Sequential nivo then ipi = ORR of 41%. Ipi followed by nivo = ORR of 20%!!!! FDA! Are you listening???????

 As Weber alluded to in the webinar included in my last post...the synopsis thus far, of the CheckMate 064 trial with sequential Ipi followed by Nivo vs Nivo followed by Ipi was put out today at the 2015 European Cancer Congress.

BOTTOM LINE:  Folks who got nivo first followed by ipi had slightly more side effects (roughly 50 vs 43%) but they also had objective response rates of 41.2% vs only 20% in the ipi first group!!!!!!!!!!!!!!!!  Here's a link to an OncLive report:  Nivolumab before ipilimumab has greater efficacy, similar AEs

My thoughts:  Boy, do we ever owe the ratties in this one!  Not to mention, all the folks who took ipi first (with its higher side effect profile, response rate of 10-15%) instead of anti-PD1 (with its much lower side effect profile and response rate of 40-45%) because the FDA in all their wisdom said so!!!  So all those folks on some boards and one ridiculous onc in particular....telling folks, "Oh, don't worry your pretty little head about it....the effects will be additive...no matter the order."  Really, sir?  NOT!!!  No, I am not in a good mood.  I am not a happy girl.  I am rather brokenhearted.  I am so sorry for all of those who had to suffer and reap fewer benefits than the lucky few of us who got a go at it the other way round.  I realize that these results are not all gloom and doom.  The arm that got the ipi followed by nivo, still beat plain ipi response rates with the 20% they attained. One other thing to keep in mind that this data indicates thus far....is that the ipi/nivo COMBO, provides still better responses (58% vs 40%).  But....the way the FDA works, trials work, and pharma works...has me very upset at the moment.  However, the love and admiration I feel for the ratties is something I do not have the words to express.  God bless you everyone.  We are forever in your debt.  Much love and thanks, les

owed an objective response rate at 25 weeks of 41.2% among patients who received nivolumab first versus 20.0% in those who started treatment with ipilimumab. The unconfirmed response rates were 47.7% with nivolumab first and 22.6% with ipilimumab first. At 25 weeks, 38.2% of patients had progressed in the nivolumab-first arm versus 60% with ipilimumab-first group.
- See more at: http://www.onclive.com/conference-coverage/ecc-2015/nivolumab-before-ipilimumab-has-greater-efficacy-similar-aes#sthash.xCTrkmYZ.dpuf

showed an objective response rate at 25 weeks of 41.2% among patients who received nivolumab first versus 20.0% in those who started treatment with ipilimumab. The unconfirmed response rates were 47.7% with nivolumab first and 22.6% with ipilimumab first. At 25 weeks, 38.2% of patients had progressed in the nivolumab-first arm versus 60% with ipilimumab-first group.
- See more at: http://www.onclive.com/conference-coverage/ecc-2015/nivolumab-before-ipilimumab-has-greater-efficacy-similar-aes#sthash.xCTrkmYZ.dpuf

showed an objective response rate at 25 weeks of 41.2% among patients who received nivolumab first versus 20.0% in those who started treatment with ipilimumab. The unconfirmed response rates were 47.7% with nivolumab first and 22.6% with ipilimumab first. At 25 weeks, 38.2% of patients had progressed in the nivolumab-first arm versus 60% with ipilimumab-first group.
- See more at: http://www.onclive.com/conference-coverage/ecc-2015/nivolumab-before-ipilimumab-has-greater-efficacy-similar-aes#sthash.xCTrkmYZ.dpuf

Here's the abstract itself:

showed an objective response rate at 25 weeks of 41.2% among patients who received nivolumab first versus 20.0% in those who started treatment with ipilimumab. The unconfirmed response rates were 47.7% with nivolumab first and 22.6% with ipilimumab first. At 25 weeks, 38.2% of patients had progressed in the nivolumab-first arm versus 60% with ipilimumab-first group.
- See more at: http://www.onclive.com/conference-coverage/ecc-2015/nivolumab-before-ipilimumab-has-greater-efficacy-similar-aes#sthash.xCTrkmYZ.dpuf

 Abstract from European Cancer Congress 2015

An open-label, randomized, phase 2 study of nivolumab (NIVO) given sequentially with ipilimumab (IPI) in patients with advanced melanoma (CheckMate 064)

Speaker: F.S. Hodi (USA) [Hodi, Horak Weber, Ruisi, Slingluff, et al.]

Background: The results of a phase 3 study in advanced melanoma showed improved progression-free survival with the combination of NIVO at 1mg/kg and IPI at 3mg/kg vs. IPI alone, with an objective response rate (ORR) of 58% and grade 3/4 treatment-related adverse events (AEs) in 55% of patients (pts). The current phase 2 study evaluated the efficacy and safety of NIVO followed by IPI vs IPI followed by NIVO in advanced melanoma.

Materials and Methods: Eligible pts had unresectable stage III or IV melanoma, were treatment-naïve or had received one prior systemic therapy, had an ECOG performance status of 0 or 1, and were enrolled regardless of BRAF mutational status. Pts from 9 US sites (N=140) were randomized 1:1 to receive sequential induction treatment with NIVO 3mg/kg IV Q2W x 6 doses followed by IPI 3mg/kg IV Q3W x 4 doses (cohort A; N=68) or IPI 3mg/kg IV Q3W x 4 doses followed by NIVO 3mg/kg IV Q2W x 6 doses (cohort B; N=70). Following induction treatment, both cohorts received NIVO 3mg/kg IV Q2W until progression or unacceptable toxicity. The primary objective was to evaluate treatment-related grade 3–5 AEs during the induction periods.

Results: During the induction periods, treatment-related grade 3–5 AEs occurred in 50.0% and 42.9% of pts in cohorts A and B, respectively [Table]. Across study periods, the incidence of treatment-related grade 3/4 AEs was higher in cohort A. There were no study drug-related deaths in either cohort. By modified RECIST v1.1 (requiring confirmation at week 33), ORR at week 25 was 41.2% in cohort A vs. 20.0% in cohort B, with a lower progression rate in cohort A.

Conclusions: The results demonstrate improved efficacy outcomes with NIVO followed by IPI vs. IPI followed by NIVO in advanced melanoma, with a similar incidence of treatment-related AEs during the induction periods. The nature of AEs was similar to that previously observed with either agent, alone and in combination, whereas the frequency of AEs was consistent with previous reports for NIVO plus IPI. Further data from this study may inform the choice of treatment regimens in advanced melanoma.

Efficacy	Week 13		Week 25
	Cohort A (N=68)	Cohort B (N=70)	Cohort A (N=68)	Cohort B (N=70)
Complete response	0	0	0	0
Partial response, n (%)	24 (35.3)	7 (10.0)	28 (41.2)	14 (20.0)
Confirmed ORR, % (95%CI)*	−	−	41.2 (29.4,53.8)	20.0 (11.4,31.3)
Progression rate, % (95%CI)**	38.2 (26.7,50.8)	61.4 (49.0,72.8)	38.2 (26.7,50.8)	60.0 (47.6,71.5)

Pick your poison: Weber and Agarwala discuss combination therapy for melanoma

Combining immunotherapy and targeted drugs for melanoma: Weber and Agarwala
(Late note:  since publication of this post, the link above has been taken down.  However, the points below are my transcription of their commentary. - c, 2018)

The link above connects to a video discussion and slides by Dr. Jeffrey Weber and Dr. Sanjiv Agarwala regarding combination therapies and other treatment information as it relates to melanoma.  Much like the prior link I discussed, material is presented in an understandable manner in the form of a continuing education program for general oncologists and others in the field...from the horse's mouth.

Points I noted:

• BRAF is the only predictive marker for the use of BRAF inhibitors.
• 40-50% of melanoma is BRAF positive.
• The RAS-RAF-MEK-ERK MAP kinase pathway is a critical signaling path in melanoma.
• MELANOMA SUB-TYPES via landscape as origin:  
• Skin with sun damage = 50% BRAF, 20% NRAS, 0 KIT
• Skin without chronic sundamage = 22% BRAF, 0 NRAS, 19% KIT
• Mucosal = 9% BRAF, 12% NRAS, 25% KIT
• Acral = 22% BRAF, 16% NRAS, 24% KIT
• BRAF resistance develops due to reactivation of the MEK pathway.  This is why the addition of MEKi to BRAFi prevents that resistance, thereby increasing effectiveness and decreasing side effects.
•  The COMBI-d trial (dabrafenib plus trametinib vs dabrafenib alone), the Combi-V trial (dabrafenib and trametinib vs vemurafenib alone) and the CoBRIM trial (vemurafenib with cobimetinib vs vemurafenib and placebo) all demonstrate the effectiveness of combination therapy when compared to one targeted therapy alone.

Here's a link addressing BRAFi info out this year as well as earlier articles about BRAFi combo's:   BRAFi : What predicts resistance.
Here's a link regarding an article this year that addressed CoBRIM as well as PDL1 in immunotherapy combinations (which the docs address later in the video as well.):  Combos looking good but if PDL1 positive - just do nivo!

 IMMUNOTHERAPY:

• CTLA4 and PD1 put brakes on the immune system (in 2 different areas, in different ways), but ultimately prevent T cells from eradicating melanoma and other cancers.  When you turn CTLA4 and PD1 "off" with ANTI-CTLA4 (ipilimumab) and ANTI-PD1 (Nivolumab/Opdivo or Pembrolizumab/Keytruda) you allow T cells to engage and do their job.
• Studies with ipi show a plateau in overall survival of 22% at 3 years.
• When ipi is combined with GM-CSF, 1 year OS is 68% vs 52% in ipi alone.
• When ipi is combined with T-VEC (an intralesional therapy) you get a better response rate...about 55% combined complete and partial responses....than with either drug alone. NOTE: You can find more info on GM-CSF using the search bubble on my blog.  Here's a link to some of the latest on intralesional therapies out of ASCO 2015:  Intralesional therapy for melanoma: ASCO 2015
• Some questions remain with ipi: What is the optimal dose?  3mg/kg vs 10mg/kg? The 169 trial is a randomized Phase 3 trial, ongoing, looking at differences in dosage.  Trials are looking at whether ipi should be administered in the current 4 dose - then stop, protocol...or are maintenance doses helpful?  Weber feels 4 doses are sufficient, but trial results are still pending.
• Ipi as adjuvant?  The 1609 trial is looking at this question and the 10mg/kg dose is showing promise, results to be out in about a year or 2.
• Overall, ipi is showing a 10-15% response rate, BUT...there are significant numbers of those demonstrating 10 YEAR survival.
• Anti-PD1 (both products) give clearly greater responses than traditional chemo and better than ipi as well...with an overall response rate of about 40-45%.
• Folks with tumors that are positive for PD-L1 respond better to anti-PD1 products.   However, many problems remain with the clarity of the test, availability of the test, consistency of results, etc.  Therefore, it is a useful...though not a predictive...marker.
• Because CTLA4 and PD-1 work differently...combining the two antibodies....can provide even better responses.  Additionally, ipi failures can respond to anti-PD1 and anti-PD1 failures can respond to ipi.
• In an early combo study of nivo and ipi, patients experienced an ORR of 53% and 40% had significant tumor reduction.
• In another nivo/ipi combo study, there was a 61% response rate and 22% rate of complete response on the combo vs 11% and none with ipi alone.
• In PD-L1 positive patients: those in the combo had a 58% overall response vs 18% ORR to ipi alone.  PD-L1 negative patients: had an ORR of 55% to the combo vs 4% ORR to ipi alone.
• Responses were durable.  Almost all responders continued to maintain their response at a rate of 82%.  Even of patients who had to stop treatment due to side effects, 2/3 of them continued to respond.
• Grade 3/4 toxicities increase almost as much as the response in the combo with a rate of 55%, though almost all are reversible.
• In the CA209-067 study, the ipi/nivo combo was compared to ipi alone and nivo alone.  ORR were 57.6% for the combo, 19% for ipi alone and 43.7% for nivo alone.
• However, when looking at PD-L1 staining:  When positive, the difference between PFS with the ipi/nivo combo vs nivo alone is negligible. So the argument may be made to go with nivo alone...since the difference in response is minimal, but side effects are much less.  However, more definitive studies are needed.
• The ipi/nivo combo overall is providing increased response rates and increased progression free survival.  
• Survival may even be better with the combo than with sequential nivo or ipi.
• However, for PD-L1 positive patients (40% of the population) concurrent therapy may be no better than nivo alone, followed by ipi if there is progression.
• For PD-L1 negative patients, the majority of patients, the ipi/nivo combo is better than a single agent, though you have to keep in mind that fewer than 1/2 of responding patients are able to tolerate the combo longer than 24 weeks.
• A study is underway looking at planned sequential therapy giving patients ipi followed by nivo, OR nivo followed by ipi....with nivo maintenance....preliminary results to be out within a week at meeting in Vienna.
• HOW TO DECIDE, in the BRAF positive patient....between immunotherapy single vs combo vs BRAF inhibitors.  These docs report that they tend to treat indolent patients with anti-PD1 alone.  However, in patients with increased LDH and a heavy disease burden, they would lean toward using BRAFi or the ipi/nivo combo.  Or to put it another way:  BRAF positive and negative patients do equally well on anti-PD1, so BRAF positive patients with indolent disease and low tumor burden, would probably be wise to place on immunotherapy.  In fast growing disease, with a high disease burden...and BRAF positive...use a BRAF/MEK combo first.  If BRAF negative - use the ipi/nivo combo.
• Question with no current answer:  With a patient who initially responded to nivo, but then progresses...should you switch to ipi or ADD ipi?  Docs feel that a trial looking at survival with these two options should be done...though it is NOT underway currently.
• Final thought, ipi is no longer these doc's first line drug choice when used alone.  They feel that anti-PD1, even as a single agent, is going to prove to have durable responses. While ipi combo's are going to be very important.

Long, I know.  Hope it helps. - c

Side effects and how to manage them in targeted and immunotherapy for melanoma

A Team Based Approach to Melanoma: Managing Side Effects with Weber and Agarwala
(Late note:  since publication of this post, the link above has been taken down.  However, the points below are my transcription of their commentary. - c, 2018)

In the link above, Dr. Jeffrey Weber and Dr. Sanjiv Agarwala provide a video discussion, with slides, regarding side effects as well as their treatment for ipi, anti-PD1, and BRAFi.  While none of the information provided is terribly "new" it is presented in an understandable manner in the form of a continuing education program for general oncologists and others in the field...from the horse's mouth.

Here are the points that stuck me:

• Most common side effects with anti-PD1 and anti-CTLA4 are:  dermatitis, enterocolitis, hepatitis and endocrinopathies.
• Toxicity does not equal response, but there appears to be a weak association.
• Order of appearance of side effects typical in anti-PD1 = skin, gastric, hepatic, pulmonary, endocrine, then renal...with most of these occurring  before week 12 of therapy.
• HOWEVER:  Both docs note that side effects, new to the patient, CAN occur late as well.  Specifically pointing out that patients can sometimes demonstrate the onset of a new side effect AFTER the 4th dose of ipi or after even 18 months out with anti-PD1.
• Lo and behold!!!!!  Docs have deemed side effects cumulative!!!!!!!!!!!!!!  Meaning they may start off very mild...but can, at times, progress to the point that the patient has to be taken off therapy.  Dr. Weber specifically notes that arthralgias and fatigue can certainly develop in this manner.

Just in case you have forgotten my small rant on this concept of CUMULATIVE EFFECTS...that I realized was a FACT some time ago!!!    Side effects of nivolumab: My thoughts...

• Again, the docs note that side effects have a weak association with effect, but folks with lots of side effects may NOT respond, while those experiencing very few side effects may still gain a positive response. 
• Steroids SHOULD be used to treat side effects, sooner rather than later.  The greater the grade of the side effect, the higher the dose of prednisone needed, with a longer taper.  STEROID USE DOES NOT DIMINISH RESPONSE!!!!
• TELL YOUR DOC....if you think you are experiencing a side effect.
• Side effects for BRAF/MEK drugs:
• Vemurafenib:  PHOTOSENSITIVITY, liver problems, rash
• Dabrafenib:  rash, FEVER
• Trametinib:  rash, diarrhea, RETINOPATHY
• As you can see...there are different problems with each.
• BRAF/MEK inhibitor side effects can be addressed via:  dose decrease, drug holiday, steroid use, and alternative dosing schedules.
• While the combining of any medications usually leaves the patient at risk for MORE side effects, combining targeted therapies has DECREASED side effects and increased efficacy!
• Pseudoprogression in immunotherapy:  Tumors can enlarge after the start of immunotherapy due to the influx of lymphocytes to the lesion.  (However, all the data I can find shows that this only happens about 5% of the time.)
• While some patients have a rapid response, others may be slower to respond:  "Be patient with the patient."
• PDL1 staining - a subject still up in the air...but:  The presence of PDL1 is predictive of a high rate of response to anti-PD1 drugs, but should not be used to decide treatment.  A staining test for PDL1 is not currently readily available nor consistent with the results provided. 
• Data shows that patients with a NEGATIVE PDL1 stain, can still attain a 20% response rate to anti-PD1 therapy.  Patients with a POSITIVE PDL1 stain are demonstrating response rates greater than 40%.

Hope this helps.  Thanks for sharing, Stevie!!! - c

As summer fades...

Despite my anticipation for a lovely fall in one of the most beautiful places to admire it...I can't help but look back to the beauty hikes in and around Cades Cove shared with me this past summer...

In early spring there are banks of mountain laurel to admire.  A bit later the rhododendrons follow in their full glory.  While beautiful, this picture does no real justice to the canopy of rhodies that surrounded us on so many trails.

There are always critters.....of various sorts and sizes...

 

Beautiful glades of poplars rival the red woods.  Especially since fairies sing and dance here...

 

Wild rhododendrons in bloom...creek side....

 

 

Even MY garden....made me smile.  Happy Autumn.  Love - c

A new option for brain mets...Involved-field fractionated radiotherapy - a step between SRS and WBR

Resection Followed by Involved-Field Fractionated Radiotherapy in the Management of Single Brain Metastasis.  Shim, Vatner, Tam, et al.  Frontiers of Oncology.  Sept 2015. 

We expanded upon our previous experience using involved-field fractionated radiotherapy (IFRT) as an alternative to whole brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) for patients with surgically resected brain metastases.

All patients with single brain metastases who underwent surgical resection followed by IFRT at our institution from 2006-2013 were evaluated. Local recurrence-free survival, distant failure-free survival and overall survival were determined. Analyses were performed associating clinical variables with:  local recurrence, distant failure, salvage approaches and toxicity of treatment for each patient.

Median follow-up was 19.1 months. Fifty-six patients were treated with a median dose of 40.05 Gy/15 fractions with IFRT to the resection cavity. Local recurrence-free survival was 91.4%, distant failure-free survival was 68.4%, and overall survival was 77.7% at 12 months. No variables were associated with increased local recurrence, however melanoma histopathology and infratentorial [below the membrane that divides the celebellum from the cerebrum...a so called eloquent area of the brain] location were associated with distant failure on multivariate analysis. Local recurrences were salvaged in 5/8 patients, and distant failures were salvaged in 24/29 patients. Two patients developed radionecrosis.

Adjuvant IFRT is feasible and safe for well-selected patients with surgically resected single brain metastases. Acceptable rates of local control and salvage of distal intracranial recurrences continue to be achieved with continued follow-up." 

Thoughts:  These numbers look pretty good, though IFRT is addressed through only in 56 patients and there is no documented comparison between results of SRS and WBR vs IFRT noted here.  There is no mention of cognition post procedure as compared to patient's ability before.  And...while brain mets here were clearly due to a variety of cancers...leave it to melanoma to be the bad boy in the room.  At any rate, perhaps it will at least come to be one more option that folks with brain mets can think about with their doc.

Best - c

An aspirin a day...keeps melanoma at bay....and makes immunotherapy work better!!!!

We have long known that NSAID's (nonsteroidal anti-inflammatory drugs) decrease the risk of many cancers.  For instance:

"NSAID's, including aspirin, decrease the incidence and mortality from colon cancer in humans by 45% to 50%."  DuBois, Cancer Research, 56(4), 1996.

That's old, y'all!!!  More recently, (well, in 2012) researchers in Denmark looked at the medical records of 18,000 people from 1991-2009 and found that: "people who had taken aspirin, ibuprofen and related painkillers -- especially at high doses and for years at a time -- were less likely to get skin cancer, compared to those who rarely used those medications.  The findings add to growing evidence that long-term use of the medications, known as nonsteroidal anti-inflammatory drugs, or NSAIDs, may help protect people against skin cancers, including melanoma, the deadliest type."  Common painkillers tied to lower skin cancer risk

And now....there's this from Zelenay et al., Cell, September 2015:  Cyclooxyenase-dependent tumor growth through evasion of immunity

Which sounds very fancy....but here's the deal:   To back up a step -  NSAIDs block an enzyme, cyclooxygenase (also called: COX1 and COX2).  Blocking those enzymes, blocks the production of prostaglandins.  Soooo..... These researchers used genetically modified mice to research the role of prostaglandins in blocking immune rejection of tumors.  Aspirin and similar NSAIDs stop the production of prostaglandins, thereby allowing immune cells to kill tumors more easily and enhancing the checkpoint inhibitors like anti-PD1 (nivo/opdivo and pembro/keytruda), anti-PDL1, and anti-CTLA4 (ipililmumab).  They note:

• Prostaglandins in tumors interferes with immune cell function.
• Blocking cyclooxygenase in tumors restores immune cell function.
• The cyclooxygenase blockers (NSAIDs) increase the action of checkpoint inhibitors.
• This mechanism is shared by mouse and human tumor systems.

My thoughts:  While you can find conflicting reports regarding effects of NSAIDs and this latest study was done with real ratties (ie the 4 legged kind!!), the benefit of COX inhibitors in the form of NSAIDs sounds like a pretty common sense, low risk, and reliable finding to aid patients' results from immunotherapy.  I am certain that my study did NOT control for NSAID use, but I imagine it is a pretty rare anti-PD1 patient who does not utilize ibuprofen to deal with arthralagias and other aches and pains the therapy produces!!  I know I certainly lived on advil and benadryl to deal with my rashes and beat up joints.  Of course, the next step will be an examination of the application in human ratties....  So, time will tell.  But, I think I'll keep taking my ibuprofen....unless Bentie makes me switch to aspirin!!!

Love - c

Sew Chaotically! - Home decor!

I've posted my sewing adventures on this blog from time to time and am always very tickled when folks notice and/or comment, likewise for my crazy cooking commentary.  My peeps have encouraged me to develop a separate sewing blog...or to write a cookbook.  I've thought about it...but...  Blogging takes considerable time and effort.  I can't tell you the number of blogs I've followed that rapidly disappear.  Nothing.  Finis.  No more...anything.  And...who knows?  That may happen here as well. But, for now....here's the deal.  I know, by a huge percentage, that folks check in to learn the latest on melanoma and its treatments.  That's great and that will continue.  However, those folks are probably not interested in cooking an octopus or black silkie chicken....and I understand that.  By the same token, those who are interested in cooking and sewing may not be so interested in the latest research on melanoma. SO....welcome to the new installments:

Sew Chaotically! And..... From Someone Else's Kitchen....  

When you see these headings....take 'em....leave 'em...enjoy them as you will.  Here goes:
                       Sew Chaotically! - Home decor!
I had a great time making some things for Roo's new place.  The work was mine....but the inspiration and design were all hers.  It was fun.  Here's what we did:

Well loved fabric, previously used as pillow covers, got a new lease on life as a window covering!

Got a cloth napkin you like?

A few nips and tucks with ribbon ties attached and you have a cute chair cover!

Or a new pillow cover....

...with bright colored remnants for the back.

Prior inhabitants leave old, dull, floor length panel drapes behind?  Bleach them out. Chop them down to size.  Hem to fit.  Attach colored buttons that match your aesthetic and add interest.

Use the bottom of the curtains you chopped off to recover old pillows.  Top them with a crocheted front....

...if the cozy, country look suits you.

Got fabric scraps?  Make a "quilt"!  No, it's not really quilted.  Rather, it's pieced and backed with an old, but thick, fleece blanket all covered by an old sheet.

Bright yellow embroidery thread was used to tie all the layers together after the edges were stitched, but hadn't yet been placed in this pic.  (P.S. Getting a pic of an entire quilt is hard!)  And to pull it all together...the last fabric used to edge the quilt....

...was used in the curtains made for the room.

A shower curtain, backed by a clear plastic one, hung on the same rod, was easy enough and lets you do things your way with window dressings to match if you like.  Thanks for letting me play at your place, Roo.  As for me....I'm looking forward to the next installment of Sew Chaotically! and the introduction of From Someone Else's Table.  Much love - c

Gregory Bald...one of the great wonders of the world!!!

When I first heard folks speak of the "balds" in the Smoky Mountains....I envisioned some sort of open expanse of barren rock.  Boy, was I wrong.  They are lovely meadows, often on a peak somewhere, with no clear explanation for their existence.  Everything from cattle grazing, to lightning strikes has been hypothesized, but geographers and scientists don't feel that they have hit on the real origin.  I have no idea.  I am only in awe.  The 11.5 mile up and back to Gregory Bald in June is nothing short of one of the true wonders of the world. The hike itself is lovely through beautiful woods and climbing trails.  When you reach the top...the bald opens magically before you...covered in the most beautiful flame azaleas...in dazzling colors....with incredible vistas of surrounding valleys....  Words cannot do it justice.  It was more beautiful, surprising, dream-like, and incredible than the Grand Canyon.  If you ever get the opportunity, take it.  Until then....enjoy:

After wandering about in such surroundings, sharing a lovely picnic lunch, and counting our blessings for one more glimpse of this beautiful world....we headed back to Cades Cove.

Hey, Bentie!!! C'mon down!!!!

- c