Impact Of Dose Reductions Research Articles

The Impact of Fitness and Dose Intensity on Safety and Efficacy Outcomes after Venetoclax-Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia

Introduction Following the results of two phase-III studies, the CLL14 study, recruiting elderly and unfit patients (pts) with chronic lymphocytic leukemia (CLL), and the CLL13 study, recruiting younger and fit pts, venetoclax-obinutuzumab (Ven-Obi) is a standard of care for pts with treatment-naive CLL. However, it is unclear whether age and/or fitness have an impact on the tolerability and efficacy of Ven-Obi. Furthermore, the impact of dose reductions on response and survival has not been explored yet. Here, we present a pooled analysis detailing the toxicity and efficacy of Ven-Obi in pts treated within the CLL13 and CLL14 studies. Methods Patients randomized to the Ven-Obi arm in CLL14 (2015-2016) and CLL13 (2016-2019) with at least one dose of study drug were considered and categorized as fit or unfit pts (cumulative illness rating scale [CIRS] > 6 and/or creatinine clearance < 70 ml/min). Patients with TP53 aberrations were excluded to ensure balanced features across the CLL13 and CLL14 populations. Correlations regarding minimal residual disease (MRD) in peripheral blood and response (both assessed at the end of treatment [EOT]) were assessed by chi² test. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier methodology and Cox proportional hazard regression modeling. Dose intensity was calculated as the relative fraction within the administered treatment cycles (excluding pts with treatment discontinuation due to PD/death). Adverse events were analyzed up to 28 days after EOT. Results In total, 410 pts were considered for this analysis, 228 from CLL13 and 182 from CLL14. The median observation time was 49 months (interquartile range [IQR] 37.0-65.8 months); for CLL13, median observation time was 38.9 months (IQR 33.8-46.3), and 66.7 months in CLL14 (IQR 64.4-70.8). Median age at enrollment was 67 years (IQR 58-73); 55.7% were grouped as unfit (median age 72), 44.3% as fit (median age 58) ( A). Overall response rate (ORR) was 89.5% in unfit and 96.1% in fit pts (p=0.011), CR rates were 51.8% and 54.1% (p=0.63), respectively. The undetectable MRD (<10 -4) rates were 80.3% in unfit and 85.1% in fit pts (p=0.2). The 3-year-PFS rates were 86.4% in unfit vs 87.5% in fit pts (HR 1.12, 95%-CI 0.70-1.81, p=0.63, B). The 3-year-OS was 91.8% in unfit vs 96.9% in fit pts (HR 2.02, 95% CI 0.90-4.55, p=0.088). Adverse events (any grade) considered of interest included neutropenia, which occurred in 62.7% of unfit and 56.9% of fit pts (febrile neutropenia 4.4% in each group), respectively. Infusion-related-reactions (IRR) occurred in 44.3% of unfit and 56.9% of fit pts. Fatigue was reported in 15.8% of unfit and 35.9% of fit pts; headaches in 9.2% of unfit and 18.2% of fit pts. Infections occurred in 57.5% of unfit and 69.6% of fit pts; in particular, nasopharyngitis was reported for 10.5% of unfit and 24.3% of fit pts. Covid-19 occurred in 3 unfit (3 fatal) and 5 fit (2 fatal) pts. Other common adverse events were balanced between fit and unfit pts. Comparable patterns were also observed when comparing young vs older pts according to exploratory age cut-offs between 65 to 80 years. Early venetoclax discontinuations for reasons other than PD or death (e.g., adverse events, withdrawal) were more common in unfit than in fit pts (15.8% vs 5.0%). Median time to early discontinuation was 6.3 months (3.1-8.7). Patients with early venetoclax discontinuation had a 3-year-PFS from EOT of 71.2%, compared with 83.0% in pts who completed venetoclax as planned (HR 2.25, 95%-CI 1.32-3.83, p=0.003). The 3-year-OS from the EOT was 84.3% and 94.0% (HR 2.48, 95%-CI 1.10-5.59, p=0.029), respectively. Dose reductions <80% (excluding PD/death) occurred in 15.7% of all pts (14.7% unfit, 16.5% fit). ORR in pts with venetoclax dose intensity <80% was 82.5% and 95.9% in pts with dose intensity ≥80% (p<0.001). CR rates were 42.9% and 55.5% (p=0.066), uMRD rates were 76.2% and 85.3% (p=0.073). The 3-year-PFS from the EOT for pts with and without venetoclax dose intensity <80% was 81.0 % and 82.2%, respectively (HR 1.47, 95%-CI 0.84-2.57, p=0.175). Conclusion This analysis confirms the feasibility and efficacy of Ven-Obi for both fit and unfit pts with CLL. The incidence of toxicities was comparable between both patient groups, although IRR and fatigue were more common in fit pts. Reduced venetoclax dose intensity had no impact on PFS, suggesting that dose modifications may have limited impact on long-term clinical outcomes.

Impact of relative dose intensity on pathologic complete response in human epidermal growth factor receptor 2 positive breast cancer patients receiving neoadjuvant TCHP.

The standard of care for locally advanced, human epidermal growth factor receptor 2 positive (HER2+) breast cancer includes neoadjuvant chemotherapy with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP). Many patients do not receive the full course of therapy due to various complications, possibly affecting the potential to achieve a pathologic complete response (pCR). The amount of therapy received is typically measured by relative dose intensity (RDI). This study aimed to evaluate pCR rates in patients receiving optimal and suboptimal RDI TCHP. This study was a retrospective chart review of patients treated between 2014 and 2021 at UK HealthCare. Patients included were 18 years of age or older with HER2+ breast cancer and received at least one cycle of neoadjuvant TCHP. The primary objective compared pCR rates in patients receiving ≥ 85% RDI or <85% RDI. Secondary objectives included pCR rates based on clinical stage, age, body mass index, or hormone receptor status; factors leading to discontinuation or delay in treatment; and impact of dose reductions and delays on pCR. A total of 101 patients were included and divided into two cohorts: 54 patients received ≥ 85% RDI and 47 patients received <85% RDI. Patients who received ≥ 85% total RDI had an approximate increase of 17% in pCR rates (59.3% vs 42.6%, p = 0.11). Additionally, 82% of patients experienced a dose delay or adjustment. Patients who received ≥ 85% RDI had increased pCR rates compared to patients receiving <85% RDI. A larger patient population is needed to formulate definitive conclusions on the impact of RDI and pCR rates.

Does the dose matter? Antiproliferative efficacy and toxicity of everolimus in patients with neuroendocrine tumors - Experiences from a tertiary referral center.

The mTOR-inhibitor everolimus has been approved for the treatment of advanced neuroendocrine tumors (NETs) but is associated with relevant toxicities in clinical practice. Hence, optimal treatment sequencing and the impact of dose reductions have yet to be clarified. This retrospective analysis assessed patients with advanced, well-differentiated NET treated with everolimus at the Medical University of Vienna. The primary objective was to evaluate the efficacy of everolimus in a real-world cohort. A total of 52 patients treated with everolimus for advanced NET grade 1 (G1) or G2 (or typical or atypical carcinoid) 2010-2021 were included in this analysis. The most common sites of origin were pancreas (44%) and lung (29%). The initial dose was decided by the treating physician based on clinical assessment and 25 patients (48%) each were started at 10 mg/day and 5 mg/day. Median progression-free survival (PFS) following everolimus in the overall cohort was 9.8 months (95% CI: 4.3-15.3), with a statistically significant PFS difference (p = .03) between NET G1/typical carcinoids (42.9 months) and NET G2/atypical carcinoids (8.9 months). PFS was numerically but not significantly shorter in patients treated with a reduced dose (7.5 months vs. 12.4 months, p = .359). Even in this mixed full/half dose cohort, 93% developed treatment-related side effects (mostly grade I, no grade IV), 63% had dose reductions or interruptions, and five stopped due to toxicity. Median survival following treatment was 40.9 months (95% CI: 21.5-60.3) and no difference with regard to dosing was observed (p = .517). These data from an unselected patient cohort show long-term outcomes similar to those reported in the pivotal studies. Comparing everolimus starting dose, median PFS did not significantly differ for patients treated at a lower dose. While this finding is limited by the sample size and warrants prospective verification, initiating therapy at a reduced dose might be practicable and safe in a distinct subset of patients.

Lorlatinib Tolerability and Association With Clinical Outcomes in Patients With Advanced ALK- or ROS1-Rearranged NSCLC: A Brief Report

IntroductionTreatment with lorlatinib for patients with advanced ALK- and ROS1-rearranged NSCLC (ALK+ and ROS1+ NSCLC) is associated with a unique set of adverse events (AEs) often requiring dose reduction. However, the impact of dose reductions on outcomes remains unclear and is mainly limited to analyses from prospective studies of lorlatinib in the first-line setting. MethodsWe reviewed the course of 144 patients with advanced ALK- or ROS1-rearranged NSCLC treated with lorlatinib in the second-line or later setting to assess the frequency of dose reductions resulting from treatment-related AEs (TRAEs) and the association between dose reductions and progression-free survival (PFS) and overall survival (OS). ResultsA total of 58 patients (40%) had TRAE-related dose reductions, most (59%) owing to neurocognitive AEs or neuropathy. Among all patients, the median PFS was 8.1 months (95% confidence interval [CI]: 6.4–11.8); the median OS was 20.7 months (95% CI: 16.3–30.5). Among patients who were started on lorlatinib 100 mg/d (n = 122), a Cox regression model with the occurrence of a dose reduction as a time-dependent covariate indicated no association between dose reduction and PFS (hazard ratio = 0.86, 95% CI: 0.54–1.39) or OS (hazard ratio = 0.78, 95% CI: 0.47–1.30). ConclusionsLorlatinib dose reductions were not associated with inferior clinical outcomes in this multicenter analysis. Prompt identification of lorlatinib TRAEs and implementation of dose reductions may help maximize tolerability without compromising outcomes.

Real-world dosing, management, and clinical outcomes of patients (pts) with metastatic pancreatic adenocarcinoma (mPDAC) treated with liposomal irinotecan.

e16780 Background: Pancreatic cancer remains one of the most lethal cancers in the United States (US) with a 5-year relative survival of 10%. Liposomal irinotecan is a topoisomerase inhibitor indicated, in combination with 5-fluorouracil and leucovorin, for pts with mPDAC following disease progression on gemcitabine-based therapy. This study examines the real-world use and therapeutic management of pts with mPDAC treated with liposomal irinotecan. Methods: This retrospective observational study utilized the Flatiron Health EHR-derived de-identified database from over 280 cancer clinics in the US. Data were analyzed for adult pts with mPDAC treated with liposomal irinotecan based regimens between Nov 2015 and Oct 2019. Pts were categorized into two starting dose groups: 70mg/m2 and &lt; 65mg/m2. Pt characteristics, overall survival (OS), duration of treatment (DOT), and impact of dose reductions (DR, reduction ≥ 7mg/m2) were assessed among pts who received ≥3 cycles of treatment (tx). Results: Of the 532 pts (median age: 69y, IQR: 62-75) included in the study, 95 (18%) had an ECOG score of 2+ at tx initiation. Of the 184 pts (69y, 42 – 84) that did not receive 3 cycles of tx, 47 (25%) had an ECOG score of 2+ and 83 (45%) had two or more prior lines of tx. 348 pts (69y, 43 – 85) received ≥3 cycles of tx. 116 (33%) pts had two or more prior lines of tx, 209 (60%) had an ECOG score of 0-1, 48 (14%) had an ECOG score of 2+, and 91 (26%) had missing scores. 220 (63%) initiated tx at 70mg/m2 and 128 (37%) initiated at &lt; 65mg/m2. 83 (38%) 70mg/m2 and 26 (20%) &lt; 65mg/m2 pts experienced a DR during tx. 43 (52%) and 14 (54%) of the DRs occurred within the first 6 wks of tx in the 70mg/m2 and &lt; 65mg/m2 cohorts, respectively. Median DOT was 12.6 weeks for 70mg/mg2 and 9.1 wks for &lt; 65mg/m2 pts; DOT was longer among pts with a DR: 19.0 wks and 16.1 wks, respectively. Median OS (mOS) was 7.2 months (95% CI: 6.2 – 8.1) and 6.2 mos (5.0 – 7.4) for pts receiving 70mg/m2 and &lt; 65mg/m2, respectively. mOS for pts with a DR was 8.9 mos (7.3 – 10.8) and 7.7 mos (5.0 – 14.9) for pts receiving 70mg/m2 and &lt; 65mg/m2, respectively. mOS for pts with no DR was 6.0 mos (4.8 – 7.2) and 6.0 mos (4.7 - 7.2) for those receiving 70mg/m2 and &lt; 65mg/m2, respectively. Conclusions: In this descriptive study among pts who were able to receive ≥3 cycles of liposomal irinotecan and remain on tx for ≥4 wks, DRs were effective in extending DOT and OS, independent of starting dose. The longest DOT and OS were observed in the pts who received 70mg/m2 with DRs. Pts who received 70mg/m2 and &lt; 65mg/m2 had similar OS in the absence of DRs.

Longitudinal cumulative dose: A novel measure to assess multiple dimensions of chemotherapy adherence over time.

3522 Background: Adjuvant chemotherapy regimens take months to complete. Despite this, trials and observational studies evaluate chemotherapy adherence via measures assessed at the end of treatment (e.g. number of patients missing any dose, relative dose intensity [RDI]). This approach misses information that impacts outcomes, like treatment delays. We propose longitudinal cumulative dose (LCD) as a way to integrate the impact of dose reductions, missed doses, and dose delays at each cycle over time. Methods: We obtained data from the 2,246 participants in the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer (MOSAIC). We evaluated proportions of patients stopping treatment early and reducing (based on protocol), missing, or delaying a dose in each arm for each chemo agent at each visit. We obtained LCD, the fraction of the final standard dose a participant reached by a given day, for each participant and each chemo agent. We compared LCD medians over time and at the end of a standard regimen (24 weeks) between treatment arms and by age and performance status. We assessed agreement between oxaliplatin LCD and RDI with Fleiss’ kappa (Table). Results: Participants randomized to FOLFOX were more likely than those randomized to 5FU to stop treatment, reduce doses, miss doses, or delay visits; these differences increased over time. Median LCD for oxaliplatin in the FOLFOX arm at 24 weeks was 77%. Graphs of median LCD for 5FU showed a clear difference between arms (FOLFOX arm median LCD: 81%; 5FU arm median LCD, 96%). While 5FU LCD decreased with age in the FOLFOX arm (median LCD in those age &lt;40: 85%; 40-64, 82%; 65-75, 76%), it was similar across ages in the 5FU arm (median LCD 94%, 96%, and 96%, respectively), with smaller performance status trends. RDI and LCD showed fair agreement (Fleiss’ kappa=0.34); 19% of those with RDI over 85% had LCD under 60%. Conclusions: Visualizing LCD highlighted the timing and scale of deviations from standard administration, with major differences in 5FU LCD across arms. Next steps include evaluating if LCD predicts clinical outcomes. [Table: see text]

Impact of dose reductions on clinical outcomes among patients (pts) with metastatic pancreatic cancer (mPC) treated with liposomal irinotecan (nal-IRI) in oncology clinics in the United States.

665 Background: The recommended starting dose for nal-IRI is 70mg/m2 (free base, equivalent to 80 mg/m2 salt-based dosing). This study evaluates the impact of nal-IRI dose reductions on clinical outcomes. Methods: Using the nationwide Flatiron Health electronic health record-derived database, de-identified data were extracted and analyzed for adult mPC pts treated with nal-IRI Jan 2014-Jan 2019 and who initiated treatment at approximately the recommended dose (RD), 70mg/m2 +/- 5mg. Initial dose was derived from structured medication records, prioritizing administrations. The cumulative dose (CD) of nal-IRI over the first six weeks of treatment, the presence of dose reductions (DR) – (a decrease ≥ 7mg/m2), overall survival (OS) from treatment initiation, and duration of treatment (DoT) were assessed. Results: 257 mPC pts treated with nal-IRI (median age: 68y, IQR: 61 - 73) were identified initiating therapy at approximately the RD. 26.5% (N = 68) of pts experienced a DR during treatment. Mean 6-week CD was 175.8 mg/m2 (SD: 77.9) among pts with no DR. For pts with DR, mean CD was 191.8 mg/m2 (53.2). Median DoT was 6.1 wks (IQR: 2.1 – 15.3). Pts that experienced a DR had a longer median DoT: 15.1 wks (7.1 – 23.0) vs 4.3. wks (2.1 – 12.1) for pts with no DR. Overall Median OS (mOS) was 4.2 months (95% CI: 3.7 – 5.4). mOS for DR pts was 7.2 mos (95% CI: 5.5 – 9.7) and 3.7 mos (3.0 – 4.1) for pts who did not experience a DR. Conclusions: This real-world analysis suggests that reducing the dose of subsequent administrations of nal-IRI during treatment is associated with pts remaining on therapy longer, experiencing a larger CD, and a with longer OS. Additional real-world prospective studies are necessary to characterize the impact of nal-IRI dosing on clinical outcomes.

Major Deviations in the Delivery of Induction Chemotherapy Are Associated with an Increased Risk of Relapse in Acute Lymphoblastic Leukaemia: Results from UKALL2003

Introduction As survival rates for acute lymphoblastic leukaemia (ALL) in children and young people improve, the need to understand and mitigate toxicity becomes increasingly important. The contribution of toxicity to mortality or significant morbidity is well described. However, the impact of dose reductions, drug omissions or delays in treatment which result from toxicity is poorly understood, other than the established association between effective count suppression during maintenance chemotherapy and a reduction in relapse rate. We report the significance of treatment delays and dose reductions in induction chemotherapy in the UKALL2003 trial. Methods UKALL2003 was a prospective multicenter phase 3 study recruiting patients aged 1-24 years with newly diagnosed Philadelphia chromosome negative ALL in the UK. Data regarding 4 different protocol deviations were prospectively collected at the end of each block of therapy; a) not given allocated regimen, b) &lt;90% of one or more of the protocol drugs administered, c) change of Asparaginase product and d) delay of &gt; 1 week in commencing the next treatment block. Univariable (UVA) and Multivariable (MVA) Cox regression was used to assess the association of each deviation with risk of relapse. To control for immortality bias, this was assessed at the end of each therapy block with only patients alive and relapse free at the end of the block included in the analysis. Patients with Down Syndrome were excluded from all analyses. Results Of 2991 patients without Down Syndrome completing induction chemotherapy, 9 patients did not receive the allocated regimen, 1558 patients received &lt;90% of one or more drugs, 9 patients were switched to an alternative Asparaginase product and 72 had a greater than 1 week delay in commencing consolidation. On UVA, reduction of &gt;90% of one or more drugs and delay of greater than 1 week was significantly associated with an increased risk of relapse with hazard ratios of 1.70 (95% CI 1.11 - 2.60, p=0.014) and 1.99 (95% CI 1.14 - 3.48, p=0.013) respectively. On MVA (complete cases, n=2464), including other factors of established prognostic significance, both deviations remained significantly associated with an increased risk of relapse (Table 1). The impact of a major deviation (defined here as dose reduction of &gt;90% of one or more drugs or treatment delay of &gt;1week) was seen in both the paediatric (&lt;16 years) and older (16-24 years) groups with a slightly larger effect in the older group (HRs 1.73 and 2.40 respectively), though the interaction between age and deviation was not significant (p=0.49)( Figure 1). Patients with dose omissions &gt;90% of one or more drugs in induction were also more likely to have major deviations in subsequent blocks of therapy (p&lt;0.001) and remained at significantly higher risk of relapse when starting the maintenance phase of treatment (n=2343, HR: 1.81 (1.06 - 3.09, p = 0.03). Conclusion Major deviations in the delivery of induction chemotherapy on UKALL2003 were significantly associated with a greater risk of further deviations in subsequent blocks of therapy and a higher risk of relapse. Further improvement in efficacy of ALL therapy in children and young people will require a greater understanding of which toxicities lead to major deviations in therapy and strategies developed to mitigate these risks. Disclosures Rowntree: Novartis: Consultancy.

Comparing the impact of dose reductions and delays on ovarian cancer patient outcomes with three-weekly versus dose dense carboplatin and paclitaxel regimens in the national prospective OPAL cohort.

5568Background: To determine if chemotherapy dose reductions and delays in the adjuvant setting impact ovarian cancer pt outcomes. Secondary objective is comparing deliverability of three weekly an...

The impact of pricing strategy on the cost of oral anti-cancer drugs during dose reductions.

e18312 Background: The pricing strategy of oral medications can affect their costs. The strategy of flat pricing per tablet may increase drug costs in the event of dose reductions requiring more tablets, as there is a single price for different tablet strengths, but the impact is largely unknown. With the strategy of linear pricing, the tablet price increases with its strength. We sought to determine the impact of pricing strategy on the cost of oral anti-cancer drugs during dose reductions. Methods: Oral anti-cancer drugs reviewed by the pan-Canadian Oncology Drug Review were identified between July 2011 to January 2015. The pricing strategy of these drugs was reviewed. We examined the percentage change in cost per mg and cost per 28 days as a result of dose reduction from dose level 0 to -1 and -2 for each drug. Results: Seventeen drugs for use in 20 indications were included in the analysis. There were 3 drugs for hematological malignancies and 14 drugs for solid cancers. Fifty-nine percent (10/17) of these drugs were available in multiple strengths; five of them utilized fixed pricing per tablet strategy and the other 5 utilized linear pricing. The remaining drugs (7/17) were available in a single strength tablet. Dose reductions generally increased the cost per mg for drugs using flat pricing per tablet, with a mean increase of 82% (range: 25%-200%) at dose level -1 and 100% (range: 0%-200%) at dose level -2. Dose reduction had no effect on the cost per mg of drug for drugs using linear pricing apart from lenalidomide, which had increased costs due to minimal price variation between the highest and lowest tablet strengths. In general, dose reduction did not decrease the cost per 28 days of drug for drugs using flat pricing per tablet, but was proportionally reduced in drugs using linear pricing. Conclusions: While there is a general expectation that the cost of drugs should decrease with dose reduction, oral anti-cancer drugs using flat pricing per tablet have increased cost per mg and no decrease in cost per 28 days despite dose reduction. Future economic evaluations should account for the impact of dose reductions for oral drugs using the flat pricing per tablet strategy on cost-effectiveness and budget.

Clinical impact of dose intensity of initial tyrosine kinase inhibitor (TKI) therapy in accelerated-phase CML (CML-AP).

6587 Background: For patients (pts) presenting with CML-AP, TKIs are recommended. Although generally well tolerated, dose reductions and/or interruptions are often required. The impact of TKI dose intensity (DI) on CML-AP outcome has not been described. Aim: To determine impact of TKI dose interruptions and/or reductions on outcome in de novo CML-AP. Methods: Overall, 58 CML-AP pts (median age 46 yrs) were treated on consecutive or parallel clinical trials with TKIs as initial therapy: imatinib (n=36), dasatinib (n=5), or nilotinib (n=17). CML-AP features included: blasts ≥15% (n=8), basophils ≥20%, (n=22), platelets &lt;100x109/L (n=3), cytogenetic clonal evolution (n=22), or &gt;1 feature (n=3). We examined the impact of dose reductions, treatment interruptions, and DI (ratio of the dose received vs. the intended dose for the entire treatment duration) on event-free (EFS), transformation-free (TFS), and overall survival (OS). Results: Among 58 pts, 37 required treatment interruptions and/or dose reductions (29 required dose reductions). 12 pts required dose reductions and/or interruptions due to hematologic toxicity and 23 for non-hematologic toxicities. Pts were divided into 3 DI tiers: 100% (n= 21), 90-99%, (n=10), and &lt;90% (n=27). Outcomes were analyzed based on DI tiers and presence or absence of dose reductions as shown in the table. Pts with dose reductions and/or interruptions for hematologic toxicities vs. non-hematologic toxicities had a 24-mo EFS rate of 87% vs. 100% (p=0.05). 24-mo EFS by dose reductions and/or interruptions within 6 mo or later were 100% and 91%, respectively (p =0.7). Conclusions: DI has no significant impact on de novo CML-AP outcome. However, dose interruptions and/or reductions for hematologic toxicities are associated with worse 24-mo EFS, suggesting myelosuppression may in some patients be more a feature of the disease than toxicity from therapy. [Table: see text]

Erlotinib in patients with advanced non-small-cell lung cancer: impact of dose reductions and a novel surrogate marker

Erlotinib is a relatively well-tolerated treatment option for patients with advanced non-small-cell lung cancer (NSCLC). Some patients suffer from severe skin toxicity or diarrhea, making dose reductions or even treatment cessation necessary. Recent clinical trials usually defined a 100 mg daily dose as the lowest acceptable dose, whereas little is known about the efficacy with lower doses. We retrospectively reviewed the files of all patients with advanced non-small-cell lung cancer (NSCLC) treated with erlotinib. We assessed demographic, disease- and treatment-related information. We tried to correlate tolerability with clinical efficacy. EGF receptor exon 18/19/21 mutations were analyzed in selected patients. Fifty-three patients with advanced non-small-cell lung cancer were treated with erlotinib. In nine patients (17%), the doses had to be reduced to 75 or 50 mg daily due to toxicity. We observed several sustained disease stabilizations in this subgroup. Patients suffering from paronychia with erlotinib had a significantly longer time to progression than did subjects without nail toxicity (P = 0.04). If patients were free from any toxicity, they were at high risk for early tumor progression (P = 0.001) and death. In patients with disease stabilization for 6 months or longer, we observed EGFR 18/19/21 wild type, exon 19 and exon 21 mutations. In conclusion, several patients required dose reductions during treatment with erlotinib. However, in tumors with sensitivity to erlotinib, even daily doses of 50-75 mg can result in sustained disease control. Paronychia represents a favorable surrogate marker for efficacy.

Impact of dose reductions of platinum compounds on survival in stage IIIB/IV non-small cell lung cancer (NSCLC)

e19055 Background: Platinum compounds are the main component of the CT in NSCLC. Standard recommended doses of cisplatin/carboplatin is usually couldn’t be administered and dose reductions are necessary because of side effects. We aimed to determine the effect of dose reductions of platinums on outcome of stage IIIB/IV NSCLC. Methods: Data of 420 patients were retrospectively reviewed. A platinum analogue was used in combination with vinorelbine, gemcitabine, paclitaxel, docetaxel or etoposide as first line treatment in 85% patients. Cumulative platinum doses and dose reduction ratios compared to standard doses were calculated. Patients with decreased GFR were excluded from the analysis. Results: Median age was 60 years (range: 28-87), 79% of patients were male, 31% were 65 yearsold/older, 55% had PS of 0, and 27% had stage IIIB disease. Histological subtypes were squamous cell in 32%, adenocarcinoma in 34%, and NSCLC in 31%. Median dose of cisplatin used per cycle was 67mg/m2 and carboplatin was 287mg/m2. 51% of the patients received standard or less than 10% reducted doses of platinum, while dose reductions were 10–20% in 19%, 21–30% in 24% of patients, and more than 31% in 6%. Median overall survival (OS) was 11 months, 1- year and 2-year OS ratios were 56% and 25%, respectively. Median time to progression was 5 months; 1-year progression free survival ratio was 18%. Gender, age, histologic subtype, and treatment with lower dose of platinum didn’t have any statistically significant impact on survival in univariate analysis. Patients with PS of 0, no weight loss, stage IIIB disease, receiving combination CT with docetaxel-cisplatin, and having partial response to treatment lived significantly longer. On multivariate analysis weight loss, stage and type of response to treatment had an impact on OS. Conclusions: Using lower doses of platinum compounds in combination chemotherapy for stage IIIB/IV non-small cell lung cancer might not have a negative impact on survival and definitely have a better toxicity profile. No significant financial relationships to disclose.

Impact of dose reductions on efficacy outcome in heart transplant patients receiving enteric‐coated mycophenolate sodium or mycophenolate mofetil at 12 months post‐transplantation

Mycophenolic acid (MPA) dose reduction is associated with increased risk of rejection and graft loss in renal transplantation. This analysis investigated the impact of MPA dose changes with enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) in de novo heart transplant recipients. In a 12-month, single-blind trial, 154 patients (EC-MPS, 78; MMF, 76) were randomized to either EC-MPS (1080 mg bid) or MMF (1500 mg bid) in combination with cyclosporine and steroids. The primary efficacy variable was the incidence of treatment failure, comprising a composite of biopsy-proven (BPAR) and treated acute rejection, graft loss or death. Significantly fewer patients receiving EC-MPS required > or =2 dose reductions than patients on MMF (26.9% vs. 42.1% of patients, p = 0.048). Accordingly, the average daily dose of EC-MPS as a percentage of the recommended dose was significantly higher than for MMF (88.4% vs. 79.0%, p = 0.016). Among patients requiring > or =1 dose reduction, the incidence of treated BPAR grade > or =3A was significantly lower with EC-MPS compared with MMF (23.4% vs. 44.0%, p = 0.032). These data suggest that EC-MPS-treated heart transplant patients are less likely to require multiple dose reductions than those on MMF which may be associated with a significantly lower risk of treated BPAR > or =3A.