BRAF inhibitors + SRS in brain mets = good. And.... BRAFi resistant tumors may be vulnerable to arginine deprivation or resistance avoided with the addition of APR-246!

Impact on overall survival of the combination of BRAF inhibitors and stereotactic radiosurgery in patients with melanoma brain metastases.  Wolf, Zia, Verma, Pavlick, et al.  J Neurooncol. 2016. Feb 6.

“The aim of this study was to evaluate the impact of BRAF inhibitors on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases. We prospectively collected treatment parameters and outcomes for 80 patients with melanoma brain metastases who underwent SRS. Thirty-five patients harbored the BRAF mutation (BRAF-M) and 45 patients did not (BRAF-WT). The median overall survival from first SRS procedure was 6.7, 11.2 months if treated with a BRAF inhibitor and 4.5 months for BRAF-WT. Actuarial survival rates for BRAF-M patients on an inhibitor were 54 % at 6 months and 41 % at 12 months from the time of SRS. In contrast, BRAF-WT had overall survival rates of 28 % at 6 months and 19 % at 12 months. Overall survival was extended for patients on a BRAF inhibitor at or after the first SRS. The median time to intracranial progression was 3.9 months on a BRAF inhibitor and 1.7 months without. The local control rate for all treated tumors was 92.5 %, with no difference based on BRAF status. Patients with higher KPS, fewer treated intracranial metastases, controlled systemic disease, RPA Class 1 and BRAF-M patients had extended overall survival. Overall, patients with BRAF-M treated with both SRS and BRAF inhibitors, at or after SRS, have increased overall survival from the time of SRS. As patients live longer as a result of more effective systemic and local therapies, close surveillance and early management of intracranial disease with SRS will become increasingly important.”

BRAF inhibitor resistance enhances vulnerability to arginine deprivation in melanoma.  Li, Wu, Chen, et al.  Oncotarget.  2016 Jan 11.

“BRAF inhibitor (BRAFi) has been used for treatment of melanomas harboring V600E mutation. Despite a high initial response rate, resistance to BRAFi is inevitable. Here, we demonstrate that BRAFi-resistant (BR) melanomas are susceptible to arginine deprivation due to inability to initiate re-expression of argininosuccinate synthetase (ASS1, a key enzyme for arginine synthesis) as well as ineffective autophagy. Autophagy and ASS1 re-expression are known to protect melanoma cells from cell death upon arginine deprivation. When melanoma cells become BR cells by long-term in vitro incubation with BRAFi, c-Myc-mediated ASS1 re-expression and the levels of autophagy-associated proteins (AMPK-α1 and Atg5) are attenuated. Furthermore, our study uncovers that downregulation of deubiquitinase USP28 which results in more active c-Myc degradation via ubiquitin-proteasome machinery is the primary mechanism for inability to re-express ASS1 upon arginine deprivation in BR cells. Overexpression of USP28 in BR cells enhances c-Myc expression and hence increases ASS1 transcription upon arginine deprivation, and consequently leads to cell survival. On the other hand, overexpression of Atg5 or AMPK-α1 in BR cells can redirect arginine deprivation-induced apoptosis toward autophagy. The xenograft models also confirm that BR tumors possess lower expression of ASS1 and are hypersensitive to arginine deprivation. These biochemical changes in BRAFi resistance which make them vulnerable to arginine deprivation can be exploited for the future treatment of BR melanoma patients.”

p53 Reactivation by PRIMA-1Met (APR-246) sensitizes V600E/KBRAF melanoma to vemurafenib.  Krayem, Journe, Wiedig, et al.  Eur J Cancer.  2016 Jan 17. “Intrinsic and acquired resistance of metastatic melanoma to V600E/KBRAF and/or MEK inhibitors, which is often caused by activation of the PI3K/AKT survival pathway, represents a major clinical challenge. Given that p53 is capable of antagonizing PI3K/AKT activation we hypothesized that pharmacological restoration of p53 activity may increase the sensitivity of BRAF-mutant melanoma to MAPK-targeted therapy and eventually delay and/or prevent acquisition of drug resistance. To test this possibility we exposed a panel of vemurafenib-sensitive and resistant (innate and acquired) V600E/KBRAF melanomas to a V600E/KBRAF inhibitor (vemurafenib) alone or in combination with a direct p53 activator (PRIMA-1Met/APR-246). Strikingly, PRIMA-1Met synergised with vemurafenib to induce apoptosis and suppress proliferation of V600E/KBRAF melanoma cells in vitro and to inhibit tumor growth in vivo. Importantly, this drug combination decreased the viability of both vemurafenib-sensitive and resistant melanoma cells irrespective of the TP53 status. Notably, p53 reactivation was invariably accompanied by PI3K/AKT pathway inhibition, the activity of which was found as a dominant resistance mechanism to BRAF inhibition in our lines. From all various combinatorial modalities tested, targeting the MAPK and PI3K signalling pathways through p53 reactivation or not, the PRIMA-1Met/vemurafenib combination was the most cytotoxic. We conclude that PRIMA-1Met through its ability to directly reactivate p53 regardless of the mechanism causing its deactivation, and thereby dampen PI3K signalling, sensitizes V600E/KBRAF-positive melanoma to BRAF inhibitors.”

For what it's worth! - c

BRAF/MEK combined with immunotherapy!!!

I thought this was a very informative article regarding BRAF inhibitors, MEK inhibitors...what we've learned and where research is looking with those drugs.

Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy.  Eroglue and Ribas.  Ther Adv Med Onc. Jan 2016.

 Treatment with BRAF inhibitors such as vemurafenib or dabrafenib in patients with advanced BRAFV600 mutated melanoma has shown objective tumor responses in approximately half of the patients. However, the duration of responses is limited in a majority of these patients, with progression-free survival rates around 6 months due to tumor progression from development of acquired resistance. Preclinical studies have suggested that concurrent inhibition of the BRAF kinases and MEK of the mitogen-activated protein kinase (MAPK) pathway could decrease MAPK-driven acquired resistance, resulting in longer duration of responses, higher rate of tumor responses, and a decrease in the cutaneous toxicities observed from paradoxical MAPK pathway activation with BRAF inhibitor monotherapy. This review provides an overview of the currently available clinical trial data on BRAF and MEK inhibitors together and in combinations with other therapeutic agents.

The article goes on to report:  "About one half of melanoma patients carry the BRAF V600E mutation.  BRAF inhibitors illicit 48-59% response rates in those patients. However, duration of response is limited in most patients with a median PFS of 5-7 months “although a minority can last for over 5 years”.  BRAF inhibitors combined with MEK inhibitors improved things further with decreased side effects and increased PFS, amounting to 11-12 months depending on the combo.  It also reviews the importance of intermittent dosing as opposed to continuous therapy with BRAFi in order to delay resistance.  Other drugs combined with BRAF/MEK , like heat shock protein 90 (HSP90) inhibitors, like XL88 can overcome resistance.  There are also plans for additional studies using a triple therapy approach.

NCT01657591:  (Active, not recruiting) - Study of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma

NCT01902173:  (stopped for assessment) - Akt Inhibitor GSK2141795, Dabrafenib, and Trametinib in Treating Patients With Stage IIIC-IV Cancer

NCT02110355:  (recruiting) - A Phase 1b/2a Study Evaluating AMG 232 in Metastatic Melanoma

BRAF/MEK has provided response rates of up to 70% in trials but with limited durability of that response, researchers are looking at combining those drugs with checkpoint inhibitors like ipi, anti-PD1, or anti-PD-L1.  When dabrafenib, trametinib and ipi were combined patients experienced colitis with perforation.  So that arm was stopped, though the ipi and dabrafenib arm is ongoing.  Another trial is currently looking at dabrafenib, trametinib and anti-PD-L1 (MEDI4736).  So far, the ratties are demonstrating a 69% ORR and 16 of 18 patients have an ongoing response."

NCT02130466 is ongoing and recruiting:  A Study of the Safety and Efficacy of Pembrolizumab (MK-3475) in Combination With Trametinib and Dabrafenib in Participants With Advanced Melanoma (MK-3475-022/KEYNOTE-022)

 Here's a link to the whole paper:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699264/ 

Hope that helps, for what it's worth - c

BRAF testing via blood rather than tumor tissue

BRAF Mutation Testing in Cell-Free DNA from the Plasma of Patients with Advanced Cancers Using a Rapid, Automated Molecular Diagnostics System.  Janku, Huang, Claes, Falchook, et al.  Mol Cancer Ther. 2016 May 20.

Cell-free (cf) DNA from plasma offers an easily obtainable material for BRAF mutation analysis for diagnostics and response monitoring. In this study, plasma-derived cfDNA samples from patients with progressing advanced cancers or malignant histiocytosis with known BRAF ^V600 status from formalin-fixed paraffin-embedded (FFPE) tumors were tested using a prototype version of the Idylla BRAF Mutation Test, a fully integrated real-time PCR-based test with turnaround time about 90 minutes. Of 160 patients, BRAF ^V600 mutations were detected in 62 (39%) archival FFPE tumor samples and 47 (29%) plasma cfDNA samples. The two methods had overall agreement in 141 patients. Idylla had a sensitivity of 73% and specificity of 98%. A higher percentage, but not concentration, of BRAF ^V600 cfDNA in the wild-type background was associated with shorter overall survival and in patients with BRAF mutations in the tissue, who were receiving BRAF/MEK inhibitors, shorter time to treatment failure . Longitudinal monitoring demonstrated that decreasing levels of BRAF ^V600 cfDNA were associated with longer TTF . In conclusion, testing for BRAF ^V600 mutations in plasma cfDNA using the Idylla BRAF Mutation Test has acceptable concordance with standard testing of tumor tissue. A higher percentage of mutant BRAF ^V600 in cfDNA corresponded with shorter OS and in patients receiving BRAF/MEK inhibitors also with shorter TTF.

Quantitative assessment of BRAFV600 mutant circulating cell-free tumor DNA as a tool for therapeutic monitoring in metastatic melanoma patients treatd with BRAF/MEK inhibitors.  J Transl Med. 2016 Apr 19.  Schreuer, Meersseman, Van Den Herrewegen, et al.

BRAF V600 mutant circulating cell-free tumor DNA (BRAF V600mut ctDNA) could serve as a specific biomarker in patients with BRAF V600 mutant melanoma. We analyzed the value of BRAF V600mut ctDNA from plasma as a monitoring tool for advanced melanoma patients treated with BRAF/MEK inhibitors.

Allele-specific quantitative PCR analysis for BRAF V600 E/E2/D/K/R/M mutations was performed on DNA extracted from plasma of patients with known BRAF V600 mutant melanoma who were treated with dabrafenib and trametinib.

245 plasma samples from 36 patients were analyzed. In 16 patients the first plasma sample was obtained before the first dosing of dabrafenib/trametinib. At baseline, BRAF V600mut ctDNA was detected in 75 % of patients (n = 12/16). BRAF V600mut ctDNA decreased rapidly upon initiation of targeted therapy and became undetectable in 60 % of patients (n = 7/12) after 6 weeks of treatment. During treatment, disease progression (PD) was diagnosed in 27 of 36 patients. An increase of the BRAF V600mut ctDNA copy number and fraction, identified PD with a sensitivity of 70 % (n = 19/27) and a specificity of 100 %. An increase in the BRAF V600mut ctDNA fraction was detected prior to clinical PD in 44 % of cases (n = 12/27) and simultaneously with PD in 26 % of patients (n = 7/27).

Quantitative analysis of BRAF V600mut ctDNA in plasma has unique features as a monitoring tool during treatment with BRAF/MEK inhibitors. Its potential as an early predictor of acquired resistance deserves further evaluation.

The sensitivity and specificity numbers are pretty good here!  Plus, if we really could detect progression via a lab draw...earlier than we can with other assessments techniques....wouldn't that be awesome?  Patients...especially in the case of BRAFi could be placed on other therapies sooner...not to mention the earlier the heads-up in melanoma...no matter the treatment...the better!!

Prior posts regarding PCR testing: 
Nov 2015:  PCR testing for melanoma
Dec 2015:  Circulating tumor cells - how they may eventually impact melanoma diagnosis and response to therapy
Dec 2015:  PCR testing for circulating melanoma DNA - one more.... 
March 2016:  Biomarkers....  

Wishing you all my best - c

BRAF inhibitors for melanoma: Dabrafenib, Vemurafenib, Dabrafenib/trametinib combo. Answers!!!!!

"You have metastatic melanoma." Those words prompt immediate panic, fear, confusion, an onslaught of new tests, new terms, generalized and specific CRAZINESS!!!  The fact that every drug name seems to be some unreal combination of letters derived from a bizarre Czech language crossed with the imaginary "Unobtainium" from Pandora in Avatar only increases confusion.  Granted, even strangely named drugs and their greatly increased effectiveness compared to interferon and even IL-2 is a boon.  Yet, when vermurafenib (Zelboraf) was granted FDA approval in August of 2011, dabrafenib (Tafinlar) in May 2013, and the BRAF/MEK combo (dabrafenib and trametinib [Mekinist]) was approved just this past January, patients were left with even more questions.

What is BRAF??? The BRAF gene tells the cell how to make a protein (B-Raf).  This protein is part of a signaling pathway that regulates cell growth, movement, and death.  When the BRAF gene changes (mutates) and fails to give the correct instructions, cells can become cancerous.

Should I want to have this mutation? Hmmm, well if you didn't have the mutation, about 50% of melanoma patients wouldn't have melanoma.  A lot of folks with cardiofaciocutaneous syndrome, Noonan's syndrome, Langerhans cell histiocytosis, and Leopard syndrome, wouldn't be dealing with their disease either.  But, in order for BRAF inhibitors to work on melanoma, you do need to have that particular mutation in your tumor cells.

Do I have it?  Docs are now routinely sending tumors of melanoma patients (or should be) for mutation testing to include: BRAF, NRAS, and cKIT.  Older BRAF tests were less accurate so folks with tumors tested some time ago may need to have the newer tests done on their tumor to determine their status.

What's with all this V600 business? Most BRAF mutations occur at the same place on the gene... codon 600. At that spot on the gene, the proper amino acid, valine (V), has been changed to either glutamic acid (E) or lysine (K).  {I know...they should be V600G and V600L...right???} Anyhow, if you have BRAF V600E or K your tumor meets the criteria to be treated with BRAF inhibitors (dabrafenib, vemurafenib) or the MEK inhibitor (trametinib).

If one BRAF inhibitor doesn't work for me, will the other one?  Do they work on brain tumors? Short answers....yes.  More info below.

GENERAL INFO:

Dabrafenib and its potential for the treatment of metastatic melanoma.  Menzies, Lon, Murali.
Drug Design, Development and Therapy. December 2012. 

Summary points:

• BRAF mutations occur in 50% of melanomas; 70%–90% are V600E and 10%–30% are V600K.
• Selective (type 1) BRAF inhibitors (dabrafenib, vemurafenib) target mutant BRAF kinase and inhibit the MAPK pathway.
• Both drugs provide high response rates and rapid modes of action, but both are limited by the rapid development of acquired resistance. (About 70-80% of BRAF positive patients respond, but most tumors figure out a work around in about 7-8 months, though there are exceptions.)
  
• Both dabrafenib and vemurafenib are effective in treating BRAF^V600E melanoma patients, with prospective evidence of dabrafenib activity in BRAF^V600K melanoma and in those with brain metastases.
• Both drugs have similar toxicity profiles (Side effects include - arthralgias, rashes, extreme sun sensitivity, development of benign skin cancers and other fun stuff.); dabrafenib appears to have less cutaneous and hepatic toxicity than vemurafenib, but is associated with pyrexia [fever].
• Emerging combination strategies, such as the CombiDT, [the dabrafenib and trametinib combo] are designed to improve response and delay resistance. [It takes tumors much longer to find  a work-around and patients experience fewer side effects when they take the combo, than when they take a single BRAFi!]
  

BRAF therapy and BRAIN METS:

Patterns of response and progression in patients with BRAF-mutant melanoma metastatic to the brain who were treated with dabrafenib.  Azer, et al.   Cancer. 2/2014.

23 patients studied. Response rates in intracranial (78%) and extracranial (90%) sites.  Of 20 patients with progressive disease, 6 had IC progressive disease and 6 had progressive disease in EC only and 8 experienced progressive disease in both sites. 5 of 6 with isolated progressive disease to the brain underwent local therapy to the brain and continued on dabrafenib longer than 30 days.  Bottom line:  IC and EC tumors respond similarly to dabrafenib.

Vemurafenib in metastatic melanoma patients with brain metastasis: as open label, single-arm, phase 2 multicenter study.  Kefford, et al.

As of April 2013, 146 patients with melanoma brain mets (Patients had an average number of 3 mets...though the range was from 1-30.) were treated with vemurafenib.  In patients with previously untreated MBMs, vemurafenib produced a response in 61% of those patients. The median progression free survival was 3.7 months and the overall survival median was 7 months.  So...Vemurafenib works on brain tumors, too.


HOW TO DEAL WITH TUMOR WORK-AROUND:

Switching therapy pre-emptively from vermurafenib (Zelboraf) to ipilimumab (ipi/Yervoy) in patients with BRAF-mutated melanoma.  Angelo et al.  Memorial Sloan Kettering.

"Median time to progression on Zel is 6.9 months; 75% of patients progress by 1 year.  Once patients progress on Zel, melanoma sometimes grows too quickly for patients to benefit from subsequent ipi treatments.  In July 2011, researchers adopted a strategy of treating previously untreated patients with BRAF-mutated melanoma with Zel for a limited time, then, after maximal response but before developing resistance, switching to ipi. Review of 19 patients:  Initial plan = 4 months of Zel, was changed to 2 months after some patients progressed at 4.  All patients were switched to ipi and received a median of 4 doses starting at a median of 1 week after last dose of Zel. At the time of the first ipi dose, 8 patients had progressed on Zel, 11 had not, but 5/11 ultimately progressed on ipi and were retreated with Zel.  Among the 11 patients switched to ipi before progression, there have been no melanoma specific deaths to date (median follow-up = 1 year) compared to 7/8 deaths among patients who had progressed at the time of the switch.  There is potential selection bias in this small, on-going experience.  However, the results are consistent with a benefit of switching patients pre-emptively from a BRAF inhibitor to ipi prior to onset of resistance."

Response to BRAF inhibition in melanoma is enhanced by the addition of immune checkpoint blockade.  Cooper, Hodi, Flaherty, et al.  Mass General, Harvard, Dana Farber.

"BRAF targeted therapy results in objective responses in the majority of patients, however responses are short lived (about 6 months).  In contrast, treatment with immune checkpoint inhibitors results in lower response rates, though responses tend to be more durable.  We...have preliminary evidence that these two strategies may be combined to provide more durable responses. ...BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8+ T cell infiltration and a decrease in immunosuppressive cytokines.  However, there may also be an increased expression of the immunoinhibitory molecule PD-L1, which may contribute to resistance.  ...[So] we sought to test the hypothesis that responses to BRAF-targeted therapy would be enhanced by the addition of immune checkpoint blockade (like anti-PD1, anti-PDL1 and ipi).  [So....when poor ratties (really....rats) were given a BRAF(V600E) melanoma tumors, then BRAF targeted therapy combined with anti-PD1 and anti-PDL1], they demonstrated enhanced response, significantly prolonging survival and slowing tumor growth....suggesting that the addition of PD1 pathway blockade may augment responses to BRAF-targeted therapy. Clinical trials combining these two strategies are ongoing..."

COMBO of Dabrafenib and Trametinib (BRAF/MEK):

Note:  From Jan 22, 2014 post - I've mentioned before various trials have demonstrated that the combination of these meds created better responses and fewer side effects than when they were used alone.  Approval of the combination was based on the demonstration of durable objective responses in trials where objective response rates and response durations were 76% and 10.5 months with the combo and only 54% and 5.6 months in the single agent arm.  Squamous cell carcinoma was 7% in the combo arm, but was 19% in the single agent arm. The most common (at least 20% incidence) side effects experienced with the combination were:  fever, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia.  The most frequent complicated adverse events (with at least a 5% incidence) were:  acute renal failure, fever, hemorrhage, and back pain.

Phase I/II expansion cohort of BRAF inhibitor GSK2118436 + MEK inhibitor GSK1120212 in patients with BRAF mutant metastatic melanoma who progressed on a prior BRAF inhibitor.  Flaherty, Infante, Falchook, et al. Pigment Cell Melanoma Res. 2011;24 (1022):  Abstract.

"Additionally, in the Part B expansion cohort of patients with prior disease progression during [single] BRAF inhibitor treatment, an impressive 19% response rate was seen with CombiDT therapy."

I realize that for the uninitiated, non-medical person this is just a bunch of mess.  But, I tried to simplify things as much as possible and hope it helps answer some of the basic questions about BRAF, BRAF-inhibitors, and how researchers are trying to make them work better for melanoma patients.  Best - c

Does previous treatment with BRAF inhibitors affect response to immunotherapy in melanoma?

We have had conflicting reports over the years regarding BRAF status and immunotherapy - to include:  "Those folks do better."  "Those folks do worse."  "It makes no difference."  Likewise, there has been conflict regarding which therapy to do first - immunotherapy or targeted therapy with BRAF inhibitors - for those who are BRAF positive. Now there is this:

Correlation between previous treatment with BRAF inhibitors and clinical response to pembrolizumab in patients with advanced melanoma. Simeone, Grimaldi, Restino, et al. Oncoimmunology. 2017 Jan 19.

The optimal sequencing of targeted treatment and immunotherapy in the treatment of advanced melanoma is a key question and prospective studies to address this are ongoing. Previous observations suggest that treating first with targeted therapy may select for more aggressive disease, meaning that patients may not gain full benefit from subsequent immunotherapy. In a single-center retrospective analysis, we investigated whether response to pembrolizumab was affected by previous BRAF inhibitor therapy. A total of 42 patients with metastatic cutaneous or mucosal melanoma who had received previous treatment with ipilimumab were treated with pembrolizumab as part of the Italian expanded access program. Sixteen of these patients had BRAF-mutated melanoma and had also been previously treated with a BRAF inhibitor (vemurafenib or dabrafenib), while 26 had BRAF wild-type melanoma (no previous BRAF inhibitor). Patients with BRAF-mutant melanoma who were previously treated with BRAF inhibitors had a significantly lower median progression-free survival (3 versus not reached mo) and disease control rate (18.6% versus 65.4%;) than patients with BRAF wild-type, while there was also a trend toward a lower response rate (assessed using immune-related response criteria) although this was not significantly different between groups (12.5% versus 36.4%;). These data are consistent with previous reports that BRAF inhibitor therapy may affect subsequent response to immunotherapy.

Hmmm....  Not sure this is terribly elucidating.  I fear the "facts" in this report are much confounded!

1.   It would not surprise me to find that one day we consider mucosal melanoma and cutaneous melanoma to be two different diseases.  They are certainly not apples to apples.
2.  Pretreatment with ipi is KNOWN to decrease the response to anti-PD-1 (Pembro/Ketruda and Nivo/Opdivo)!  Remember this?  Sequential nivo then ipi = ORR of 41%. Ipi followed by nivo = ORR of 20%!!!! FDA! Are you listening???????
3.  Also, BRAF wild-type vs BRAF mutated - again, not apples to apples.
4.  What we need is a study in which one group of folks with cutaneous melanoma (or strictly mucosal melanoma) with BRAF positive status are treated with targeted therapy then given anti-PD-1 vs another BRAF positive group of folks are treated with anti-PD-1 followed by BRAFi.

It's just me, but... C'mon man!!!!  Hang in there, ratties!  - c

Better news for MEK and BRAF/MEK combos!

MEK (still available only in trials for melanoma) is a downstream inhibitor in the same pathway as the BRAF inhibitors.  Meaning - it turns off the signal the melanoma cells are getting to grow.  MEK162 seems to work in patients with NRAS mutations as well as those having V600 BRAF.  Patients with NRAS showed a 68% rate of clinical benefit per Sosman, quoted in Uptodate.com.  This is important since, while most MEK products have only been tested in V600 BRAF positive patients, at least one MEK product (MEK 162) has activity in, and is therefore an option for, patients who are not positive for the BRAF mutation, though it does require the NRAS mutation.  (Clear as mud, yes????)

In September of 2012 the New England Journal of Medicine published the article, "Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations."  By: Flaherty, Infante, Sosman, Falchook, Weber, et al. 

Basically, they noted that "resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted [trials] of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor."

So...in 247 patients with metastatic melanoma and  BRAF V600 mutations, they gave various doses of dabrafenib or trametinib to 85 patients and randomly assigned 162 patients to a combo of dabrafenib plus trametinib or dabrafenib only. (Seriously!!!  Who names this shit?????)

Anyhow...Squamous cell carcinoma was seen in 7% of patients getting the combo, but in 19% of patients getting monotherapy.  Fever was more common in the combo group. "Median progression-free survival in the [combo] group was 9.4 months, as compared with 5.8 months in the monotherapy group.  The rate of complete or partial response with combo therapy was 76% vs 54% with monotherapy."

Bottom line....despite increased fevers....the combination group did better in regard to fewer skin lesions and better in progression-free survival.

Meanwhile...the MEK inhibitor trametinib (GSK 1120212), according to a report in Nature Biotechnology, published online on Jan 9, "might be close to reaching the market". The writer reports that, on December 4, an FDA advisory committee "discussed the drug's effectiveness for treating unresectable or metastatic BRAF V600 mutation positive melanoma, including safety monitoring in light of ophthalmologic and cardiac toxicities observed in adults taking the drug." Several MEK products (MEK 162 from Novartis, AZD 6244 [called selumetinib] from AstraZenceca, GADC-0973 from Genentech, as well as trametinib from GlaxoSmithKline, noted above) are to be in Phase 3 trials in 2013. "Roche is also starting a phase 3 trial in melanoma combining its BRAF inhibitor (Zelboraf/vemurafenib) with Genentech's MEK inhibitor." "For now, trametinib is the only MEK inhibitor with major clinical data behind it..."   As demonstrated in the article I reported on above.  An assistant professor at Moffitt is quoted saying...."results may start to iron out as more companies go into bigger trials."

Bottom, bottom line(s)....
I am glad more MEK products are coming to trial.
I hope all of them work as they should....as melanoma patients will be desperately trying to get into these trials...and ratties will pay the price if they don't.
MEK products may turn out to be effective in a broader group of patients than originally thought.
It seems that combinations of MEK and BRAF inhibitors may be yet another way to make the amazing results of BRAF inhibitors more durable and their side effects more tolerable.

Keep making things better, ratties.  - c

BRAFi better when combined with or after immunotherapy and surgery!!!

Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade.  Cooper, Juneja, Sage, et al.  Cancer Immunology Research.  April 2015.

"BRAF targeted therapy results in objective responses in the majority of patients, however responses are short lived (approx - 6 months).  In contrast, immunotherapy results in lower response rates, but responses tend to be more durable. BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8+ T cell infiltrates and a decrease in immunosuppressive cytokines.  However, there is also increased expression of the immunomodulatory molecule PD-L1, which may contribute to resistance."  So, with that info these peeps figured that BRAF therapy may play well with the PD-1 pathway to get rid of tumors.  They produced mice with BRAF positive melanoma and found that sure enough BRAF inhibition increased intratumoral CD8+ T cell density and cytokine production like it does in people.  When they gave the mice anti-PD1 or anti-PD-L1 WITH the BRAF inhibitors the got an "enhanced response, significantly prolonging survival and slowing tumor growth, as well as significantly increasing the number and activity of tumor infiltrating lymphocytes....demonstrating synergy between combined BRAF-targeted therapy and immune checkpoint blockade."

Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy.  Wyluda, Cheng, Schell, et al.  Cancer Biol Ther.  March 2015.

"We report 3 cases of complete response in patients with BRAF-mutated metastatic melanoma who were initially treated unsuccessfully with sequential immunotherapies (HD IL2 followed by ipi with or without concurrent radiation).  After progression during or post immunotherapy, these patients were given BRAFi and developed complete responses.  Based on the concomitant presence of autoimmune manifestations (vitiligo and hypophysitis), we postulated that there was a synergistic effect between the prior immune therapy and the BRAFi.  Accordingly, the inhibitors were gradually weaned off beginning at 3 months and were stopped completely at 9-12 months.  The 3 patients remain well and in CR off all therapy at up to 15 months with radiographic follow-up....with high levels of non-T-regulatory CD4 positive effector phenotype T cells, which persisted after completion of therapy."


Successful (neo)adjuvant BRAF-targeted theapy in patient with locally advanced BRAF V600E mutant melanoma.  Seremet, Suppa, Trepant, et al.  Melanoma Research. January 2015.

62 year old patient, dx'd with Stage IIIB melanoma with large, inoperable, primary lesion surrounded by ~25 secondary satellite and intransit lesions.  She started on 960 mg daily vemurafenib.  Stopped and resumed at 720 mg twice daily.  Was then placed on combined dabrafenib and trametinib to decrease side effects.  Successive exams showed gradual reduction in the thickness of the lesion.  After about 5 months of therapy, surgery was performed and the path analysis showed almost complete regression of tumor cells.  Dabrafenib/trametinib therapy was continued only 3 months after surgery and stopped at the patient's request.  She remains in complete remission 8 months after surgery.

My thoughts:
1.  Really heartening to hear that BRAF inhibitors can improve outcomes in these patients.
2.  Especially so, when these responses are already more durable than is typically seen when BRAF inhibitors are given alone AND responses have continued with patients OFF the meds!!!
3.  Combining BRAFi and immunotherapy can cause real problems with side effects.
4.  Like the rest of us, it remains to be seen how durable these "durable" responses will be.

Go, ratties!  GO! - c

Treating melanoma by COMBINING targeted therapy AND immunotherapy!!

As usual, I've written on this topic previously:

As long ago as 2015, there was this:  BRAFi better when combined with or after immunotherapy and surgery!!!

And this in 2016:  BRAF/MEK combined with immunotherapy!!!

This from 2017:  The whole she-bang - immunotherapy WITH BRAF/MEK for melanoma...

This from ASCO 2017:  ASCO 2017: Atezo (anti-PDL1) with Cobimetinib (MEKi) and Vemurafenib (BRAFi) for BRAF V-600 melanoma

Now there are these reports (highlights = my own):

Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma.  Ribas, Lawrence, Atkinson, Agarwal, ..., Hodi, ..., Hamid.  Nat Med. 2019 Jun;25. Oncogene-targeted therapy with B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors induces a high initial response rate in patients with BRAFV600-mutated melanoma, with a median duration of response of approximately 1 year. Immunotherapy with antibodies to programmed death 1 (PD-1) produces lower response rates but with long response duration. Preclinical models suggest that combining BRAF and MEK inhibitors with PD-1 blockade therapy improves antitumor activity, which may provide additional treatment options for patients unlikely to have long-lasting responses to either mode of therapy alone. We enrolled 15 patients with BRAFV600-mutated metastatic melanoma in a first-in-human clinical trial of dabrafenib, trametinib and pembrolizumab ( NCT02130466 ). Eleven patients (73%) experienced grade 3/4 treatment-related adverse events, the most common being elevation of liver function tests and pyrexia, most of which resolved with drug interruption or discontinuation of either the anti-PD-1 antibody or the targeted therapy combination. Eleven patients (73%) had an objective response, and six (40%) continued with a response at a median follow-up of 27 months (range = 10.3-38.4+ months) for all patients. This study suggests that this triple-combined therapy may benefit a subset of patients with BRAFV600-mutated metastatic melanoma by increasing the frequency of long-lasting antitumor responses.

Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients.  Sullivan, Hamid, Gonzalez, et al.  Nat Med. 2019 Jun;25.

Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAF^V600 mutations. BRAF/MEK-targeted therapies have effects on the tumor microenvironment that support their combination with PD-1/PD-L1 inhibitors. This phase Ib study (ClinicalTrials.gov, number NCT01656642 ) evaluated the safety and anti-tumor activity of combining atezolizumab (anti-PD-L1) with vemurafenib (BRAF inhibitor), or cobimetinib (MEK inhibitor) + vemurafenib, in patients with BRAF^V600-mutated metastatic melanoma. Triple combination therapy with atezolizumab + cobimetinib + vemurafenib, after a 28-d run-in period with cobimetinib + vemurafenib, had substantial but manageable toxicity. Exploratory biomarker data show that the cobimetinib + vemurafenib run-in was associated with an increase in proliferating CD4⁺ T-helper cells but not with an increase in T-regulatory cells, as observed in the vemurafenib-only run-in period. The confirmed objective response rate was 71.8%. The estimated median duration of response was 17.4 months with ongoing response in 39.3% of patients after 29.9 months of follow-up. Further investigation in a phase III trial is underway.

Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors.  Hellmann, Kim, Lee, et al.  Ann Oncol. 2019 Mar 27.

Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a PD-L1 inhibitor, atezolizumab, in patients with solid tumors.

This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a dose-escalation stage and then in multiple, indication-specific dose-expansion cohorts. In most patients, cobimetinib was dosed once daily orally for 21 days on, 7 days off. Atezolizumab was dosed at 800 mg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary endpoints included ORR, PFS and OS.

Between 27 December 2013 and 9 May 2016, 152 patients were enrolled. As of 4 September 2017, 150 patients received greater than/= to 1 dose of atezolizumab, including 14 in the dose-escalation cohorts and 136 in the dose-expansion cohorts. Patients had mCRC (n = 84), melanoma (n = 22), NSCLC (n = 28), and other solid tumors (n = 16). The most common all-grade treatment-related adverse events (AEs) were diarrhea (67%), rash (48%) and fatigue (40%), similar to those with single-agent cobimetinib and atezolizumab. One (1%) treatment-related grade 5 AE occurred (sepsis). Forty-five (30%) and 23 patients (15%) had AEs that led to discontinuation of cobimetinib and atezolizumab, respectively. Confirmed responses were observed in 7 of 84 patients (8%) with mCRC (6 responders were microsatellite low/stable, 1 was microsatellite instable), 9 of 22 patients (41%) with melanoma, and 5 of 28 patients (18%) with NSCLC. Clinical activity was independent of KRAS/BRAF status across diseases.

Atezolizumab plus cobimetinib had manageable safety and clinical activity irrespective of KRAS/BRAF status. Although potential synergistic activity was seen in mCRC, this was not confirmed in a subsequent phase III study.

So - small numbers.  Pretty significant toxicity.  Only effective in the roughly 1/2 of melanoma patients who are BRAF positive.  Looks like BRAF/MEK with anti-PD-1/PD-L1 is demonstrating a 70% objective response rate while anti-PD-L1 with a MEK inhibitor alone attained a 40% response rate (ie = no better than the ipi/nivo combo).  Again, no matter the result...small numbers treated (only 37 melanoma patients total were in the first and last studies reported here - and Hamid et al ain't sharing their #'s unless you buy the paper - FYI).  Still, throwing the "kitchen sink" at melanoma may be a worthwhile treatment for some.

Hang tough ratties!!! - c

Melanoma patients want to know! What do I choose? Targeted or immunotherapy? What happens then?

We melanoma patients all want to know!  Should I opt for targeted or immunotherapy?  What happens to me during treatment?  What happens after?  While there are no absolutes, here are some reports that attempt to provide a few answers.

TARGETED THERAPY:

The first addresses outcomes in Stage III/IV patients treated with the targeted therapy combo, Dabrafenib plus trametinib:

Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma.  Robert, Grob, Stroyakovskiy, et al.  N Engl J Med. 2019 Jun 4. 

Patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors.

We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively.

A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (17 to 24) at 4 years and 19% (15 to 22) at 5 years. The overall survival rates were 37% (33 to 42) at 4 years and 34% (30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (62 to 79) at 5 years.

First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.

Here are some links to earlier posts on the subject:
2014:  BRAF inhibitors for melanoma: Dabrafenib, Vemurafenib, Dabrafenib/trametinib combo. Answers!!!!!

2015:  BRAFi: What predicts resistance? Discontinuation after complete remission? Dabrafenib/trametinib combo and quality of life?

2016:  Factors predictive of response, progression and OS with dabrafenib and trametinib

Also from 2016:  ASCO 2016 - Cobimetinib and Vermurafenib - coBRIM study

IMMUNOTHERAPY:

For comparison to the targeted therapy outcomes above, here's a report on immunotherapy from the dark ages of 2014:  Review of immunotherapy and durable benefit in melanoma!!!

This report documents the 4 year outcomes for ipi/nivo vs nivo alone for melanoma patients from December 2018:  CheckMate 067 - 4 year outcomes for nivo/ipi combo vs nivo alone in melanoma patients 

2019:  IPI/NIVO - results - in melanoma brain mets and long term follow-up in advanced melanoma

LOS DOS:

Here is a report from this year (with many links within) on combining targeted and immunotherapy:
Treating melanoma by COMBINING targeted therapy AND immunotherapy!!

HOW RATTIES REPORT THEY WERE AFFECTED BY EITHER TREATMENT:

Here are the results of a survey of 105 melanoma patients treated with either immunotherapy or BRAF/MEK who had an "objective response or stable disease" and were asked about the impact of said treatment on their lives:

The survivorship experience for patients with metastatic melanoma on immune checkpoint and BRAF-MEK inhibitors.  Lai-Kwaon, Khoo,Lo, et al.  J Cancer Surviv. 2019 Jun 4. 

Immune checkpoint inhibitors (ICI) and BRAF and MEK inhibitors (BMi) have improved survival in metastatic melanoma (MM). However, the experience of long-term responders remains undescribed. This study characterised survivorship issues faced by long-term responders to ICI or BMi.

Patients with MM, aged greater than/equal to 18 years old, greater than/= to 6 months post-ICI or BMi initiation with an objective response or stable disease. A 72-question survey assessed physical and psychological effects, impact on lifestyle, access to information, satisfaction with care, and availability of supports.

One hundred and five of 120 (88%) patients completed the survey (ICI 69/BMI 36). For the ICI cohort, 39 (57%) were receiving ongoing treatment, 17 ceased due to toxicity and 13 due to a sustained response. For the BMi cohort, 31 (85%) were receiving ongoing treatment, 4 ceased due to toxicity and 1 due to a sustained complete response. At data cut-off on 18 December 2018, median PFS (range) was 2.5 years (1.3-8.5) for ICI and 3.1 years (0.6-7.3) for BMi. Long-term toxicities included dry/itchy skin (ICI 51, 74%/ BMi 25, 69%), arthralgias (ICI 30, 58%/ BMi 23, 64%) and fatigue (ICI 62, 90%/ BMi 33, 92%). Psychological morbidity was common, including anxiety awaiting results (ICI 50, 72%/ BMi 29, 81%), fear of melanoma recurring or progressing (ICI 56, 81%/ BMi 31, 86%) or death (ICI 44, 64%/ BMi 26, 72%).

MM survivors experience chronic treatment toxicities and frequently report psychological concerns.  Survivors may benefit from discussions regarding long-term toxicities and tailored psychological supports

WHAT TREATMENT TO CHOOSE:

If you are lucky enough to be a BRAF positive melanoma patient (about 1/2 of us) you have the option of targeted therapy or immunotherapy.  But picking which therapy to utilize is really tough for melanoma patients.

Here is some advice from some Melanoma Big Dogs in 2015:  Pick your poison: Weber and Agarwala discuss combination therapy for melanoma

Some advice on sequencing from 2018:  ASCO 2018 - Optimal sequencing of anti-PD-1 and BRAFi in Stage III patients

This post includes a report on what ratties have to consider re immunotherapy:  Balancing the Hype with Reality: What Do Patients with Advanced Melanoma Consider When Making the Decision to Have Immunotherapy?

Here is advice and thoughts from Weber and Allison this year:  Progress in the Treatment of Advanced Melanoma: Where We Are Now, and Why the Future Is So Promising 

Melanoma gives us no easy answers. Yet, we continue to learn more about the disease and more about how to survive it!!  Hang tough, ratties.  Hang tough. - c