Landscape analysis of adverse events and dose intensity for FDA approved oncology small molecules

Abstract

As development of new oncology small molecule therapies is focused mainly on molecularly targeted agents, the dose selection paradigm has shifted from the maximum tolerated dose (MTD)-based approach traditionally utilized with cytotoxic drugs towards determining an optimal dose with long-term tolerability while maintaining efficacy. To assess overall tolerability in recently approved oncology small molecules, we surveyed 54 compounds approved by the FDA since March 2017 with respect to dose intensity, dose modifications, and treatment emergent adverse events (TEAEs). Of the 54 new molecular entities surveyed, only 15 were approved at a label dose equal to the MTD (Label Dose = MTD). Compared to compounds where the label dose was less than the MTD, compounds where the Label Dose = MTD reported overall lower dose intensity and higher dose modifications due to adverse events, though treatment discontinuations due to adverse events were similar. A post-marketing requirement (PMR) for dose optimization was issued for 7 compounds in the dataset, of which 3 were at the Label Dose = MTD. None of these 7 compounds reported a positive exposure-response relationship in efficacy and only 4 reported an exposure-response in safety events. Overall, dose intensity was lower, and incidence of dose modifications, discontinuations, and Grade ≥ 3 TEAEs were higher in compounds issued a PMR vs. the latter. This analysis suggests that while recently approved oncology small molecules have a reasonable relative dose intensity (RDI), the higher incidence of Grade ≥ 3 TEAEs and dose modifications where Label Dose = MTD highlight the continuing need for dose optimization while developing oncology therapeutics.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00280-024-04721-0.

Introduction

Traditional oncology drug development follows a dose selection paradigm that is primarily driven by the safety and tolerability of the compound. Phase I studies involve dose escalation of a new drug to identify the maximum tolerated dose (MTD), which is defined as the highest dose with a dose-limiting toxicity rate of < 33%. The MTD is typically carried forward as the dose to be tested in Phase II and III studies. The assumption is that a higher concentration of drug is generally associated with increased tumor cell death, which is relevant in the age of cytotoxic chemotherapeutics. However, due to the broad effect of these chemotherapeutics on healthy cells in addition to tumor cells, high incidence of treatment-related adverse events is accepted as necessary to maximize the likelihood of patient response to the treatment [1]. Recent advances in oncology drug development resulted in shifting away from broadly cytotoxic drugs toward molecularly targeted agents (MTA), which often have less off-target effects and wider therapeutic indices [2].

In the age of MTAs, the path of drug development has shifted towards different approaches to elicit maximal efficacy, such as target saturation or biomarker response, to reach the maximal efficacy with the goal of determining an optimal dose that has long-term tolerability while maintaining efficacy [3, 4]. As such, in 2021 the FDA initiated Project Optimus to shift drug development programs towards exploring multiple dose levels for safety and efficacy [5–7]. The overall goal of Project Optimus is to implement early, preferably randomized dose-optimization evaluations. The intention is to identify an optimal dose earlier in drug development that can achieve similar levels of efficacy, but with better tolerability for patients and several recent articles have highlighted strategies to begin effective dose optimization earlier in development [8] and dose selection paradigms [9]. In light of Project Optimus, we surveyed recently (FDA) approved oncology small molecules with respect to dose intensity and safety-related events to identify differences between compounds that were approved at a dose equal to the MTD versus compounds that were approved at a dose below the MTD.

Methods & data overview

54 oncology small molecule new molecular entities (NMEs) that were approved by the FDA between March 2017 and October 2023 were included in the analysis. Relevant compound data was extracted from FDA application review files, including the multidisciplinary review, and clinical pharmacology and biopharmaceutical review, which are available from the drugs@FDA website (https://www.accessdata.fda.gov/scripts/cder/daf/).

Extracted data for each oncology small molecule NME included maximum tolerated dose (MTD), maximum studied dose in the absence of MTD (MSD), approved/label dose (LD), and observance of exposure-response relationship for safety or efficacy to support final dose selection, as well as post-marketing requirements (PMR) or post-marketing commitments (PMC) required for each drug. Safety-related data gathered included the total percentage of patients experiencing a grade ≥ 3 treatment emergent adverse event (TEAE), and high incidence (occurring in ≥ 10% of patients) grade ≥ 3 TEAEs at the approved dose. Dose intensity-related data gathered included the median relative dose intensity (RDI), as well as the percentage of patients who had at least one dose interruption or reduction due to adverse event(s), as well as the percentage of patients who discontinued the study drug due to adverse event(s). It should be noted that reporting of key data including dose intensity, dose modifications, and adverse events reported in the FDA application review files were not standardized across compounds. As such, some data was omitted for several compounds (as specified below) and consolidation of the remaining data to generate summary figures should be interpreted in the context of this limitation.

With respect to dose modifications, all 54 compounds reported the percentage of patients who discontinued the study drug due to adverse event(s). However, dose modifications due to adverse event(s) were typically reported using two different methods– (1) separately as percentage of patients experiencing at least one dose interruption and percentage of patients experiencing at least one dose reduction or (2) were reported with dose interruptions and reductions pooled under the general term ‘dose modifications’ as percentage of patients experiencing at least one dose modification. Three compounds only reported the latter ‘dose modifications’, while 51 compounds reported the former ‘dose interruptions and dose reductions’. For comparability, the 3 compounds in the latter were not included in the analysis of dose modifications due to adverse event(s).

With respect to dose intensity, only 42 of the 54 compounds surveyed reported relative dose intensity (RDI). In addition, the definition of RDI within the FDA application review files was not standardized. Some compounds reported RDI as dose intensity after a specific cycle, while others reported the percentage of patients receiving a specified percentage of planned dose. For comparability between compounds, only compounds that included median RDI in the review files were included in the RDI analysis. In general, median RDI was assumed to be reported as (actual dose intensity / planned dose intensity) * 100, unless otherwise specified. Only the 34 drugs that reported median relative dose intensity (RDI) were included in the dose intensity analysis.

Results & discussion

Dose modifications and treatment discontinuations

Of the 54 compounds included in the analysis, all had dose modifications and discontinuations reported in some form. Overall, dose modifications due to adverse events (AEs) were high. Across all compounds, a median of 45.8% of patients reported at least one dose interruption due to AE(s), and 21.0% of patients reported at least one dose reduction due to AE(s) (Table 1). Forty-one compounds (76%) reported > 33% of patients with at least one dose interruption due to AE(s). Eleven compounds (20%) reported > 33% of patients with at least one dose reduction due to AE(s), with six compounds reporting > 50% of patients with at least one dose reduction due to AE(s). Treatment discontinuations due to AE(s) occurred in a median of 12.8% of patients across all compounds, ranging from 2 to 35% of patients.

Table 1.

Relative dose intensity (RDI) and dose modifications due to adverse events, categorized by label dose relative to the MTD or MSD

Label dose	Number compounds	Number compounds with PMR in dose optimization	% Median relative dose intensitya median (Min, Max)	% Discontinuation median (Min, Max)	% Interruptionb median (Min, Max)	% Reductionb median (Min, Max)
All Compounds	54	7	98.0 (72.5, 100)	12.8 (2.0, 35.0)	45.8 (2.7, 87.0)	21.0 (2.0, 69.0)
Label Dose < MSD	20	1	98.0 (79, 100)	9.5 (2.0, 26.7)	39.0 (13.0, 69.3)	10.5 (2.0, 53.0)
Label Dose < MTD	5	1	95.0 (80, 100)	19.5 (6.8, 35.0)	52.0 (23.0, 87.0)	24.0 (7.5, 50.0)
Label Dose = MSD	14	2	100 (97.1, 100)	9.3 (3.7, 29.0)	34.0 (2.7, 46.0)	5.0 (3.7, 18.9)
Label Dose = MTD	15	3	91.9 (72.5, 100)	13.0 (5.0, 24.6)	58.0 (27.1, 77.0)	28.0 (5.5, 69.0)

% RDI reflects the median RDI reported for the registrational trial. % of dose discontinuations, % dose interruptions, and % dose reductions reflect the % of patients receiving the study drug at the approved dose with at least 1 of those events

a) Number of compounds with dose intensity reported as median RDI at the registrational dose were 34. 11 for Label Dose < MSD, 8 for Label Dose < MTD, 4 for Label Dose = MSD, and 11 for Label Dose = MTD

b) Number of compounds with separate dose reductions and interruptions were 51. 19 for Label Dose < MSD, 12 for Label Dose < MTD, 5 for Label Dose = MSD and 15 for Label Dose = MTD

Of the 54 compounds, 15 (28%) were approved at a dose equal to the identified MTD (Label Dose = MTD) and the remaining 39 (72%) were either approved at a dose lower than the MTD, or the MTD was not identified. Of these 39 compounds, 14 (26%) identified an MTD (Label Dose < MTD), 5 (9%) did not identify an MTD but were approved at the maximum studied dose (Label Dose = MSD), and 20 (37%) did not identify an MTD and were approved at a dose lower than the maximum studied dose (Label Dose < MSD). When comparing dose modifications by label dose classification, (Fig. 1A), compounds where the MTD was identified had a notably higher percentage of patients experiencing at least one dose interruption due to AE(s) (52.0% and 58.0% of patients for Label Dose = MTD and Label Dose < MTD, respectively) than compounds where the MTD was not identified (34.0% and 39.0% of patients for Label Dose = MSD and Label Dose < MSD) (Table 1). Of note, only one compound in the Label Dose = MTD group reported < 33% of patients undergoing at least one dose interruption, with most compounds in this group exceeding 50% of patients. Dose reductions due to AE(s) followed a similar trend when comparing by label dose classification, with a median percentage of patients experiencing at least one dose reduction of 28.0% and 24.0% in the Label Dose = MTD and Label Dose < MTD groups, vs. 5.0% and 10.5% in the Label Dose = MSD and Label Dose < MSD groups. Seven out of fifteen compounds in the Label Dose = MTD group (with reductions data available) reported > 33% of patients experiencing at least one dose reduction, compared to 4/36 compounds (with reductions data available) in the other groups.

Fig. 1.

Label dose classification of compounds with respect to MSD or MTD as described by dose modifications, reported as % of patients with drug discontinuation, or at least 1 dose interruption or dose reduction due to adverse events from the registrational trial (A). Relative Dose Intensity (RDI) reported from the registrational trial for each approved oncology small molecule (B). Percent of patients experiencing at least 1 Grade ≥ 3 TEAE while being administered the label dose of approved drug from the registrational trial (C). Label dose groups were compared for statistical significance by one-way ANOVA with Tukey’s post hoc HSD (* p < 0.05, ** p < 0.01, *** p < 0.001)

Interestingly, treatment discontinuations due to AE(s) were similar across groups when comparing by label dose classification, with a median of 13.0% and 19.5% of patients in the Label Dose = MTD and Label Dose < MTD groups, compared to 9.3% and 9.5% of patients in the Label Dose = MSD and Label Dose < MSD groups. Only 2 compounds (duvelisib and glasdegib) reported > 33% of patients discontinuing treatment due to AE(s), both in the Label Dose < MTD group. For duvelisib, the discontinuation rate was attributed primarily to diarrhea/colitis (10% of discontinuations), followed by rash (4%), pneumonia (3%), and pneumonitis (3%) [10]. For glasdegib, the discontinuation rate was attributed primarily to pneumonia (6%), QT interval prolongation (5%), sepsis (4%), and febrile neutropenia (4%) [10].

Dose intensity

Overall, RDI was high, with a median RDI of ~ 98% reported for all compounds (Table 1). Most compounds had RDI > 90%, with only four compounds < 80%. No compounds reported a median RDI of < 70%. Of the 11 compounds within the Label Dose = MTD group (with median RDI data available), the median RDI was 91.9%, which was slightly lower than the median RDI of 95.0% for the Label Dose < MTD group, 100% for the Label Dose = MSD group, and 98.0% for the Label Dose < MSD group (Table 1). Overall, the Label Dose = MTD group skewed lower compared to the other groups, with 3 compounds reporting median RDI < 80% versus only 1 compound (which was Label Dose < MSD) reporting median RDI < 80% in all other groups (Fig. 1B). While the median RDI appears high for all groups, it should be noted that reporting of dose intensity was not standardized across compounds. Many compounds did not have a summary of dose intensity readily available (n = 12), and several other compounds reported dose intensity using methods other than mean or median RDI (n = 6). This bias should be taken into consideration in conjunction with reported dose modifications and discontinuations when interpreting overall compliance with the labeled dosing regimen.

Grade ≥ 3 treatment emergent adverse events

Of the 54 compounds included in the analysis, AE data in terms of the total % of patients experiencing at least 1 Grade ≥ 3 TEAE at the approved dosing regimen was reported for all compounds, as was the incidence of specific Grade ≥ 3 TEAEs at the approved dosing regimen. Overall, Grade ≥ 3 TEAEs were high, with a median of 60.8% of patients experiencing a Grade ≥ 3 TEAE. Comparing the Label Dose = MTD vs. other groups, the Label Dose = MTD group reported a median of 63.7% of patients experiencing at least one Grade ≥ 3 TEAE, which was similar to the Label Dose < MTD (median 65.5% of patients) and Label Dose = MSD (median 68.1% of patients), but overall higher as compared to Label Dose < MSD group, with a median of 51.5% of patients, respectively (Fig. 1C).

To understand the driver of these high number of Grade ≥ 3 TEAEs, we looked at the Grade ≥ 3 TEAEs occurring at high incidence, defined as occurring in > 10% of patients at the approved dosing regimen. Of the compounds, 14/54 reported 0 high incidence Grade ≥ 3 TEAEs, 17/54 reported 1, and 23/54 reported ≥ 2 Overall, the high number of Grade ≥ 3 TEAEs appeared to be driven primarily by hematological events (Table 2), with 25/54 compounds reporting at least 1 hematological Grade ≥ 3 TEAE occurring in > 10% of patients. In most cases, high incidence hematological TEAEs occurred in multiples (for example a compound with > 10% of patients having Grade ≥ 3 thrombocytopenia may also have > 10% of patients having Grade ≥ 3 anemia), Other common high incidence Grade ≥ 3 TEAEs included gastrointestinal and cardiovascular events, occurring in > 5 compounds.

Table 2.

Number of compounds with > 10% incidence of at least 1 Grade ≥ 3 TEAE of the CTCAE version 4.0 classification. If a compound had multiple Grade ≥ 3 TEAEs of the same classification, the compound was not double counted (left) or were double counted (right)

High incidence (> 10% Patients) Grade ≥ 3 treatment emergent adverse event	Number compounds (including duplicates)
Hematological	25 (57)
Gastrointestinal	6 (6)
Metabolic	5 (6)
Cardiovascular	6 (6)
Hepatic	5 (5)
Respiratory	10 (14)
General	4 (4)
Infection	5 (5)
Skin	2 (2)
Endocrine	1 (1)
Other	1 (1)

Comparing the relationship between percentage of patients experiencing at least 1 Grade ≥ 3 TEAE and treatment compliance, a moderate correlation between Grade ≥ 3 TEAEs and dose reductions, interruptions, and discontinuations was observed. However, no positive correlation between Grade ≥ 3 TEAEs and RDI was observed (Table 3).

Table 3.

Correlation matrix showing Pearson correlations of Grade ≥ 3 TEAEs to dose intensity, dose discontinuations, and percentage of patients experiencing at least 1 dose interruption or reduction due to adverse events while taking the study drug

	Grade 3 + TEAE	Dose intensity	Reduction	Interruption
Dose Intensity	-0.13
Reduction	0.41**	-0.82***
Interruption	0.55***	-0.51*	0.72***
Discontinuation	0.40**	-0.22	0.28*	0.36**

* p < 0.05, ** p < 0.01, *** p < 0.001

PMRs in dose optimization

Of the 54 compounds included in the analysis, a total of 7 compounds were issued a PMR for dose optimization at registration. Dose intensity, dose modifications and discontinuations due to AE(s), and incidence of Grade ≥ 3 TEAE were analyzed, grouped by compounds receiving a PMR for dose optimization (Fig. 2). Compounds issued a PMR for dose optimization trended lower in RDI and higher in dose modifications due to AE(s) and incidence of Grade ≥ 3 TEAEs than compounds not issued a PMR for dose optimization. Regarding dose modifications, a higher percentage of patients experiencing at least one dose modification due to AE(s) were reported for molecules issued a PMR in dose optimization vs. the latter (median 66.0 vs. 45.6% interruptions, and 45.0 vs. 20.1% reductions, respectively) (Table 4). The incidence of discontinuations due to AE(s) were similar among groups, where compounds receiving a PMR for dose optimization reported a median of 14.8% of patients discontinuing due to AE(s), whereas the latter reported a median of 11.1% of patients. The trend continued with dose intensity, as compounds issued a PMR for dose optimization reported a median RDI of 86.6%, notably lower than the median RDI of 98.1% reported in compounds without. Incidence of high grade TEAEs also followed the trend, wherein the compounds receiving a PMR for dose optimization a median of 77.0% of patients were reported as experiencing at least one Grade ≥ 3 TEAE vs. 55.2% of patients in the latter. Interestingly, none of the 7 compounds issued a PMR for dose optimization reported a positive exposure-response relationship in efficacy and only 4 out of 7 reported a positive exposure-response in safety events.

Fig. 2.

Compounds that received a PMR in dose optimization as described by dose modifications, reported as % of patients with drug discontinuation, or at least 1 dose interruption or dose reduction due to adverse events from the registrational trial (A), Relative Dose Intensity (RDI) reported from the registrational trial for each approved oncology small molecule (B), percent of patients experiencing at least 1 Grade ≥ 3 TEAE while being administered the label dose of approved drug from the registrational trial (C). PMR groups were compared for statistical significance by Welch two sample t-test (* p < 0.05, ** p < 0.01, *** p < 0.001)

Table 4.

Relative dose intensity (RDI) and dose modifications due to adverse events, categorized by if the compound received a PMR for dose optimization

Label dose	Number compounds	% Median relative dose Intensitya median (Min, Max)	% Discontinuation median (Min, Max)	% Interruptionb median (Min, Max)	% Reductionb median (Min, Max)
All Compounds	54	98.0 (72.5, 100)	12.8 (2.0, 35.0)	45.8 (2.7, 87.0)	21.0 (2.0, 69.0)
PMR in Dose Optimization	7	86.6 (78.0, 100)	14.8 (8.0, 26.7)	66.0 (34.0, 77.0)	45.0 (5.0, 60.2)
No PMR in Dose Optimization	47	98.1 (72.5, 100)	11.1 (2.0, 35.0)	45.6 (2.7, 87.0)	20.1 (2.0, 69.0)

% RDI reflects the median RDI reported for the registrational trial. % of dose discontinuations, % dose interruptions, and % dose reductions reflect the % of patients receiving the study drug at the approved dose with at least 1 of those events

a) Number of compounds with dose intensity reported as median RDI at the registrational dose were 34. 6 for compounds receiving a PMR in dose optimization and 28 for the latter

b) Number of compounds with separate dose reductions and interruptions were 51. 7 for compounds receiving a PMR in dose optimization and 44 for the latter

Out of these 7 compounds with a PMR issued for dose optimization, 3 were in the Label Dose = MTD group (adagrasib, futibatinib, infigratinib) and 2 were in the Label Dose = MSD group (sotorasib, quizartinib) (Table 4). The 2 remaining compounds were ribociclib (Label Dose < MTD) and selinexor (Label Dose < MSD). The specific justification for issuing these 2 compounds (ribociclib and selinexor) a PMR in dose optimization has been discussed previously [11] and is also available in the FDA multidisciplinary review [10]. Briefly, for ribociclib, while the pivotal trial dose was below the identified MTD, a positive exposure-response relationship was identified with regard to QT interval prolongation, but a flat exposure-response relationship with efficacy. The dose modifications due to AE(s) for ribociclib were also higher than the all-compound median, at 44.6% of patients experiencing at least one reduction and 71.3% of patients experiencing at least one interruption. For selinexor, while the pivotal trial dose was below the MSD, the percentage of patients experiencing at least one dose reduction or interruption due to AE(s) were also higher than the all-compound median, reported at 43.1% and 69.3%. This compound reported a positive exposure-response relationship in safety events but did not report a positive exposure-response relationship in efficacy.

Two compounds that received a PMR for dose optimization, sotorasib and quizartinib, were exceptions to the RDI trend, as they both reported a median RDI of around 100%. Sotorasib was approved for KRAS G12C-mutated NSCLC at 960 mg QD, the MSD. With respect to dose modifications and discontinuations due to AE(s), the percentage of patients experiencing at least one reduction was 5%, interruption was 34%, and discontinuation was 9%, which were below the all-compound median reported in Table 4. Sotorasib ultimately received a PMR to test a lower dose level of 240 mg QD due to a relatively flat dose-exposure relationship between the clinically tested dose ranges of 180 mg and 960 mg QD, attributed to saturable absorption. Quizartinib was approved for newly diagnosed AML that is FLT3 internal tandem duplication positive at a starting dose of 35.4 mg QD in combination with induction cytarabine and anthracycline, cytarabine consolidation, and as a maintenance monotherapy following consolidation chemotherapy. During maintenance, quizartinib can be administered at 26.5 mg QD for the first 14 days if QTcF is ≤ 450ms and escalated to 53 mg QD on Day 15 if QTcF ≤ 450ms. Quizartinib reported a positive concentration relationship with QTcF prolongation and other safety events but did not show a positive exposure-response in efficacy with the 53 mg QD maintenance dose. Therefore, the FDA issued a PMR in dose optimization to test a lower maintenance dose of quizartinib [10]. Of note, the percentage of patients experiencing at least one AE-related quizartinib dose reduction was 18.9% and interruption was 34.0%, which are similar to the all-compound median reported in Table 4, though the discontinuation rate was slightly higher at 20.4%.

Conclusion

In summary, of the 54 oncology small molecule NMEs that were FDA approved between March 2017 and October 2023 the approved dose was associated with an overall high RDI (> 90%), suggesting that the compliance to the label dose is high for patients who remain on treatment. From this dataset, ~ 28% (15/54) of recently approved oncology small molecules were approved at the MTD. Compounds where the Label Dose = MTD are associated with a higher incidence of dose interruptions and reductions due to AE(s), as well as Grade ≥ 3 TEAEs overall, especially compared to compounds where Label Dose ≤ MSD. Compared to those without a PMR for dose optimization, molecules with a PMR had a lower RDI and a significantly higher rate of AE-related dose modifications. Moreover, 20% (3/15) compounds that received a PMR for dose optimization had Label Dose = MTD, compared to 10% (4/39) in remaining compounds. Overall, the findings from this analysis are in line with the need for improving dose-optimization processes indicated by the FDA’s Project Optimus. Given the higher number of patients experiencing dose modifications and generally increased toxicities for compounds where Label Dose = MTD, dose optimization is crucial and an urgent need in the development of new oncology small molecules to enhance the therapeutic benefit for the patients.

Electronic supplementary material

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Author contributions

KPC and RKM gathered the data and prepared the figures. All authors wrote the manuscript text and reviewed the manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

KPC, DY, YKP, RKM are employees of Pfizer and hold Pfizer stock or stock options.