ASCO 2018 - PIVOT, PIVOT, PIVOT!!!!! (Sorry, FRIENDS flashback to Ross moving a couch in a stairwell!!!) But, really - NKTR-214 plus nivo

Okay.  SO, yeah...the trial's name gave me major FRIENDS flashbacks....but all 4 of my boys (B, J, Eric, and Ed) sent me the bones of this report in varied forms!  There was this...

NKTR-214 (CD122-biased agonist) plus nivolumab in patients with advanced solid tumors: Preliminary phase 1/2 results of PIVOT. Diab, Hurwitz, Cho, … Sznol. ASCO 2018.

PIVOT is an ongoing, open-label, phase 1/2 study of NKTR-214 (214; CD122-biased agonist) plus PD-1 inhibitor nivolumab (N) in patients (pts) with advanced cancers (MEL, RCC, NSCLC, TNBC, and UC). 214 monotherapy increases newly proliferative CD8+ T cells in tumors and increases cell surface PD-1 and PD-L1 expression, demonstrating a potentially synergistic mechanism with anti-PD-1 therapy.Methods:In P1 dose escalation, pts received 214 (0.003, 0.006 or 0.009 mg/kg) with N (240 mg or 360 mg) administered IV as outpatient Q2W or Q3W; in P2 expansion, the RP2D of 214 (0.006 mg/kg) with N (360 mg) Q3W was administered concurrently. Response was assessed Q8W by RECIST v1.1. Matched tumor samples were evaluated for changes from baseline in immune cell populations, gene expression, and T cell receptor repertoire. Tumor baseline and on treatment PD-L1 protein expression was assessed (28-8 IHC assay).Results:As of 7FEB2018, 162 pts (P1, n = 38; P2, n = 124) were evaluable for safety. The most common TRAEs of all grades at the RP2D ( > 25%) in pts were flu-like symptoms (63%), fatigue (39%), rash (38%) and pruritus (30%). G3+ TRAEs at the RP2D were 11%. No pts discontinued treatment or died from TRAEs. A total of 60 IO-treatment naïve stage IV pts (P1, n = 30; P2, n = 30) were efficacy evaluable (≥1 scan) (23 MEL, 24 RCC, 6 NSCLC, 4 UC, 3 TNBC). 22/30 P2 pts had only 1 scan. ORR (CR+PR) and DCR (CR+PR+SD) in 23 MEL (1L) pts was 52% and 78%. 18/23 MEL pts had known PD-L1 status. ORR was 5/9 (56%) for PD-L1(+) pts and 4/9 (44/%) for PD-L1(-) pts. ORR and DCR in 24 RCC (1L) pts was 54% and 79%. 20/24 RCC pts had known PD-L1 status. ORR was 4/7 (57%) for PD-L1(+) pts and 7/13 (54%) for PD-L1(-) pts. ORR and DCR in 6 NSCLC (1-2L) pts was 50% and 67%. 5/6 pts had known PD-L1 status. ORR was 3/5 (60%) in PD-L1(-) pts. ORR and DCR in 4 UC (1L) was 75% and 100%. ORR/DCR in 3 TNBC (1- 2L) pts was 33%. In 60 evaluable pts, 32/32 responses are ongoing (0.3+ to 12.0+ mos) with 45/60 pts still on treatment.Conclusions:214 plus N was well-tolerated with no TRAE discontinuations. Preliminary efficacy shows encouraging ORR/DCR with responses observed in 5 of 5 tumor types in I-O treatment naïve 1-2L pts. Updated data to be presented. Clinical trial information: NCT02983045

OR.....depending on how you like to read your data...there is this:

OncLive - NKTR-214/Nivolumab Efficacy Sustained in Phase II Findings

Combining the CD122-biased cytokine NKTR-214 with the PD-1 inhibitor nivolumab (Opdivo) showed promising antitumor activity, particularly in PD-L1–negative patients, according to updated data from the phase I/II PIVOT-02 trial presented at the 2018 ASCO Annual Meeting.

Data were presented from the phase II dose expansion part of the study demonstrating an overall response rate (ORR) of 50% in treatment-naïve patients with melanoma, including an ORR of 42% in PD-L1–negative patients. The overall ORR and PD-L1–negative ORR were 46% and 53%, respectively, in previously untreated patients with renal cell carcinoma (RCC). Among cisplatin-ineligible patients with urothelial carcinoma receiving frontline treatment, the ORR was 60% both overall and in PD-L1–negative patients.  

“Prespecified efficacy criteria were achieved [in the frontline setting] in melanoma, renal cell carcinoma, and cisplatin-ineligible urothelial carcinoma, which support the evaluation of NKTR-214 plus nivolumab in registrational trials,” lead investigator Adi Diab, MD, from the MD Anderson Cancer Center, said during his presentation of the results.

“Robust translational data confirm the rational for activation of the immune system in the tumor microenvironment with a conversion of PD-L1–negative tumors to PD-L1 positive on treatment,” Adi added. 

Phase I data for the dose escalation cohort of PIVOT-02 were previously presented at the 2017 SITC Annual Meeting. At the time of that analysis, 38 total patients with melanoma (n = 11), RCC (n = 22), and non–small cell lung cancer (NSCLC; n = 5) had received treatment with the combination. 

In the dose-escalation portion of trial, patients received nivolumab at 240 mg every 2 weeks (Q2W) or at 360 mg every 3 weeks (Q3W) with NKTR-214 at 0.003 or 0.006 mg/kg Q2W or Q3W. The identified recommended phase II dose for NKTR-214 was 0.006 mg/kg Q3W with nivolumab at 360 mg Q3W.

At ASCO, Diab first presented updated data on these cohorts, which had a cutoff of November 2, 2017, for the SITC results, and May 29, 2018, for the ASCO findings.

For the frontline cohort of patients with stage IV melanoma, the ORR was sustained between the SITC and ASCO results at 64% (7 of 11 patients). The disease control rate (DCR) was 91% (n = 10). The ORR among PD-L1–negative patients (expression <1 4="" 5="" 60="" 67="" 6="" among="" and="" expression="" nbsp="" of="" patients="" pd-l1="" positive="" span="" was="">

Among the frontline cohort of patients with stage IV RCC, the ORR at SITC was 46% (6 of 13 patients) and the DCR was 85% (11 of 13 patients). At the ASCO update, there was an additional patient, and the ORR was 71% (10 of 14 patients), with a DCR of 79% (n = 11). Five of 8 (63%) PD-L1–negative patients had a response and the ORR was 80% (4 of 5 patients) in the PD-L1–positive group. The PD-L1 status was unknown for 1 patient. 

For the patients with stage IV NSCLC, the ORR and DCR at SITC were both 75% (n = 3) among 4 patients receiving second-line therapy. The ASCO data included 1 extra patient receiving frontline treatment and the updated ORR was 60% (n = 3), with a DCR of 80% (n = 4). All 3 responders were PD-L1 negative, with 2 achieving a complete response.

The phase II dose expansion cohort of the trial has a target enrollment of approximately 330 patients. The cohorts include melanoma (first through third line), RCC (first through third line), NSCLC (first and second line, as well as second line immune-relapsed/refractory), urothelial carcinoma (first line cisplatin ineligible, as well as second and third line), and triple-negative breast cancer (first and second line).

At ASCO, Diab presented data for the 3 cohorts that have met the trial’s prespecified efficacy criteria: frontline melanoma, frontline RCC, and frontline cisplatin-ineligible urothelial carcinoma.

“The other tumor types continue to be at various stages of enrollment and the data has not yet met the prespecified stopping criteria either for futility or efficacy,” explained Diab.

Forty-one patients have been enrolled in the frontline melanoma cohort, 24 are male and 17 are female. The median patient age was 63 years (range, 22-80). Three-fourths of patients had an ECOG performance score of 0. Twenty patients were PD-L1 positive, 14 were PD-L1 negative, and the status was unknown for 7. Regarding BRAF status, 36.6% were positive, 61.0% were wild-type, and 2.4% were unknown.

Diab reported data for 28 of these patients, among whom 14 responded, for an ORR of 50%. The DCR was 71% (n = 20). The median time on study for these patients was 4.6 months. The ORR was 42% (5/12) among PD-L1–negative patients and 62% (8/13) among PD-L1–positive patients. PD-L1 status was unknown for 3 patients.

The frontline RCC cohort had enrolled 48 patients, comprising 10 females and 38 males. The median age was 61 years (range, 40-78). The ECOG performance score was 0 for 60.4% of the patients and 1 for 39.6%. The PD-L1 status was unknown for 4 patients, 30 were negative, and 14 were positive.

At ASCO, Diab shared findings for 26 patients from this cohort. The ORR was 46% (n = 12) and the DCR was 77% (n = 20). The median time on study was 5.6 months. The ORR was 53% (9/17) for PD-L1–negative patients and 29% (2/7) for PD-L1–positive patients. PD-L1 status was unknown for 2 patients.

Sixteen patients had been enrolled in the frontline cisplatin-ineligible urothelial carcinoma group, comprising 5 females and 11 males. The median patient age was 70 years (range, 54-83). Six patients had an ECOG performance score of 0 and 10 had a score of 1. There were 7 PD-L1–positive patients, 7 PD-L1–negative, and 2 whose status was unknown.

Diab reported data for 10 of these patients. The ORR was 60% (n = 6) and the DCR was 70% (n = 7). The median time on study was 3.9 months. The ORR was 60% (3 each) among the 5 PD-L1–negative patients and the 5 PD-L1–positive patients.

Safety data were available for 283 patients treated at the recommended phase II dose. Grade ≥3 treatment-related adverse events (AEs) occurred in 14.1% of patients, including hypotension (n = 5), syncope (n = 5), increased lipase (n = 4), rash (n = 4), and dehydration (n = 3).

Immune-mediated grade ≥3 AEs occurred in 3.5% of patients. One patients died of grade 5 pneumonitis related to nivolumab. The patients had NSCLC previously treated with carboplatin/pemetrexed and a history of brain metastases.

...and this....

ASCO 2018 - NKTR-214 (CD-122-biased agonist) plus nivolumab in patients with advanced solid tumors: Preliminary phase 1/2 results of PIVOT  (This link gives you all the nifty slides from the ASCO presentation!)

So here's the gist.  We already know that urothelial cancers and melanoma are odd bed fellows.  In my own experience, my first oncologist, with tears in his eyes said, "Oh, I hate telling patients that they have renal cell carcinoma or melanoma.  They are just the worst cancers."  You think YOU hate dealing with it, buddy!!!!  But, I digress...  We already know that treatment options for melanoma patients made huge strides with ipilimumab (Yervoy) and its 15% response rate.  We were over-the-moon with the 40% response rates attained with the anti-PD-1 products (Nivolumab/Opdivo and Pembrolizumab/Keytruda)!  Folks with urothelial cancers and NSCLC (non small cell lung cancer) benefited as well.  Still, no matter how great a 40% response rate is for some of us melanoma peeps...it sure leaves a lot of folks....60% of us to be exact...with no help!!!

Researchers worked to fill the void!!  The major working premise became ~ find something to add to immunotherapy to boost the response rate!  IDO inhibitors looked super promising.  Melanoma Big Dogs agreed.  Preliminary trials looked really good.  But then, not so much.  Here's a link that covers a post I made regarding the rise and fall of epacadostat:  Such a bummer!!!! An apparent end to the ECHO 301 trial testing epacadostat (an IDO inhibitor) combined with the anti-PD-1 product Keytruda (pembrolizumab) for melanoma

Here is another bit of an "op-ed" (not by me) about the conundrum of how to improve immunotherapy:  The difficult search for the right recipe in cancer immunotherapy

Yet, there are those who think that IDO inhibitors, perhaps even epacadostat itself, still hold promise and one poor showing doesn't mean they should be given the boot:  Sciencemag.org - A promising new cancer drug has hit a major setback, raising questions about whether the field is moving too fast

At any rate, back to NKTR-214 combined with nivo.  Like many drugs/trials in cancer/melanoma world, the Phase 1 trials were super promising.  Phase II results were a little less so.  Responses as noted in the article above were "(ORR) of 50% in treatment-naïve patients with melanoma, including an ORR of 42% in PD-L1–negative patients".  We have already determined that treatment naive patients tend to have the best responses.  But even so, 50% beats 40%.  Additionally, we also know that PD-L1 status has not been particularly definitive in attaining responses to anti-PD-1 drugs, but it is still good to note a 42% ORR in PD-L1 negative patients and that side effects were really no worse in this combo than when anti-PD-1 is taken alone.  So....

I still hold out hope ~ for vaccines, for IDO-inhibitors, and the current responses to NKTR-214 combined with nivo to hold.  BUT!  Unlike Melanoma Big Dogs in their ivory towers....we canaries in the coalmines...the ratties...you and me...can't afford to pontificate on the hypothetical.  We have to deal with the real live results that are happening for real.  Today.  To us.

Hang tough ratties.  And great thanks.  Love, c

PD-L1 positive? Which immunotherapy is best? Same song, second verse...

Differential activity Nivolumab, Pembrolizumab, and MPDL3280A according to the tumor expression of Programmed Death-Ligand (PD-L1):  Sensitivity Analysis of trials in melanoma, lung, and genitourinary cancers.  Carbognin, Pilotto, Milella, et al.  PLos One.  June 18, 2015.

The potential predictive role of PD-L1 expression on tumor cells in the context of solid tumor treated with checkpoint inhibitors targeting the PD-1 pathway represents an issue for clinical research.  ORR was extracted from Phase I-III trials investigating nivolumab, pembrolizumab, MPDL3280A [an anti-PD-L1 product] for advanced melanoma, NSCLC, and genitourinary cancer...  Interaction test according to tumor PD-L1 was accomplished, and analysis performed.  Twenty trials (1,475 patients) were used.  A significant interaction per tumor PD-L1 expression was found in the overall sample with an ORR of 34.1% in the PD-L1 positive and 19.9% in the PD-L1 negative population.  ORR was significantly higher in PD-L1 positive in comparison to PD-L1 negative patients for nivo and pembro, with an absolute difference of 16.4% and 19.5% respectively.  A significant difference in activity of 22.8% and 8.7% according to PD-L1 was found for melanoma and NSCLS, respectively with no difference for gu cancer.  Overall, 3 antibodies provide a significant differential effect in terms of activity according to PD-L1 expression on tumor cells.  The predictive value of PD-L1 on tumor cells seems more robust for anti-PD-1 antibody (nivo and pembro) and in the context of melanoma and NSCLC.

Thoughts:
1.  Background info on MPDL3280A:  Anti-PD-L1 for melanoma phase 1 trial
2.  Note that you can still respond, even if PD-L1 negative.  Is that true?  Does that reflect action of the medication?  Or, is the current test for PD-L1 not terribly accurate?
3.  Let's standardize testing tumors for the presence of PD-L1 and make it available to all melanoma and NSCLC patients so treatments can be chosen more wisely!!!  NOW!!!  Prior rant on my tumor testing for PD-L1:  Info on test for PD-L1 from 2012!
4.  I think we ratties have given you enough intel over many years.  Researchers and FDA weirdo's...get with it!  Make this happen, TODAY!!!

Don't make me come back there!  c

COX-2 expression correlates with PD-L1 expression on melanoma cells - or....how NSAID's like aspirin and advil might help melanoma patients????

COX-2 expression in melanoma cells is what has given the hope (??? data) that the use of NSAID's (advil, aspirin, etc) might enhance the response from immunotherapy in melanoma patients as noted in this post (with links to others within):  Sooo....advil works for SOME melanoma patients?????

COX-2 expression positively correlates with PD-L1 expression in human melanoma cells. Botti, Fratangelo, Cerrone, et al. J Transl Med. 2017 Feb 23.

The resistance to PD-1/PD-L1 inhibitors for the treatment of melanoma have prompted investigators to implement novel clinical trials which combine immunotherapy with different treatment modalities. Moreover is also important to investigate the mechanisms which regulate the dynamic expression of PD-L1 on tumor cells and PD-1 on T cells in order to identify predictive biomarkers of response. COX-2 is currently investigated as a major player of tumor progression in several type of malignancies including melanoma. In the present study we investigated the potential relationship between COX-2 and PD-L1 expression in melanoma.

Tumor samples obtained from primary melanoma lesions and not matched lymph node metastases were analyzed for both PD-L1 and COX-2 expression by IHC analysis. Status of BRAF and NRAS mutations was analyzed by sequencing and PCR. Co-localization of PD-L1 and COX-2 expression was analyzed by double fluorescence staining. Lastly the BRAF^V600E A375 and NRAS^Q61R SK-MEL-2 melanoma cell lines were used to evaluate the effect of COX-2 inhibition by celecoxib on expression of PD-L1 in vitro.

BRAF^V600E/V600K and NRAS^Q61R/Q61L were detected in 57.8 and 8.9% of the metastatic lesions, and in 65.9 and 6.8% of the primary tumors, respectively. PD-L1 and COX-2 expression were heterogeneously expressed in both primary melanoma lesions and not matched lymph node metastases. A significantly lower number of PD-L1 negative lesions was found in primary tumors as compared to not matched metastatic lesions. COX-2 expression significantly correlated with PD-L1 expression in both primary and not matched metastatic lesions. Furthermore, in melanoma tumors, cancer cells expressing a higher levels of COX-2 also co-expressed a higher level of PD-L1. Lastly, inhibition of COX-2 activity by celecoxib down-regulated the expression of PD-L1 in both BRAF^V600E A375 and NRAS^Q61R SK-MEL-2 melanoma cell lines.  

COX-2 expression correlates with and modulates PD-L1 expression in melanoma cells. These findings have clinical relevance since they provide a rationale to implement novel clinical trials to test COX-2 inhibition as a potential treatment to prevent melanoma progression and immune evasion as well as to enhance the anti-tumor activity of PD-1/PD-L1 based immunotherapy for the treatment of melanoma patients with or without BRAF/NRAS mutations.

Breaking it down:  This report supports the notion that there is a relationship between COX-2 and PD-L1 expression in melanoma. Therefore, if we could block COX-2 we would reduce PD-L1 expression in melanoma cells and make anti-PD-1 drugs more effective. That's the theory anyway!!   - c

Why doesn't immunotherapy work for all melanoma patients?

WHY?????  And what should we do when it fails?  Dismaying questions with no clear answers, right?  But, researchers are working on them!

First - what to do when immunotherapy fails?

What to Do When Anti-PD-1 Therapy Fails in Patients With Melanoma.  Mooradian, Sullivan.  Oncology, April 2019.

Monotherapy with immune checkpoint inhibitors, specifically those targeting programmed death 1 (PD-1), has revolutionized the treatment of metastatic melanoma: approximately 40% of patients achieve a partial or complete response, many of which are durable. However, a subset of patients who initially respond to therapy will progress, leaving the majority of patients in need of an effective second-line approach. While some standard therapies exist, there has been robust interest in utilizing targeted immunotherapy combinations in this population to overcome primary or acquired resistance. Other approaches include treatment with anti-PD-1 agents beyond progression; targeting oligometastatic disease with surgery, radiation, and/or intratumor injections; and the use of other approved systemic therapies. This review summarizes the current available treatment strategies for patients with advanced melanoma when PD-1-directed therapy is not enough.

You should be able to get the entire article via this link: 
https://www.ncbi.nlm.nih.gov/pubmed/30990567

Note:  We already know that combining ipi with anti-PD-1 provides improved response rates as compared to anti-PD-1 as monotherapy, though for some, even that is not enough.  Here is a primer of basic melanoma treatments I put together that covers some of the treatments described above:
Melanoma Intel: A primer for current standard of care and treatment options

But, back to the first question ~ as Fierce Biotech put it in their article linked here:  What causes immuno-oncology drug resistance? 2 research teams uncover clues! 

The article notes: 

Checkpoint-inhibiting drugs have revolutionized the treatment of melanoma and other cancers by freeing up the immune system to attack tumors. But the medicines don’t work for as many as half of patients, even when they’re combined with other cancer treatments.

Now, two separate research groups have uncovered different mechanisms of immuno-oncology drug resistance. One involves the gut microbiome, while the other is related to vesicles that are produced by cancer cells.

First, a worldwide consortium of 40 scientists led by Sanford Burnham Prebys released a study demonstrating that the gut microbiome orchestrates the immune system’s response to cancer. They published their observations in the journal Nature Communications.  The Sanford Burnham Prebys-led team made the discovery by working with mice engineered to lack RING finger protein 5 (RNF5), a gene that normally works to clear damaged proteins from cells. These mice mounted a strong immune response to melanoma, so the researchers used bioinformatics technology to identify 11 bacterial strains that were plentiful in the animals’ guts. They then transferred the bacteria to normal mice and found it also induced a strong immune response to melanoma in those animals.  The researchers mapped out the immune components that were active in the gut, and they discovered that a signaling pathway called the unfolded protein response (UPR) was reduced when immune cells were activated. Then they studied tumor samples from people who had received checkpoint inhibitors, and they found reduced UPR expression correlated with a good response to treatment. 

The findings “identify a collection of bacterial strains that could turn on anti-tumor immunity and biomarkers that could be used to stratify people with melanoma for treatment with select checkpoint inhibitors," said senior author and Sanford Burnham Prebys professor Ze'ev Ronai, Ph.D...

The second study, from a team at the University of California, San Francisco (UCSF), focused on the protein PD-L1, the target of some checkpoint-inhibiting drugs. Normally, checkpoint inhibitors work by recognizing PD-L1 on the surface of cancer cells and then interfering either with it or the related protein PD-1. The UCSF researchers discovered that in some patients, PD-L1 travels throughout the body, inhibiting immune cells before they can reach the cancer.

In those patients, the PD-L1 ends up in exosomes, which are vesicles that come from cancer cells and travel in the bloodstream to the lymph nodes, the UCSF team discovered. While there, they “disarm” the immune cells, so they’re unable to launch an attack against the cancer. They published their findings in the journal Cell.  The prevailing view of why patients sometimes don’t respond to PD-L1 inhibitors is that their cancers are not making enough of the protein. But the UCSF researchers showed "the protein was in fact being made at some point, and that it wasn't being degraded,” senior author Robert Blelloch, M.D,. Ph.D.... said... “That's when we looked at exosomes and found the missing PD-L1."  In a second experiment, the UCSF team used the gene-editing technology CRISPR to delete two genes necessary for exosome production from cancer cells. Mice that received those cells had more activated immune cells in their lymph nodes than did animals that got unedited cancer cells.  They then treated a mouse model of colorectal cancer with a combination of a PD-L1 inhibitor and a drug that prevents exosomes from forming. Those mice survived longer than animals treated with either drug alone did.  Blelloch’s team plans to conduct further studies, with the ultimate goal of developing a “tumor cell vaccine” to help patients who don’t currently respond to checkpoint inhibitors.

SO...two very different things are addressed within this article....
1.  The cooties in our gut make a difference.  I've been writing about this for some time.   Here is a recent report with links to many more within:  DECREASED progression free survival in melanoma patients treated with antibiotics prior to or at start of immunotherapy!!!!    Side note:  Additional studies show that you have to consume the real deal.  Probiotics out of a bottle won't do the trick.  In fact, attaining your cooties that way may actually DECREASE your response to immunotherapy.
2.  The whole PD-L1 positive vs NOT positive thing!  We have long known that having PD-L1 positive tumors does not guarantee a response.  AND... folks with tumors NEGATIVE for PD-L1 can still sometimes gain one!  Here are a bunch of reports addressing the PD-L1 conundrum!

There is also this report on the same research in the NY Times from April: Cancer’s Trick for Dodging the Immune System, where the author notes:

Cancer immunotherapy drugs, which spur the body’s own immune system to attack tumors, hold great promise but still fail many patients. New research may help explain why some cancers elude the new class of therapies, and offer some clues to a solution.  The study, published on Thursday in the journal Cell, focuses on colorectal and prostate cancer. These are among the cancers that seem largely impervious to a key mechanism of immunotherapy drugs.  The drugs block a signal that tumors send to stymie the immune system. That signal gets sent via a particular molecule that is found on the surface of some tumor cells.  The trouble is that the molecule, called PD-L1, does not appear on the surface of all tumors, and in those cases, the drugs have trouble interfering with the signal sent by the cancer.  The new study is part of a growing body of research that suggests that even when tumors don’t have this PD-L1 molecule on their surfaces, they are still using the molecule to trick the immune system.  Instead of appearing on the surface, the molecule is released by the tumor into the body, where it travels to immune system hubs, the lymph nodes, and tricks the cells that congregate there.

“They inhibit the activation of immune cells remotely,” said Dr. Robert Blelloch, associate chairman of the department of urology at the University of California, San Francisco, and a senior author of the new paper.  The U.C.S.F. scientists discovered that they could cure a mouse of prostate cancer if they removed the PD-L1 that was leaving the tumor and traveling to the lymph nodes to trick the immune system. When that happened, the immune system attacked the cancer effectively.

Furthermore, the immune system of the same mouse seemed able to attack a tumor later even when the drifting PD-L1 was reintroduced. This suggested to Dr. Blelloch that it might be possible to train the immune system to recognize a tumor much the way a vaccine can train an immune system to recognize a virus.  The work was done not in humans but in laboratory experiments and in mice, and it is not clear whether the results will translate in people. Dr. Ira Mellman, vice president of cancer immunology at Genentech, called the findings “a most interesting result.”  “But as with all mouse experiments, you get insight into basic mechanisms, but how it translates to the human therapeutic setting is unclear,” said Dr. Mellman. He is skeptical, he said, but plans to meet shortly with Dr. Blelloch to discuss the implications of the work.  The new research dovetails with other recent studies, including a paper published last year in the journal Nature that showed that PD-L1 molecules released from skin cancer tumors can suppress the body’s immune function.  When these bits of PD-L1 travel outside the cell, they are known as exosomal, and the discovery of their role is one of many fast-moving developments refining an area of medicine that has become among the most promising in decades.

Late last year, the Nobel Prize was awarded to two scientists — James P. Allison of the M.D. Anderson Cancer Center in Houston, and Tasuku Honjo of Kyoto University in Japan — who did groundbreaking work in immunotherapy.  An explosion of additional research is aimed not only at refining the therapies — which can have profound side effects — but also at searching for other molecules involved in the perilous dance between cancer and the immune system.  Far more study is needed. But Dr. Blelloch said the findings have him looking for ways to take the next steps into turning the discovery into a concrete therapy.  Interfering with the PD-L1 traveling to lymph nodes “can lead to a long-lasting, systemic, anti-tumor immunity,” the paper concluded.

While this research leaves us with plenty of unanswered questions...it is the first in a long while that begins to answer the PD-L1 conundrum!!!    Here's a link to a related article from Nature if you like to read all the science for yourself:  Exosomal PD-L1 Contributes to Immunosuppression and is Associated with anti-PD-1 Response  

Hopefully, more complete answers and treatment solutions will be developed SOON!!!  Hang in there, ratties! - c  

In melanoma, if you are worried about your PD-L1 level....DON'T wig out yet!!!!

While a wide variety of folks have been gettin' folks fired up about the presence or absence of PD-L1 expression in relation to response to immunotherapy (checkpoint inhibitors)...there's this:

Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden.  Morrison, Pabla, Conroy, et al.  J Immunother Cancer. 2018 May 9.  

Immune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma.  

Cutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8⁺ T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario.

PD-L1 positivity greater than or equal to 1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity.

In this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden.

Immunotherapy works in about 40% of melanoma patients, if you are talking about anti-PD-1 (Nivo/Opdivo or Pembro/Keytruda) and we REALLY need to figure out how to make that response rate better.  Here, researchers from 8 facilities looked at a lot of factors ~ PD-L1 expression, CD8 T cell infiltration, tumor mutational burden and other funky immune factors.  After examination of 231 patients (as best as I can tell), while PD-L1 positivity "correlated with response and OS...but demonstrated limited predictive performance."  "Comprehensive immune profiling demonstrated higher sensitivity (72%) compared to PD-L1 (34%) and tumor mutational burden (32%)."

Clearly, the presence of PD-L1 on your tumor is not the end all be all in determining response to immunotherapy.  Would that it were that simple!  But, y'all know melanoma don't play that way!!  Hang in there ratties!  - c

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

The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600.  Massi, Brusa, Merelli, et al. Ann Oncol, June 2, 2015. 

BRAF inhibitors improve survival in metastatic melanoma patients but the duration of clinical benefit is limited by development of drug resistance.  Here, we investigated whether the expression of Programmed Death-Ligand 1 (PD-L1) and the density of tumor-infiltrating mononuclear cells (TIMC) predict the occurrence of resistance, hence affecting the clinical outcome in BRAFi-treated melanoma patients. 
PD-L1 expression (cut-off - 5%) and TIMC were analyzed...from 80 consecutive melanoma patients treated with BRAFi at a single institution.  46 and 34 patients received vemurafenib and dabrafenib, respectively.  Membraneous expression of PD-L1 was detected in 35% of patients.  After analysis:  ABSENCE of tumoral PD-L1 staining and the presence of TIMC were associated with a better response to treatment.  Median PFS and OS were 10 and 15 months respectively.  Additionally, analysis demonstrated, PD-L1 expression and absence of TIMC correlated with SHORTER PFS.  Our results provide the first proof-of-principle evidence for the predictive and prognostic relevance of PD-L1 expression and density of immune cell infiltration of BRAF V600 mutated melanoma treated with BRAFi.

Thoughts:
1.  The study used a 5% cut-off for PD-L1 expression, while many studies use 1%, not sure that matters.
2. According to this study, patients treated with BRAF inhibitors did better if their tumors were negative for PD-L1 and loaded with TIMC.
3.  Now...these results can't (yet) be determined to mean that BRAFi was undermined by the presence of PD-L1 or facilitated by the presence of TIMC.  It is just one more study that demonstrates the presence of PD-L1 and absence of TIMC are bad prognostic indicators...unless...at least in the case of the PD-L1...you are taking anti-PD1 drugs.
4.  Notice...one more time...PD-L1 was present in 35% of patients.
5.  Clearly, we have lots to learn.

Complete remission of metastatic melanoma upon BRAF inhibitor treatment - what happens after discontinuation?  Tolk, Stzger, Mohr, et al.  Melanoma Res. June 8, 2015.

Treatments with BRAFi leads to complete remission in 3-6% of patients with BRAF mutant melanoma.  In cases of complete remission, it is unclear whether BRAFi therapy should be continued.  We retrospectively analyzed the clinical course of patients with metastatic melanoma who discontinued BRAFi therapy after achieving CR.  In 12 patients, CR of melanoma was diagnosed after a median BRAFi treatment duration of 13 (0.3-32 months) months.  Reasons for d/c were side effects in 7 and patient demand in 5.  Six patients are still in CR after a median 17 months (2-26 months) after discontinuation of BRAF inhibition.  Six patients developed a melanoma recurrence after a median of 3 (range 2-17) months of discontinuation of BRAFi therapy.  Subsequently, these patients were again treated with a BRAFi, which resulted in 3 CR, one stable disease, and one progressive disease, and one patient who could not be assessed.  Melanoma patients achieving CR during BRAFi therapy represent a heterogenous group.  Discontinuation of BRAFi therapy after CR has to be balanced carefully with the potential risk of nonresponding to BRAFi retreatment in the case of relapse.

Thoughts:
1.  While BRAFi provides a beneficial response in approximately 70-80% of BRAF positive patients, apparently only 3-6% of those gain complete remission.
2.  But, if you do....it seems that half of those will maintain remission (for at least 17 months...so far) after discontinuation of BRAFi.
3.  The half who do recur after stopping BRAFi, appear to have a 50% chance of regaining complete remission on retreatment. 
4.  These are very small numbers...but something to think about.

Health-related quality of life impact in a randomized phase III study of the combination of dabrafenib and trametinib vs dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma.  Schadendorf, Amonkar, Stroyakovskiy, et al.  Eur J Cancer, March 17, 2015.

The COMBI-d trial that combined dabrafenib and trametinib vs dabrafenib monotherapy showed that patients taking the combo experienced significantly prolonged progression-free survival.  These same patients were evaluated regarding quality of life using an established questionnaire.  Questionnaire completion rates were more than 95% at baseline, less than 85% to week 40 and less than 70% at disease progression.  Baseline scores across both arms were comparable for all dimensions.  Global health dimension scores were significantly better at weeks 8, 16, and 24 for patients receiving the combo during treatment and at progression.  Pain scores were improved and meaningful in patients receiving the combo for all follow-up assessments vs those receiving monotherapy.  For other symptoms (nausea, vomiting, diarrhea, dyspnea, constipation) scores trended in favor of monotherapy.  This analysis demonstrates that the combo of dabrafenib and trametinib provides better preservation of quality of life measures and pain improvements vs dabrafenib monotherapy, while delaying progression.

Thoughts:
Given the better results and decreased side effects noted in the COMBI-d study when dabrafenib was combined with trametinib...improved quality of life is not really a surprise, but still nice to know.  For a refresher regarding BRAFi:  BRAFi for melanoma - dabrafenib, vemurafenib, and the dabrafenib/trametinib combo  For more info:  Data on BRAFi combo's

Wishing you all my best. - c

PD-L1 expression by tumor and response to Pembro - more expression = more response

Not really news here.  We're known this for sometime.  Patients with greater PD-L1 expression on their tumors respond better to anti-PD1, though those with lesser expression can still gain a response.

Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma.  Daud, Wolchok...Weber, Ribas, Hodi,... Hamid, et al.  J Clin Oncol. 2016 Dec;34.  

Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome; a score greater or = to 2 (membranous staining in greater or = to 1% of cells) was considered positive. Of 451 patients with evaluable PD-L1 expression, 344 (76%) had PD-L1-positive tumors. Demographic and staging variables were equally distributed among PD-L1-positive and -negative patients. An association between higher MEL score and higher response rate and longer PFS and OS  was observed. Objective response rate was 8%, 12%, 22%, 43%, 57%, and 53% for MEL 0, 1, 2, 3, 4, and 5, respectively. Conclusion PD-L1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1-negative tumors may also achieve durable responses.

So....when are we going to actually USE this information?????  PD-L1 positive???? Which treatment is best???  This is from 2015 y'all...with links within to other posts from 2012! And, no....I still don't know the results of my tumor testing.

Hang in there ratties!!  The ride sometimes lasts longer than we wish....but we ARE getting there! - c 

Info on test for PD-L1 and the availability of anti-PD1

As I mentioned in my June 10th post, I agreed (as did most other patients in my study) for BMS to test my tumor for the expression of PD-L1 on its surface.  The presence of this ligand on tumors, as reported June 2, 2012, New England Journal of Medicine, from the BMS-936558 anti-PD1 study of patients with a variety of tumor types, indicated that 25 of the 42 patients [tested] had tumors that were positive for PD-L1. "Of these 25 patients, 9 (36%) had an objective response. NONE of the 17 patients with PD-L1 NEGATIVE tumors had an objective response....These preliminary results must be interpreted with caution..." Yada yada yada!!!!  So...at this point BMS....as well as innumerable anxious melanoma patients would like to know if their tumor expresses PD-L1 or not.  Since, given the data (minimal though it is), it is unlikely that a tumor WITHOUT PD-L1 would respond to anti-PD1, while a tumor that does have that ligand....might.

So....Where's the test?  Where's the result?  Dr. Weber still does not have the results himself.  He says that BMS keeps giving him the run-around, saying that they have to create a test that is valid, reliable, etc. (Important to be sure.) Currently, he is under the impression that he might get results in October.  When will I get results?  On MY tumor?  Probably....about never.  I am told that to give me results is tricky because this is still an experimental test on an experimental point about an experimental ligand whose implications are unclear, ambiguous, and with questionable import.  SERIOUSLY??????  Do you think, that at this point in the game, there are any folks in this study who do not realize that this is all a crap shoot?????  Do you not see that we deal with the ambiguities of the whole entire thing.....DAILY?????  Is it not clear to you peeps, that I, and all my fellow ratties, sign, and acknowledge said crap shoot papers, repeatedly...putting in writing that we KNOW this is an EXPERIMENT and the outcome is variable...at best?????  You think, at this point, that we will not be able to comprehend that the results of this test for PD-L1 were acquired with a new technology, yet to be fully proven?  You think, we are unable to realize that the ramifications of the presence of PD-L1, or not, on our tumors, is not fully determined?????  I'm not sure what any of you really think, but, I suspect you know we understand all the bull, much better than you do.  However, here's the rub...for you and BMS....you think we will run for the hills and leave your study in the lurch, and seek better treatment elsewhere, if we learn our tumors are negative for PD-L1.

So, folks keep asking me...."When will the test for PD-L1 be available for us like the BRAF testing currently is, so we can make more informed decisions about taking anti-PD1 or not?"  My answer....not soon.  It all depends on when BMS (or some other company) is ready to put it out there.  And that, depends on many things.  It depends on how well their anti-PD1 product really does in its Phase 1 trials.  Then, how it does in Phase 2 trials.  And then, what the correlation between those results and the presence of PD-L1 on those tumors turns out to be.  For all the folks who want anti-PD1 to be magically available TODAY....I have some sobering news.  While there is talk, of starting Phase 3 trials as early as 2013 with a BMS statement regarding a 'registrational development program' in which they are reportedly trying to move via a filing they have made with the FDA, 'from early clinical development in Phase 1 trials straight to a Phase 3 registrational program and expect the registrational trials for melanoma to begin at the end of this year, early next year'.  The Phase 1 trials are not completed. In fact, they are not even close.  Take my trial for instance. It is set up to last 2 1/2 years from start to finish. Some of us have been in that trial for almost 2 years.  That's just the first group.  They didn't start ENROLLING the third group until around January or so of this year.  In March, only one patient was two doses in, in the 10mg/kg group.  So, that means, that the results for my study, that started treating patients in 2010 will not be reported out, with final results, until the last patient (yet to be enrolled!!) has completed 2 1/2 years in the study.  At best, that will be roughly in 2015!  At, best.  Sorry.  But, that is the sad truth.

So, when will anti-PD1 be made available?  When will a test for the PD-L1 ligand be out?  I don't know.  And, it is very frustrating indeed...to be the rat...with no say or voice in the decision.  Well....maybe a little voice!  I'll keep speaking, if you keep reading.  Hang in there my friends - c.

C'est moi!!! Results from the 33 ratties in my Nivolumb/Opdivo trial...published!

Wow!  When it rains it pours!!!  Nivoumab, now called Opdivo, was FDA approved today!  Unfortunately, with the same prerequisites (ipi/Yervoy and BRAFi, if BRAF positive, must be failed first) that Keytruda (Merck's Pembrolizumab/anti-PD1 product) has. Not what I was hoping for.  As far as the publication of my trial data.... No real surprises here....with the help of Ruthie and Bentie (for their good ears and memory during rapid fire, free floating discussions at my appointments and YEARS of tremendous support!!!) and all the other 32 ratties who signed up and put their lives on the line...I have been able to pretty accurately document our struggles and successes.  But...it is nice to see it in print somewhere other than my own ramblings.  Here is my synopsis of the article:

Safety, correlative markers and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma.  Gibney, Kudchadkar, DeConti, Tetteh, Weber, et al.  clincancerres.aacrjournals.org December 20, 2014.

Nivo (at 1mg/kg in cohort 1, at 3mg/kg in cohort 2, or 10mg/kg in cohort 3...all IV) along with a multi-peptide vaccine was to be given every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses were given to 33 HLA-A *0201 positive melanoma patients {due to the vaccine} with completely surgically resected disease.  Two patients had stage IIIC disease and 31 had stage IV melanoma.  Prior systemic therapy (if given prior to surgery) and radiation were allowed except for anti-PD-1, anti-PD-L1/PD-L2, or anti-CTLA-4 agents.  Imaging studies (CT scan of the neck, chest, abd, and pelvis and MRI or CT of the brain) were performed at baseline and every 12 weeks during the trial, then every 6 months for 3 years.  Ten patients per cohort were selected based on sufficient samples for immune assessments.  Patients were replaced if not evaluable for safety and leukapheresis collection after the first induction phase. Patients were followed until relapse and/or death.  Correlative studies were performed on leukapheresis blood samples collected at baseline, week 12 and week 24.  Cells collected were assessed for...anti-CD3, CD8, CD25, CTLA-4 and PD-1 antibodies. Tregs and Myeloid-derived supproessor cells (MDSCs) were also assessed.  Tumors were tested for PD-L1 positivity.

Background:  Within the tumor microenvironment, the function of T-cells is thought to be impaired due in part to engagement of the programmed death 1 (PD-1) receptor found on T-cells with its ligand, programmed death receptor ligand (PD-L1), which is expressed by antigen presenting cells such as dendritic cells and macrophages as well as tumor and other cells.  Tumor cells can "hijack" this pathway by ectopically expressing PD-L1 on their surface, which often is associated with a poor outcome.  This interaction within the tumor microenvironment inhibits immune cell function leading to T-cell "exhaustion," thereby inhibiting T-cell function and promoting tumor growth.  A promising immunotherapy strategy being evaluated in multiple cancer centers is inhibition of this interaction between PD-1 and PD-L1 by the use of blocking antibodies, thereby overcoming a critical immune checkpoint to facilitate tumor cell destruction. 

Recent results from clinical trials of PD-1 and PD-L1 abrogating antibodies suggest that they can induce significant rates of tumor regression in melanoma, as well as renal cell, non-small cell lung and bladder cancer.  Objective response rated in ipi-naive and ipi-refractory metastatic melanoma patients treated with anti-PD-1 agents (nivo and pembro) range from 25-43%....

Adjuvant therapy for resected high-risk melanoma continues to be an area in need of more effective strategies.  Patients with resected stage IV melanoma have no FDA-approved adjuvant therapy option.  Median relapse free survival (RFS) has been reported to be as short as 5 months with overall survival (OS) ranging from 12 to 36 months.  Similarly, subset analysis of resected stage IV patients [in a] study comparing GM-CSF vs placebo demonstrated a median disease-free survival of 12 months and 6 months, respectively. ... Due to the high relapse rate (more than 80%), long-term survival of less than 30% and the need for evaluation of new adjuvant treatments for these resected melanoma populations we [engaged in this study].

Patients:  33 patients. 12 in cohort 1 {I was one of these}, 10 in cohort 2, and 11 in cohort 3.  Median age = 47.  2 patients had ocular melanoma and 2 had mucosal primaries.  10 had resected brain metastases. Radiation therapy was administered to 18 patients prior to or after surgery including 9 with resected brain mets.  16  received one or more systemic therapies prior to surgery and the study.  Chemo/biochem (6), adjuvant interferon (6), vaccine (3) and high-dose IL-2 (2).  All underwent surgery to be rendered free of disease (NED).

Dosing:  12 of 33 have received all 20 treatments of nivo and vaccines (36%).  Two additional patients completed the full course but skipped 1-2 doses due to transient grade 2 toxicities.  Of 13 who prematurely discontinued therapy, 8 were due to relapse and 5 were due to toxicity and/or withdrawal.  Two patients relapsed after finishing all planned therapy.

Toxicities:  481 grade 1-5 adverse events were reported with 286 attributed to treatment.  AE distribution was similar across cohorts (#1 = 81, #2 = 104, and #3 = 101).  Most common AE's were vaccine injection site reaction (discomfort, granuloma, and/or reactive lymphadenopathy - 94% of patients), fatigue (82%), rash (55%), pruritis (42%), nausea (42%), arthralgias (42%), diarrhea (36%), headache (36%). 5 drug related grade 3-5 AE's were noted:  hypokalemia (1 in cohort 2), rash (1 in cohort 1), enteritis (1 in cohort 3), and colitis (2 in cohorts 2 and 3).  The colitis patients responded to high-dose steroids and supportive care. The patient with the grade 3 rash was re-challenged with the study drug after recovery; there was no recurrence of serious rash. Other immune-related events = grade 2 hypophysitis (2) leading to adrenal insufficiency in both patients, grade 2 thyroiditis (7) leading to primary hypothyroidism, and grade 1 pneumonitis (1) without clinical sequelae.  Adrenal insufficiency and hypothyroidism were successfully managed with hormone replacement.

Results:  Median f/u from enrollment = 32.1 months.  Of 33 patients, 10 (30%) have had a relapse event.  6 patients relapsed during weeks 1-12, 1 during weeks 12-24, 1 during weeks 24-120, and 2 after completing all treatment (more than 2.3 years).  All other patients remain disease free, and 14 (42%) have finished all treatment.  Estimated relapse free survival was 47.1 months. Median overall survival has not yet been reached.  The estimated 12 and 24 month survival rates are 87% and 82% respectively. Of the 10 relapsed patients, 5 died due to metastatic disease, 3 were rendered free of disease surgically and remain disease-free at 2, 27, and 54 weeks after relapse.  One patient had spontaneous regression of disease after a biopsy-proven relapse and has been free of disease for over 3 years.  One additional relapsed patient is alive and on active therapy with dabrafenib plus trametinib.

Brain metastasis subgroup:  10 patients with resected CNS disease were enrolled.  3 in cohort 1, 2 in cohort 2, and 6 in cohort 3.  Only 2 of these 10 patients have relapsed after median follow up time of 22.5 months, both were in cohort 1.  The first patient completed all doses of study drugs and developed a new solitary lung met that was resected after 47 months on protocol; she again has no clinical evidence of disease.  The second was diagnosed with recurrent CNS disease after her first treatment with study drugs and expired 3 weeks from start of protocol from CNS hemorrhage.

Post relapse spontaneous regression {THAT GUY!!!}:  Cases of regression of melanoma after RECIST progression have been well documented for ipi and anti-PD1 antibodies, and have led to new criteria for anti-tumor response called immune related response criteria.  This may complicate evaluation of patients on adjuvant trial[s]... Patient noted in 'results' = with resected chest wall and pulmonary disease initiated treatment in the 3mg/kg cohort.  At week 12, CT scans showed new chest wall disease and a splenic nodule of 2.7cm, biopsy proven with fine needle aspirate to be melanoma.  While waiting to initiate treatment for metastatic disease, a repeat CT scan 4 weeks later showed shrinkage of both lesions.  Over the  next 24 weeks, repeat CT scabs showed further regression and eventual disappearance of both lesions, he remains free of disease 38.8 months since relapse.

Correlative Studies:  The identification of potential biomarkers to predict relapse was explored.  There were (in all cohorts together) a trend towards lower baseline CD25+Treg/CD4+ T-cell and MDSC levels in non relapsing patients compared to relapsing patients. Baseline PD-L1 tumor expression was assessed on archived tumor specimens from 28 of the 33 enrolled patients.  Using a 1% PD-L1 cutoff, 18 samples were positive and 10 were negative.  Relapse occurred in 5/18 (28%) PD-L1 positive patients and 4/10 (40%) PD-L1 negative patients.  At a threshold of 5% PD-L1 staining, 12 samples were positive and 16 were negative.  Relapse occurred in 3/12 (25%) PD-L1 positive patients and 6/16 (38%) negative patients. ....there was no statistically significant association between PD-L1 tumor staining and relapse free survival in this population, although there is a non-statistically significant trend towards better relapse free survival in those whose tumors were PD-L1 positive using either threshold...

Discussion:  Nivo and vaccine were well tolerated with only 4 of 33 patients discontinuing due to drug toxicities, and only 2 dose limiting toxicities (colitis) observed.  Grade 3 events occurred in 4 of 33 patients (12%) and were manageable.  Adverse events with adjuvant high-dose or pegylated interferon [show] 40-60% of patients experienced grade 3 events, 5-10% experience a grade 4 event, and as many as 31%...discontinued therapy due to toxicities.  Rate of grade 3 events for ipi at 10mg/kg for resected stage III melanoma patients [was reported as] 36.5% and 5.5% of patients experienced grade 4 AE's.
                    High dose and pegylated interferon have both been approved by the FDA as adjuvant therapy for resected stage III melanoma patients....but studies have failed to show a statistically significant improvement in overall survival [with these treatments].  Studies looking at bevacizumab (AVAST-M) and GM-CSF have each demonstrated improvement in disease free survival over placebo, but no statistical improvements in overall survival were seen.  Adjuvant ipi for resected melanoma is currently under investigation in two large randomized phase III trials.  Recent preliminary data presented in resected stage III patients demonstrated a median relapse free survival of 26.1 months with ipi compared to 17.1 months in the placebo group.
                    Our data suggest that nivo is clinically active in resected stage IIIC/IV melanoma, based on low rate of relapse (10 of 33), impressive relapse-free survival - estimated RFS of 47.1 months, and median overall survival not yet reached with over 32 months of follow up.  Median RFS for Canvaxin-IV trials was 7.2 months with median OS of 32 months.  Median OS for patients with metastasectomy {surgical removal of mets alone} has been found to be 12 months.  Overall, ...data suggests that a median RFS over 12 months would be a reasonable benchmark by which to judge the potential of an adjuvant treatment for stage IIIC/IV high risk resected melanoma.  By that criterion, our data with adjuvant anti-PD1 therapy surpasses RFS expectations and longer follow up will clarify whether superior median OS can be achieved.  Furthermore, the low event rate in resected brain metastases patients suggests a potential benefit in this very high risk population.
                    Enthusiasm for the use of PD-L1 as a predictive biomarker has diminished as other studies have shown that patients with PD-L1 negative melanomas can still respond to anti-PD-1, albeit at lower rates.  In our study, there were slightly fewer relapses in patients with PD-L1 positive tumors, but this was not statistically significant.  Other correlative studies showed that non-relapsing patients tended to have lower baseline levels of CD25+Treg/CD4+ and MDSC populations. This is supported by other data indicating the suppressive role of these immune cell populations, which may mitigate the effect of cytotoxic T-cells (and other immune cells) expected with anti-PD-1/PL-L1 therapy, resulting in dampened anti-tumor activity.

Wow. Very weird to read a scientific journal article that is talking about ME and my fellow ratties.... Lots to think about.  My thoughts will follow.  best - c

ASCO 2015: Stage IIIA melanoma, deciding treatment by testing sentinel node?

PD-L1 expression, immune cell correlates, and PD-1 + lymphocytes in sentinel lymph node positive melanoma patients:  Implications for adjuvant PD-1 clinical trials.  Kakavand, Vilain, Wilmott, et al.  J Clin Oncol 33, 2015.

Patients with positive sentinel lymph node biopsies that undergo a completion lymphadenectomy have variable five-year survival rates ranging from 39-70%.  PD-1 and PD-L1 inhibitors have significantly improved recurrence free survival (RFS) and overall survival (OS) in stage IIIC/IV melanoma patients.  The aims of this study were to characterize populations of lymphocytes that interact with metastatic melanoma cell in sentinel lymph node biopsy, to determine tumoral PD-L1 expression and to identify whether the PD-1/PD-L1 pathway contributes to immune escape in these patients to provide a rationale for the use of anti-PD-1 inhibitors in the adjuvant setting and aid in the selection of patients for this treatment modality.

The metastatic melanoma containing sentinel nodes from 60 treatment naive patients were analyzed for CD3, CD4, CD8, FOXP3, PD-1 and PD-L1 and correlated clinico-pathologic features and outcomes.  Tumoral PD-L1 expression (greater/= to 1%) was present in 43.3% (n=26) cases.  Cox analysis showed a positive correlation between intratumoral CD3+ lymphocytes and RFS/OS, a positive correlation between intratumoral CD4+ lymphocytes and RFS/OS, and a positive correlation between intratumoral CD8+ lymphocytes and RFS/OS.  There was a negative correlation between peritumoral PD-1+ lymphocytes and RFS/OS.  

CONCLUSION:  Expression of PD-L1 in metastatic melanoma-positive sentinel node biopsy provides a rationale for trials of anti-PD1 therapy in stage IIIA melanoma patients, particularly those with peritumoral PD-1+ lymphocytes.  The expression of immune markers may also be useful to predict the outcome of patients following a positive sentinel lymph node biopsy.

So....it seems that these results indicate that if you have a sentinel node that is positive for melanoma, you should have it tested for the presence of immune cells.  (How readily available this testing is...I'm not sure.)  Then...if your tumor contains intratumoral CD3+, CD4+, CD8+ lymphocytes...you have a better chance of recurrence free survival/overall survival.  If your tumor contains PD-1+ lymphocytes you may do less well, but may respond better to anti-PD1 therapy.  It is not likely a coincidence that in this study, 43% of the tumors present were positive for PD-L1...as that is the rough number of treatment naive patients who attain a response to anti-PD1 therapy.

By the way....none of this was remotely on the horizon much less available as a test when I had a positive sentinel node in 2003, so I have no idea what immune cells were present in my tumor. Additionally, though my melanoma tumor samples have since been tested in the course of my clinical trial, I still don't know if PD-1 or PD-L1 positive lymphocytes were present.

For what it's worth. - c

The Future for Melanoma Treatment = Combo's! Dr. Weber breaks it down -

This interview/report is pretty cool and clear.  I'll just let the Wizard break it down - 

Novel Immunotherapy Combinations May Be the Future of Melanoma Treatment

By Caroline Helwick December 10, 2016  The ASCO Post

Anti–PD-1/PD-L1 will be the backbone upon which all combinations will be based. The only question is whether we will have enough patients to enroll on these combination studies. — Jeffrey Weber, MD, PhD

The future treatment of melanoma may rely on combinations of immunotherapy agents beyond the current checkpoint inhibitors, and they are entering clinical trials, according to Jeffrey Weber, MD, PhD, Deputy Director of the Laura and Isaac Perlmutter Cancer Center at New York University Langone Medical Center, who has spearheaded clinical trials in melanoma. At the 2016 European Society for Medical Oncology (ESMO) Congress, Dr. Weber gave attendees a taste of what’s to come in this tumor type.

“It’s become obvious that multiple checkpoints exist that are both antagonistic and agonistic molecules controlling adaptive immunity and innate immunity,” Dr. Weber said. He counted more than 50 members of the immunoglobulin or tumor necrosis factor (TNF) receptor superfamilies that could act as controlling or regulatory molecules.

In other words, the pipeline is rife with drugs that will target far more than cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). T cells also express TIM-3, LAG-3, GITR, and other factors, which, if agonized or antagonized, could boost an immune response and yield potential clinical benefit. They include many receptor agonists, “which press on the gas pedal,” he added, and receptor antagonists, such as CTLA-4 and PD-1, which “release the brakes.” In addition to antibodies in development, up to 15 new indications could be approved for the current CTLA-4 and PD-1/programmed cell death ligand 1 (PD-L1) inhibitors, Dr. Weber predicted.

A High Bar to Surpass
The best results so far in advanced melanoma have been achieved by the combination of the anti–PD-1 agent nivolumab (Opdivo) and the anti–CTLA-4 agent ipilimumab (Yervoy). Nivolumab/ipilimumab yielded a 2-year survival rate of 63.8%, vs 53.6% for ipilimumab alone, in the CheckMate-069 trial.²

“In developing new checkpoint inhibitors, that’s the number we will have to be beat. If you want to add an inhibitory or agonistic molecule, you must at least match this, with less toxicity, and that’s a daunting challenge,” admitted Dr. Weber. “The fact that anti–PD-1 was developed early on sets a very high bar, which ironically could be a significant barrier to the successful development of other checkpoint inhibitors.”

Dr. Weber expects all new checkpoint agents to be tested in combination. Although 64% survival at 2 years is “fantastic,” he said, “at the end of the day, at least half the patients will need other therapy.” In all the tumor types for which these agents are important, “there is space for improvement,” he added.

Rationale for Novel Combinations
Immunotherapy combinations, with anti–PD-1/PD-L1 agents as backbones, will be driven by four key aims:

1. To bring T cells into tumors and overcome suppression of the immune system: For this, anti–PD-1/PD-L1 agents can be combined with anti–CTLA-4, immune-activating antibodies of cytokines, Toll-like receptor agonists, oncolytic viruses, indoleamine 2,3-dioxygenase (IDO) inhibitors, macrophage inhibitors, and targeted therapies.
2. To generate de novo T cells: This might be accomplished by vaccines, T-cell receptor–engineered adoptive-cell transfer, and chimeric antigen receptor–engineered adoptive-cell transfer.
3. To increase immune recognition: Stimulators of interferon genes (STING) agonists and interferons may help here.
4. To facilitate T-cell infiltration: This will be especially important for “cold” tumors that are deficient in T cells; the aim is to turn these “cold” tumors into “hot” ones. T-cell suppression, which occurs via multiple active and passive processes, must also be overcome.
These aims will be the mission of novel agonists, including anti-ICOS, anti-GITR, anti-OX40, anti-41BB, and anti-CD27, and novel antagonists, including anti–LAG-3, anti–TIM-3, anti-VISTA, anti-A2AR, anti-TIGIT, and IDO inhibitors.
“With T-regulatory cells, M2 macrophages, myeloid-derived suppressor cells—each a different lineage that requires a different maneuver to overcome—it’s amazing that any of this works at all,” he commented.

Sampler of Novel Combinations
Novel immunotherapies are not expected to be particularly potent as single agents, but in combination with other checkpoint inhibitors or targeted drugs, they are showing promise. More than a dozen combinations (including some triplets) are in phase II and phase III trials, including the following agents:

• Ipilimumab plus IDO inhibitors, talimogene laherparepvec (also known as T-VEC), interferon, and nivolu­mab/histone deacetylase (HDAC) inhibitor
• Nivolumab plus anti-CD137, TRAIL-R2 antibody, and LAG-3 antibody
• Pembrolizumab (Keytruda) plus IDO inhibitor, talimogene laherparepvec, BRAF/MEK inhibitors, interferon, and JACK/STAT inhibitor
• Atezolizumab (Tecentriq; anti–PD-L1) plus BRAF/MEK inhibitors
• Durvalumab (anti–PD-L1) plus BRAF/MEK inhibitors.
  

“Looking at all the mouse data from almost every antibody, results are better with combinations than with single drugs alone,” he said. “Anti–PD-1/PD-L1 will be the backbone upon which all combinations will be based. The only question is whether we will have enough patients to enroll on these combination studies.”

Promising Early Data
Early data suggest that, for mutated patients, checkpoint inhibition plus BRAF and MEK inhibition is a powerful approach. In a study of the anti–PD-L1 antibody atezolizumab plus vemurafenib (Zelboraf) and cobimetinib (Cotellic), all patients in a 16-patient study had a reduction in target lesions; 3 patients had complete responses.³ The anti–PD-L1 antibody durvalumab plus a BRAF and MEK inhibitor produced a 69% response rate in another study, and all responses were ongoing at the time of analysis.⁴ In KEYNOTE 022, pembrolizumab in combination with dabrafenib (Tafinlar) and trametinib (Mekinist) produced tumor regression in almost all patients.⁵

Novel Combinations in Melanoma

• The future treatment of advanced melanoma may involve combinations of agents, with anti–PD-1/PD-L1 and anti–CTLA-4 as backbones.
• The pipeline is replete with agonistic and antagonistic molecules that target new checkpoints.
  

Pembrolizumab plus the IDO inhibitor epacadostat produced responses in 56% of 61 patients (63% of treatment-naive patients), and a disease control rate of 78% (and 75% of treatment-naive patients).⁶ Hepatotoxicity can be an issue with epacadostat, but it was not concerning in this study, he said.

One of the “more innovative” compounds targets OX40, an agonistic molecule that is expressed on activating T cells. An antibody against OX40 has shown significant and long-lasting antitumor activity in a mouse model of ovarian cancer when paired with an anti–PD-1 antibody.⁷ “This combination looks very impressive,” Dr. Weber commented. “You see very long survival [mean of 80 days, vs < 40 days for either agent alone], and, in fact, many of these mice were resistant to re-challenge. It’s clear that an adaptive immune response is promoted by the combination.”

An OX40 antibody (MOXR0916) was also combined with the PD-L1 inhibitor atezolizumab in a phase Ib study in solid tumors, but only 2 responses were observed among 51 patients, which he considered “disappointing.” However, this regimen will be further tested in melanoma and in other histologies with demonstrated responses to atezolizumab.

Checkpoint Inhibition Plus Talimogene Laherparepvec
The injectable oncolytic virus talimogene laherparepvec may prove to be a much better therapeutic when paired with a checkpoint inhibitor, vs its solo use, Dr. Weber said. “If you can inject enough tumors with enough volume, I think you will begin to turn cold tumors into hot tumors, and you could follow this with checkpoint inhibition,” he explained.

The combination of ipilimumab and talimogene laherparepvec doubled the response rate over ipilimumab alone, in a study in which even patients with visceral disease (not directly injected) experienced significant responses.⁸ “This looks very promising. Only time will tell whether we see a very good duration of response,” he commented.

Also quite promising is the combination of talimogene laherparepvec and pembrolizumab. In the phase IB ­MASTERKEY-265 trial of 21 previously untreated patients, responses were seen in 57% of patients, including complete responses in 7 patients, with no dose-limiting toxicities.⁹ This regimen is now in phase III trials.

Wishing strength and peace to all my fellow melanoma ratties and fighters.  We've come a long way, baby!!!  And though there are miles to go...We Will GET THERE!!!! - love, c  

ASCO 2017: Anti-LAG-3 plus nivo, for melanoma already treated with anti-PD-1/PD-L1

Here is what I have on LAG-3:
2014:  How to make anti-PD1 work better with a new player...LAG-3????
2016:  The Future for Melanoma Treatment = Combo's! Dr. Weber breaks it down -

Now, there's this ~ anti-LAG-3 with Nivo:

Initial efficacy of anti-lymphocyte activation gene-3 (anti–LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti–PD-1/PD-L1 therapy.

ASCO 2017. J Clin Oncol 35, 2017. Ascierto, Melero, Bhatia, et al.

Background: Signaling via LAG-3 and other T-cell inhibitory receptors (eg, PD-1) can lead to T-cell dysfunction and tumor immune escape. Simultaneous blockade of LAG-3 + PD-1 may synergistically restore T-cell activation and enhance antitumor immunity. In a phase 1/2a study, BMS-986016 (IgG4 mAb targeting LAG-3) ± nivo (IgG4 mAb targeting PD-1) demonstrated tolerability, peripheral T-cell activation, and preliminary clinical activity. Here we describe preliminary efficacy of BMS-986016 + nivo in pts with MEL whose disease progressed on/after prior anti–PD-1/PD-L1 therapy, along with updated safety from all dose expansion pts. Methods: Pts with MEL must have had prior anti–PD-1/PD-L1 (± anti–CTLA-4 or BRAF/MEK inhibitors) and progressive disease (PD). Pts received BMS-986016 80 mg + nivo 240 mg IV Q2W. Primary objectives were safety and objective response rate (ORR; complete [CR] + partial [PR] response), disease control rate (DCR; CR + uCR + PR + uPR + stable disease [SD] greater than 12 wk), and duration of response. Results: At data cutoff, 43 pts with MEL had been treated with BMS-986016 + nivo following PD on/after prior anti–PD-1/PD-L1 with known prior best responses of 1 CR, 9 PR, 12 SD, and 16 PD. Of the 43 pts, 30 (70%) also had prior anti–CTLA-4, 20 (47%) had greater than/ = to 3 prior therapies, and 15 (35%) had BRAFmutations. In the 31 efficacy-evaluable pts to date, ORR was 16% (confirmed/unconfirmed) and DCR was 45% with benefit observed even in some pts refractory to prior anti–PD-1. Evaluations are ongoing for most pts, with median treatment duration of 10 wk for all 43 pts.  Any grade and grade 3/4 treatment-related AEs occurred in 46% and 9%, respectively, across all dose expansion pts (n = 129). Conclusion: Addition of BMS-986016 to nivolumab demonstrates encouraging initial efficacy in pts with MEL whose disease progressed on/after prior anti–PD-1/PD-L1 therapy, and a safety profile similar to nivolumab monotherapy. Clinical trial information: NCT01968109

43 melanoma patients with progression on or after treatment with anti-PD-1 or anti-PD-L1, 30 of whom had also been previously treated with ipi - were treated with nivo and BMS-986016 (anti-LAG-3).  In the end, 31 patients were evaluated.  ORR = 16%.  DCR (disease control rate) = 45% "with benefit observed even in some patients refractory to prior anti-PD-1".  Median treatment duration = 10 weeks. 

Small numbers. Patients who had already been through a lot.  Fingers crossed. - c