraisal by the French HTA body. The retrieved information included the clinical study report, protocol, and statistical analysis plan submitted by the industry. All events of the composite endpoint and all causes of censored observations were measured. The design characteristics and treatment effect estimates were recorded. FindingsSeventy-six submissions were selected, including seven without a right-censored endpoint and four evaluating associations, resulting in 65 analysed records: 17 for haematological and 48 for solid tumours. Out these 65 submissions, 47 (72·3%) used a randomized controlled design, and 18 (27·7%) a non-comparative design. The most frequently used composite endpoint was progression-free survival, used in 54 (83·1%) of the submissions. Censoring was possibly informative in 51 (92·7%) cases, mostly due to the onset of new treatment (44/51, 86·3%) and/or discontinuation of follow-up (33/51, 64·7%). In contrast, 38 (58·5%) trials reported a quantification of censored observations, with only 12/51 (23·5%) quantifying the informative ones. The estimated treatment effect on the composite outcome increased with the amount of censoring, suggesting a higher benefit of the drug, but remained below that on survival with poor evidence of surrogacy (R-squared=0·23). InterpretationClinical study reports should be improved in terms of reporting censoring, while stakeholders should be aware of this potential source of bias. At a minimum, sensitivity analysis that ignores intercurrent events should be requested.