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Nov 29, 2015 - moved to a modified 2/1 schedule of sunitinib experience an improved safety profile compared with that observed, in the same population ...
letters to the editor

Annals of Oncology

references 1. Lee SY, Choi JE, Jeon HS et al. A genetic variation in microRNA target site of KRT81 gene is associated with survival in early-stage non-small-cell lung cancer. Ann Oncol 2015; 26: 1142–1148. 2. Robles AI, Ryan BM. KRT81 miR-SNP rs3660 is associated with risk and survival of NSCLC. Ann Oncol 2016; 27: 360–361. 3. Campayo M, Navarro A, Vinolas N et al. A dual role for KRT81: a miR-SNP associated with recurrence in non-small-cell lung cancer and a novel marker of squamous cell lung carcinoma. PLoS One 2011; 6: e22509.

doi: 10.1093/annonc/mdv556 Published online 16 November 2015

More colors to the palette

the acceptable safety profile and the PFS observed in this group may justify prospective evaluation of this schedule. Less than 45% of patients starting sunitinib at a dosage of 50 mg/day were not able to maintain this full dose, even after switching. Our colleagues suggested that this finding is ‘a demonstration that the 2/1 schedule may still frequently require dose reductions to ameliorate tolerability’. We respect their opinion, but at the same time we consider again another shade of gray, i.e. the possibility of further widen treatment options for tailored treatment. The RAINBOW analysis was aimed at providing clinicians’ palette with more colors to choose from, and not to indicate the right one. S. Bracarda1,2* 1

San Donato Hospital USL8, Istituto Toscano Tumori (ITT), Arezzo; 2 Tumor National Institute, Milan, Italy (*E-mail: [email protected])

2

Umberto Basso and Marco Maruzzo provided the readers of Annals of Oncology with a summary and a careful comment of our RAINBOW analysis [1]. We wish to thank those experienced colleagues for their interest, and at the same time we take this opportunity to add more ‘colors” to the RAINBOW results [2]. First, our colleagues are right in further clarifying the number of biases of the RAINBOW analysis, e.g. selection biases and suboptimal registration of toxicities. These limitations are however inherent to any retrospective, hypothesis-generating study [3]. Due to this potential risk of biased efficacy results, we decided to focus our analysis on safety. Indeed, we showed that the 208 metastatic renal cell carcinoma (mRCC) patients who moved to a modified 2/1 schedule of sunitinib experience an improved safety profile compared with that observed, in the same population, during their initial period on the 4/2 schedule —a finding that can be considered the brightest color on the RAINBOW palette. This group of patients also reported a prolonged progressionfree survival (PFS) compared with the other groups analyzed, likely due to the reduced incidence of toxicity. However, it has been documented that 20%–30% of mRCC patients are primary refractory to tyrosine-kinase inhibitors and progress within the first three months of first-line therapy. The prognosis for these patients is poor [4]. In our analysis, we were not able to report the actual proportion of these patients. Taking into account that in the 4/2 → 2/1 group the median treatment duration with the initial schedule 4/2 was 4.3 months, it could be hypothesized that this subgroup of patients did not spend enough time on sunitinib to be switched to the 2/1 schedule. We suggest that the incidence of primary refractory patients should be reported in future studies [5]. Another interesting observation raised by Basso and Maruzzo concerns the use of sunitinib in the 41 patients with poor clinical conditions who started on the 2/1 schedule, as judged by the treating clinician in a field-practice setting. Our colleagues correctly point out that also temsirolimus, sorafenib or pazopanib could have been suitable treatment options in this difficult-totreat population. However, we selected for our analysis those subjects who received sunitinib, in order to evaluate the safety and—with an explorative intent—treatment duration and survival associated with the 2/1 schedule of the molecule. Overall,

disclosure The author has declared no conflict of interest.

references 1. Basso U, Maruzzo M. More on sunitinib 2 weeks on/1 week off schedule: the Rainbow analysis. Ann Oncol 2016; 27: 202–203. 2. Bracarda S, Iacovelli R, Boni L et al. Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis. Ann Oncol 2015; 26: 2107–2113. 3. Rizzo M, Cartenì G, Pappagallo G. We need both randomized trials and real-world data: the example of everolimus as second-line therapy for mRCC. Future Oncol 2014; 10: 1893–1896. 4. Porta C, Sabbatini R, Procopio G et al. Primary resistance to tyrosine kinase inhibitors in patients with advanced renal cell carcinoma: state-of-the-science. Expert Rev Anticancer Ther 2012; 12: 1571–1577. 5. Iacovelli R, Verri E, Cossu Rocca M et al. Sunitinib 2 weeks on, 1 off: strengths and weaknesses. Ann Oncol 2015; 26: 1512–1513.

doi: 10.1093/annonc/mdv555 Published online 29 November 2015

Reply to ‘Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumour response and tolerance’ by Funck-Brentano et al. We read with great interest the manuscript by FunckBrentano et al. [1], reporting in a prospective study the association of low plasma vemurafenib concentrations (PVC) with tumor progression disease (PD) according RECIST criteria in 23 advanced BRAFV600 mutated melanoma patients. †

Both authors contributed equally to this work.

Volume 27 | No. 2 | February 2016

doi:10.1093/annonc/mdv538 | 

letters to the editor In a monocentric prospective study enrolling 48 patients (28 M/20 F) with metastatic BRAFV600 mutated unresectable melanoma treated with vemurafenib monotherapy (American Joint Commitee on Cancer stage IIIC n = 9 or IV n = 39), we extended these results on a larger series and provided new insight on a PVC cutoff predicting progression. Vemurafenib (960 mg b.i.d. n = 44; 720 mg b.i.d. n = 4) was used as first-line therapy in 29 patients (60.4%), second-line in 12 patients (25%) and third-line or more in 7 patients (14.6%). Blood samples (n = 148, supplementary Figure S1, available at Annals of Oncology online) were collected monthly at any time during a dosing interval at steady state, as PVC during a dosing interval varies by only 16% over time [2]. Patients were followed every month for tolerance and response evaluation was carried out every 2 months using total body computed tomography scan with RECIST 1.1 criteria. PVC was measured using a routine high-performance liquid chromatography coupled with ultraviolet detection method. Regression analysis was carried out with R-software. PVC cutoff to predict progression was determined on median PVC for each patient by ROC curve analysis and progression-free survival (PFS) was assessed by multivariate Cox analysis (R Package). After 12 months median follow-up (1–50), overall response rate was 52.1% [95% confidence interval CI (50–54%)] and median overall PFS reached 5.5 months (95% CI 4.5; 8 months), which was consistent with clinical trial data (BRIM3) [3]. As expected, mean intrapatient variability reached 20.1% [3]. In line with Funck-Brentano et al. [1], PVC displayed a wide interindividual variability nonrelated to dose [2] (5.3–135.2 µg/ mL, median 66.8) and median PVC tented to be lower in patients experiencing PD (51 ± 22 µg/mL) compared with complete, partial or stable responders (67 ± 24 µg/mL, P = 0.060, Wald test for logistic regression). Furthermore, we extended these findings by establishing a predictive PVC cutoff for progression that was consistent with Kramkimel et al. results [4]. Indeed, patients with median PVC higher than 42 µg/mL presented a significantly lower risk of PD than patients with median PVC below 42 µg/mL during the first year after vemurafenib initiation (P = 0.005, supplementary Figure S2, available at Annals of Oncology online), confirming that low PVC could favor emerging resistance. However, such effect is no more significant after 1 year of treatment (P = 0.071). Therefore, we observed that even with optimized PVC, resistance occurs in the majority of cases through non-pharmacokinetics mechanisms. In our cohort, as reported by Funck-Brentano et al. [1] no exposure–tolerance relationship was observed as PVC during adverse event occurrence ranged from 26.9 to 117.6 µg/mL. With a longer follow-up and the determination of a PVC cutoff value predictive of PD, our study brings new insight for vemurafenib therapeutic drug monitoring during the first year of treatment. These data need to be confirmed in a larger independent study of patients treated with combination of BRAF and MEK inhibitors, now considered to be the standard of care of targeted therapy in BRAF mutated advanced melanoma.

 | letters to the editor

Annals of Oncology

L. Goldwirt1*, I. Chami2,3,4, J.-P. Feugeas5, C. Pages2,3,4, F. Brunet-Possenti2,3,4, C. Allayous2,3,4, B. Baroudjian2,3,4, I. Madelaine6, H. Sauvageon1, S. Mourah1,† & C. Lebbé2,3,4,† 1

Department of Pharmacology, AP-HP, Saint-Louis Hospital, Inserm, U976 Université Paris Diderot, Sorbonne Paris Cité, UMR-S-976, Paris; 2 Department of Dermatology, AP-HP, Saint-Louis Hospital, Paris; 3 Inserm, U 976, Paris; 4 Faculté de Médecine, Université Paris Diderot, Sorbonne Paris Cité, Paris; 5 INSERM, IAME, UMR 1137, Université Paris Diderot, Paris; 6 Deparment of Pharmacy, AP-HP, Saint-Louis Hospital, Paris, France (*E-mail: [email protected])

disclosure CL: Scientific committee board and consultation for Roche. SM: Scientific committee board for Roche. The other co-authors have declared no conflicts of interest.

references 1. Funck-Brentano E, Alvarez JC, Longvert C et al. Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumour response and tolerance. Ann Oncol 2015; 26: 1470–1475. 2. EMEA. Public assessment report on Zelboraf®, EMA/200986/2012. 2012. 3. McArthur GA, Chapman PB, Robert C et al. Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 2014; 15: 323–332. 4. Kramkimel N, Thomas-Schoemann A, Sakji L et al. Vemurafenib pharmacokinetics and its correlation with efficacy and safety in outpatients with advanced BRAF-mutated melanoma. Target Oncol 2015 Jul 25 [epub ahead of print], doi:10.1007/s11523-015-0375-8.

doi: 10.1093/annonc/mdv538 Published online 16 November 2015

Reply to the letter to the editor ‘Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumor response and tolerance’ by Funck-Brentano et al. We thank Goldwirt et al. [1] for their independent confirmation of our results [2] on the difference, although it did not quite reach statistical significance in their dataset, between plasma vemurafenib concentrations (PVC) among patients with unresectable metastatic BRAFV600mut melanoma who experienced tumor progression and those who responded to vemurafenib. They also confirm the large interindividual variability of PVC in these patients. Goldwirt et al. suggest a PVC cutoff value predicting disease progression. Based on a receiver operating characteristics (ROC)

Volume 27 | No. 2 | February 2016