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    Hey Folks – sorry for delays in posting but it’s been busy (and this LONG post!)! I’m sitting here hanging out at the MIF booth in the exhibits hall. I’d have to say that yesterday’s focus – MELANOMA! and PD1 drugs!

    I’m sure many of you have seen the news coming out of ASCO. It’s a pretty exciting time for the treatment of Melanoma. My first day here I went thru all the poster boards (I’ll post pictures later! along with Abstract details…).

    But this morning when I picked up the ASCO daily news front page headline is: Investigational Immunotherapies Offer Bring Prospects in Advanced Melanoma! Of course with the FDA approval of Ipilimumab a few years ago (aka Yervoy), it seems that more and more focus is going towards developing these types of drugs vs. the standard type Chemos! You wouldn’t believe how many different exhibitors are here with that as their focus!

    I think you are all seeing the numbers, but in case you haven’t here they are:

    The interim overall response rate for lambrolizumab was 38%, according to investigators, who reported interim data on 135 patients with advanced melanoma. The highest response rate was an impressive 52% in the arm receiving 10 mg/kg every two weeks, the highest dose in the study. Ten percent of the patients in that arm achieved a complete response, with response duration ranging from 28 days to 8 months. Four out of five patients who responded stayed on treatment. And after a median follow-up time of 11 months, the median rate of response has not yet been reached in the study.

    (article can be found here – http://chicago2013.asco.org/immunotherapies-offer-bright-prospects-advanced-melanoma?et_cid=31868877&et_rid=555962827&linkid=http%3A//chicago2013.asco.org/investigational-immunotherapies-offer-bright-prospects-advanced-melanoma)

    Or I posted it below:

    Investigational Immunotherapies Offer Bright Prospects in Advanced Melanoma

    June 3, 2013

    Inspired by the 2011 approval of ipilimumab, the immunotherapy paradigm is experiencing a fervent revival in metastatic melanoma. As attendees heard at the Melanoma/Skin Cancers Oral Abstract Session on Saturday afternoon, three novel strategies that provoke the body’s immune system to attack melanomas are enabling patients to live better and longer with their disease, further fueling the remarkable advances achieved in the field over the past 2 years.

    Harnessing the Oncolytic Power of Viruses

    The cancer-killing virus talimogene laherparepvec (T-VEC) constitutes the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanoma in a phase III trial. Interim results from the OPTiM study showed that the virus significantly improved the durable response rate compared with granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with metastatic disease (16.3% vs. 2.1%; p < 0.0001), thus meeting the study’s primary endpoint (Abstract LBA9008). A durable response was defined as a complete or partial response that began within 12 months of treatment initiation and lasted 6 months or more. Durable responses were particularly enhanced in patients who had nonvisceral disease (stage IIB/C, stage IV M1a) and in those who received T-VEC as first-line therapy, noted Presenter Howard L. Kaufman, MD, of Rush University Medical Center. T-VEC, like other oncolytic viruses, wields a one-two punch against tumors by directly killing tumor cells and eliciting host defense mechanisms that indirectly target distant cancer cells for destruction. Researchers engineered T-VEC by taking herpes simplex virus type-1—a largely innocuous virus that causes cold sores—and introducing genetic mutations to knock out its herpes-causing capacity and transform it into a cancer-killing machine. One of the key genetic modifications introduced into the virus is the gene encoding GM-CSF. After injection into a patient’s tumor, T-VEC selectively replicates in tumor tissue, secreting GM-CSF in the process. The cancer cells eventually become overrun with virus and GM-CSF and rupture, expelling new viruses, GM-CSF, and an array of tumor-specific antigens. Newly released GM-CSF acts as a beacon to inflammation-responsive dendritic cells, which process and present the tumor-specific antigens to T cells that then become programmed to seek and destroy antigen-bearing tumor cells throughout the body. Between May 2009 and July 2011, 436 patients with unresectable stage IIIB, IIIC, or IV melanoma were enrolled in OPTiM and randomly assigned in a 2:1 ratio to receive intratumoral T-VEC or subcutaneous GM-CSF. Patients were required to have at least one cutaneous, subcutaneous, or nodal lesion amenable to injection, as well as to measurable disease. Mirroring the durable response results, the objective response rate also favored T-VEC over GM-CSF, reaching 26.4% versus 5.7%, respectively. Similarly, the median time to treatment failure was 8.2 months with T-VEC as compared with 2.9 months with GM-CSF (hazard ratio 0.42, 95% CI [0.32, 0.54]; p < 0.0001). Encouragingly, an early look hints at a survival benefit with T-VEC. Interim data based on more than 85% of the required events revealed that median overall survival reached 23.3 months with T-VEC versus 19.0 months with GM-CSF (hazard ratio 0.79, 95% CI [0.61, 1.02]). A final analysis of overall survival is expected in late 2013. Although patients assigned to T-VEC received treatment more than twice as long as those assigned to GM-CSF (median of 23 vs. 10 months, respectively), the most common grade 3/4 adverse event observed with T-VEC was cellulitis and occurred at an incidence of only 2.1%. T-VEC proved to be well tolerated, most commonly causing symptoms of fatigue (50.3%), chills (48.6%), fever (42.8%), and nausea (35.6%). “The big elephant in the room is the rationale for the comparator,” said Discussant Kim A. Margolin, MD, of the Seattle Cancer Care Alliance, who pointed out that GM-CSF is not a standard treatment option. “T-VEC isn’t really ready for prime time as it’s been reported… but it might be ready for the next melanoma therapy strategy, including something like ipilimumab plus or minus [T-VEC],” she said. Benefits of Adding an Immune System Booster Although GM-CSF appeared paltry when used alone in the OPTiM trial, adding the cytokine to an increased dose of ipilimumab yielded stunning results in E1608, a proof-of-principle phase II trial presented by F. Stephen Hodi, MD, of the Dana-Farber Cancer Institute (Abstract CRA9007). The combination regimen not only prolonged overall survival, enabling more than two-thirds of patients to survive beyond the 1-year mark, it also offered reduced toxicity compared with ipilimumab alone. Both ipilimumab and GM-CSF target the immune system, which may cause synergistic activity in melanoma. Whereas ipilimumab functions to knock out the activity of CTLA-4, a protein that dampens T-cell activation, GM-CSF promotes white blood cell production and recruits immune cells to sites of inflammation. A total of 245 patients with unresectable stage III melanoma who had received up to one prior therapy were randomly assigned to get ipilimumab induction and maintenance at a dose of 10 mg/kg either with or without the addition of GM-CSF. Given the inflammatory effects sometimes produced by immunotherapies that can resemble disease progression, patients could continue therapy even if their target lesions doubled in size and up to four new lesions appeared, so long as their general well-being held steady. Given that the ipilimumab/GM-CSF arm showed no difference from the ipilimumab-alone arm in overall response (15.5% vs. 14.8%, respectively) or median progression-free survival (3.1 vs. 3.1 months, respectively), the improvement in overall survival with the combination regimen was rather surprising. Based on a median follow-up of 13.3 months, median overall survival—the primary study endpoint—stretched to 17.5 months with ipilimumab and GM-CSF compared with 12.7 months with ipilimumab alone (hazard ratio 0.64; p = 0.014; Fig. 1). Data are still being collected for the final overall survival analysis. Another fortuitous finding was that the addition of GM-CSF to ipilimumab decreased the occurrence of severe toxicities. Overall grade 3 to 5 toxicities significantly fell from 58.3% with ipilimumab alone to 44.9% with combination therapy, driven largely by decreases in grade 3 to 5 gastrointestinal events (26.7% vs. 16.1%) and pulmonary events (7.5% vs. 0%) (p < 0.05 for all comparisons). Which of the several potential mechanisms may contribute to the therapeutic synergy between ipilimumab and GM-CSF remains unclear. As one audience member commented, and Dr. Margolin agreed, it may be possible that the benefit of combination therapy may not result from immune-based mechanisms but, instead, the ability of GM-CSF to overcome the “horrendous toxicity” of ipilimumab. New Support for PD-1 Blockade As with the CTLA-4 class before it, a new group of checkpoint inhibitors that block the programmed death 1 (PD-1) and PD-1 ligand (PD-L1) may yet again change the standard of care for melanoma in the near future. Fueling these high hopes, in part, are long-term data from an expanded phase I trial of the PD-1 inhibitor nivolumab in heavily pretreated patients with advanced melanoma that showed a median overall survival duration of nearly 17 months, complemented by a favorable safety profile (Abstract CRA9006^). Similar to CTLA-4, upregulated PD-1 expression on the surface of tumor-infiltrating lymphocytes puts the brakes on T-cell activation, in turn preventing these immune cells from fighting off cancer. Nivolumab is a fully human anti-body that binds to the PD-1 receptor, thereby keeping T cells primed and ready for tumor attack. In this study, 107 patients with advanced melanoma received up to twelve 8-week cycles in which intravenous nivolumab was administered every 2 weeks at five different doses. All patients had disease that progressed despite one to five prior lines of systemic therapy. Two-thirds of patients had received at least two prior therapies, and one-quarter had received three or more. As noted by Presenter Mario Sznol, MD, of the Yale Cancer Center, the response to nivolumab treatment was both rapid and durable. The objective response rate across all nivolumab doses was 31%, but reached 41% among patients treated with 3 mg/kg of nivolumab—the dose being pursued in further clinical development. Unlike the CTLA-4 inhibitors that sometimes take several months to induce a response, nearly half (45%) of responding patients showed at least 30% tumor shrinkage at the first tumor assessment 8 weeks following the start of treatment. As of March 2013, the overall median duration of response was 24.0 months, and 58% of responding patients continued to show tumor shrinkage compared with baseline. Dr. Sznol further pointed out, “Of 17 patients who went off drug for reasons other than disease progression, 12 [71%] continued to respond for 16 or more weeks since the end of therapy.” Median overall survival with nivolumab reached 16.8 months across all doses and 20.0 months at the 3-mg/kg dose, thus comparing favorably with historical data from agents such as ipilimumab and vemurafenib. Moreover, 62% of patients survived to 1 year and 43% to 2 years. The most common adverse events associated with nivolumab were toxicities affecting the skin, gastrointestinal tract, and endocrine system. However, grade 3/4 occurrence of these events was rare and never exceeded 2%. Nivolumab is currently being evaluated in three ongoing phase III trials in advanced melanoma. “I think there’s a general sense that the therapeutic index [of nivolumab] over ipilimumab is positive,” commented Dr. Margolin. “I doubt that many of us in this audience really have a strong hesitation about putting our patients in such a phase III trial.”


    Thanks Erin!!

    Say were Merk and BMS giving out any free PD-1 samples? 😆



    Jeff –

    Too funny! But with all the trials being added its almost like they are giving it away!

    I’ll keep you guys posted on other things as I finish sorting threw it! I’m sure also that Catherine will have lots to update on since she was running all over the place!



    Shirley Z

    Great job Erin! Thanks! Hope you are feeling well.

    Shirley Z


    Thank you! Would be great if brain mets were allowed, too.


    Angela21 wrote:

    Thank you! Would be great if brain mets were allowed, too.

    We have to believe that day is coming.

    Catherine Poole

    Thanks Erin, you are terrific for helping us out. I barely got home to catch my breath and ended up in the ER for an injury this morning. Erin has filled you in very nicely and I have written a short piece for our blogs andf newsletter to reach you soon. Access will improve, competition is fierce! Pd1s will emerge from many big pharma and combinations seem the most promising. BRaf/mek will be available by perscription by July or sooner. Great new weapon in our arsenal.

    Erin, you are the best, thanks so much for holding down the fort while I traversed Chicago and ASCO!

    PS Still no great news on brain mets, but radiation works pretty darn good for now.

    Shirley Z


    Are you ok? Hope its nothing serious. Slow down a bit.

    Shirley Z


    Thanks Catherine for inviting me along!

    Shirley! doing alright… at this point totally exhausted! Got home Monday from asco and Tuesday morning left for Baton Rouge for work. Realized this evening I have hit my exhaustion level when I left my purse in the rental car… luckily our hotel wasn’t too far!

    Time for rest. 4:30am shuttle to the airport! Hope you’re doing well!



    Thank you both for the great updates. Hope everything is ok Catherine.

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