Sunday, September 28, 2014

All things BRAFi...latest articles

BRAF mutation status as an independent prognostic factor for resected stage IIIB and IIIC melanoma:  Implications for melanoma staging and adjuvant therapy.
Barbour, Tang, Amour, et al.  Eur J Cancer. 2014 July 25.

5 year survival for melanoma metastasis to regional lymph nodes is less than 50%.  Knowledge of outcomes following therapeutic lymphadenectomy for stage III melanoma related to BRAF status may guide adjuvant use of BRAF/MEK inhibitors along with established and future therapies.  DNA was obtained from patients with TLND who also had 2 or more positive nodes, largest node of greater than 3 cm, or extracapsular invasion.  Mutations were most commonly detected in BRAF (46%) and NRAS (21%).  Patients with BRAF mutations had higher 3-year recurrence rate of 77% vs 54% for BRAF wild-type patients.  The only prognostically significant mutations occurred in BRAF:  median recurrence-free disease and disease specific survival for BRAF mutation patients was 7 mo and 16 mo vs 19 months and not reached for BRAF wild-type patients, respectively.
CONCLUSION:  Patients with BRAF mutations experienced rapid progression of metastatic disease with locoregional recurrence rarely seen in isolation, supporting incorporation of BRAF status into melanoma staging and use of BRAF/MEK inhibitors post-TNLD.

This seems to be important data to consider to me.  Wonder if I would have progressed had I been given BRAFi after my first lymphadenectomy with a positive node.  I would not have met this criteria as it was only one microscopically positive node....but something to think about as I experienced my second primary just before making it 5 years out.

The nature and management of metastatic melanoma after progression on BRAF inhibitors:  Effects of extended BRAF inhibition.
Chan, Haydu, Menzies, et al.  Cancer. 2014 July 1.

"Dabrafenib and vemurafenib have high response rates in BRAF-mutant metastatic melanoma, however, 50% of patients progress by 7 months." 95 of 114 BRAFi treated patients (treated between July 2009 and September 2012, whose data was collected and analyzed) had disease progression.  53 of 95 patients progressed in extracranial sites alone, 18% progressed in intracranial and extracranial sites simultaneously, and 16% progressed in intracranial sites alone. 29 of the 95 patients progressed in a single site or organ, 48% progressed in existing mets only, and 18% had new mets alone.  At the time of progression, 35 of 95 patients received no subsequent systemic treatment, 20% changed systemic treatments and 39% continued BRAFi for a median of 97 days.  BRAFi continued beyond disease progression and known prognostic factors (LDH, RECIST sum of dimension of target lesions) were associated with overall survival from the time of disease progression.

Ok.  So....perhaps continued BRAFi after progression is helpful.

Features and management of pyrexia with combined dabrafenib and trametinib in metastatic melanoma.
Lee, Menzies, Haydu, et al.  Melannoma Res. 2014 July 22.

CombiDT (dabrafenib and trametinib) is an effective treatment for BRAF-mutant metastatic melanoma.  However, over 70% of patients develop drug-related pyrexia [fever].  32 patients reviewed.  14 (44%) developed pyrexia.  Fever was recurrent in 11/14.  Pyrexia was not associated with age, sex, disease burden, RECIST response, progression-free, nor overall survival.  Paracetamol, NSAIDs and/or dose reduction were ineffective secondary prophylaxis for pyrexia, whereas corticosteroids were effective in all patients.  In patients with previous dose reductions who commenced steroids, CombiDT doses were re-escalated without pyrexia. 

So....treating fevers with steroids stops the fever and allows patients to continue effective therapy!

Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.
Curl, Vujic,  van't Veer, et al.  2014 September 8.

Genetically-targeted therapies are both promising and costly advances in the field of oncology.  They extend life but are more expensive than the previous standard of care - dacarbazine.

NOTE:  Don't forget what Weber said about Dacarbazine:  "...when talking about some of these trial options with Dr. Weber, he acknowledged that had ipi or anti-PD1 had been discovered first....Dacarbazine would never have attained FDA approval...yet, we continue to use it.  Incredible." 

Vemurafenib costs $13,000 per month ($207,000 for a patient with median survival).  Patients failing vemurafenib are often given ipi at $150,000 per course.  "Present value of lifetime costs and quality-adjusted life years" were analyzed.   The incremental cost-effectiveness for vemurafenib vs dacarbazine was $353,993 per quality-adjusted life years.  For vemurafenib followed by ipi compared with vemurafenib alone was $158, 139. In sensitivity analysis, treatment cost had the largest influence on results:  the incremental cost-effectiveness for vemurafenib vs dacarbazine dropped to $100,000 per quality-adjusted life years gained with a treatment cost of $3,600 per month.  CONCLUSION:  The cost for time gained by treatments with vemurafenib alone or in combination exceeds...thresholds for cost-effectiveness.  These strategies may become cost-effective with lower drug prices or confirmation of a durable response without continued treatment.

Wow Curl and Vujic et al.  I hope you don't get melanoma.  You can't afford it!!!!

BRAF V600 mutations and pathological features in Japanese melanoma patients.
Yamazaki, Tanaka, Tsutsumida, et al.  Melanoma Res. 2014 July 19.

Primary sites of melanoma and the frequency of BRAF mutations might differ between races.  Melanoma is rare in Japan (1500-2000 cases per year compared with 132000 per year worldwide) and frequency and distribution of BRAF V600 mutations are unknown. Testing methods were defined.  BRAF V600 mutations were found in 41.8% of tested tumours.  Mutation rate = more than 60% in patients aged less than 60 years and more than 36% of patients with stage III/IV disease.  BRAF V600 mutations were detected in 18.8% of acral lentiginous melanomas. 64.7% of superficial spreading melanoma, 50% of lentigo maligna melanomas and 20% of nodular melanomas.

I'd have to do a little research to be positive, but those percentages for BRAF positive peeps seem about equivalent to folks in the states and Europe.  As far as BRAF status, perhaps the Japanese do better in avoiding the sun and other risk factors (known or unknown) that contribute to melanoma...or there are genetic factors we don't even know anything about...that are keeping their rates of melanoma lower than those for the rest of us.

Not sure what all this is worth....but there you go!  Best - c

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