Tuesday, December 10, 2019

Reviews of T-VEC in melanoma patients: alone, with ipi or with pembrolizumab ~


I have been a fan of intraleional (also referred to as intratumoral) treatment - therapies that are injected directly into melanoma lesions - for a long time.  Here are a bazillion reports: Intralesional therapies for melanoma

While T-VEC is currently the only version with FDA approval, here is a list of some of the drugs most often used:
CAVATAK - derived from the Coxsackievirus
T-VEC - also called OncoVEX, Imlygic,  or Talimogene Laherparepvec - uses the herpes virus with GM-CSF
PV-10 - derived from Rose Bengal
HF10 - also derived from HSV
SD101 - a TLR9 agonist
IL-2 -  is also being used

Now this -

Patterns of response with talimogene laherparepvec in combination with ipilimumab or ipilimumab alone in metastatic unresectable melanoma.  Chesney, Puzanov, Collichio, et al. Br J Cancer. 2019 Jul 29. 

Talimogene laherparepvec (T-VEC) has demonstrated efficacy for unresectable melanoma. We explored response patterns from a phase 2 study evaluating patients with unresectable stage IIIB-IVM1c malignant melanoma who received T-VEC plus ipilimumab or ipilimumab alone. Patients with objective response per modified irRC were evaluated for pseudo-progression (single greater than/= to 25% increase in tumour burden before response). Patients without pseudo-progression were classified by whether they responded within or after 6 months of treatment start; those with pseudo-progression were classified by whether pseudo-progression was due to increase in existing lesions or development of new lesions. Overall, 39% (n = 38/98) in the combination arm and 18% (n = 18/100) in the ipilimumab arm had an objective response. Eight responders (combination, n = 7; ipilimumab, n = 1) had pseudo-progression; most occurred by week 12 and were caused by an increase in existing lesions. These data reinforce use of T-VEC through initial progression when combined with checkpoint inhibitors.

We already have this report from 2017:  T-VEC plus ipi vs ipi alone ~ along with additional T-VEC data...  where it is noted that:  "...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."...

Now, this -

Response to the Rechallenge With Talimogene Laherparepvec (T-VEC) After Ipilimumab/Nivolumab Treatment in Patient With Cutaneous Malignant Melanoma Who Initially Had a Progression on T-VEC With Pembrolizumab.  Afzal, Shirai.  J Immunother. 2019 Mar 29.  

Talimogene laherparepvec (T-VEC) is approved for unresected stage III-IV malignant melanoma. T-VEC has a direct cytotoxic effect and enhances the antitumor immunity of host cells. Immune checkpoints inhibitors also enhance the immunity of host cells by increasing the recruitment of antigen-presenting cells or activation and restoration of T-cell functions. Both type of therapies can potentiate the effect of the other therapy. We are reporting a case of T-VEC rechallenge who initially progressed on T-VEC with pembrolizumab but then responded to T-VEC rechallenge after intervening ipilimumab/nivolumab. An 83-year-old man developed a subungual lesion of the left thumb and found to have AJCC V. 7 stage IIIb melanoma. Few months later, he developed axillary lymphadenopathy and multiple subcutaneous nodules (AJCC V. 7 stage IIIc). The patient was started on intralesional rose Bengal and pembrolizumab. After 4 cycles of pembrolizumab with rose Bengal, a positron-emission tomography/computerized tomography scan showed the progression of disease. He was started on T-VEC intralesional injections with concurrent pembrolizumab, however, after 3 T-VEC injections and 2 more cycles of pembrolizumab, there was the progression of disease. Subsequently, ipilimumab/nivolumab was started and patient responded partially. Ipilimumab/nivolumab was held due to toxicity. Eight weeks from the last dose of ipilimumab/nivolumab, he experienced locoregional progression and was rechallenged with T-VEC monotherapy. The patient showed a significant response after second T-VEC injection and continued to show response 6 months since rechallenge. After, initial progression on T-VEC with pembrolizumab, intervening immune checkpoints inhibitors may favorably modify the antitumor immunity and potentiate antitumor effect of T-VEC rechallenge.

Cases like this are so difficult to understand - by the patient - poor soul, mostly - but also:  Did the rechallenge with T-VEC really turn the tide?  Or - did all the other therapies - or ONE of the other therapies - finally kick in and just needed more time to work?  We really can't say.  Patients who have experienced multiple therapies and then finally respond, hold the key to many questions.  I'm just not sure we know what exactly they unlock.

Then, this -

Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma.  Andtbacka Collichio, Harrington, et al.  J Immunother Cancer. 2019 Jun 6.

Talimogene laherparepvec is an oncolytic immunotherapy approved in the US, Europe, Australia and Switzerland. We report the final planned analysis of OPTiM, a randomized open-label phase III trial in patients with unresectable stage IIIB-IVM1c melanoma.

Patients were randomized 2:1 to receive intratumoral talimogene laherparepvec or subcutaneous recombinant GM-CSF. In addition to overall survival (OS), durable response rate (DRR), objective response rate (ORR), complete responses (CR), and safety are also reported. All final analyses are considered to be descriptive and treatment responses were assessed by the investigators.

Of 436 patients in the intent-to-treat population, 295 were allocated to talimogene laherparepvec and 141 to GM-CSF. Median follow-up in the final OS analysis was 49 months. Median OS was 23.3 months (19.5-29.6) and 18.9 months (16.0-23.7) in the talimogene laherparepvec and GM-CSF arms, respectively . DRR was 19.0 and 1.4%; ORR was 31.5 and 6.4%. Fifty (16.9%) and 1 (0.7%) patient in the talimogene laherparepvec and GM-CSF arms, respectively, achieved CR. In talimogene laherparepvec-treated patients, median time to CR was 8.6 months; median CR duration was not reached. Among patients with a CR, 88.5% were estimated to survive at a 5-year landmark analysis. Talimogene laherparepvec efficacy was more pronounced in stage IIIB-IVM1a melanoma as already described in the primary analysis. The safety reporting was consistent with the primary OPTiM analysis.

In this final planned OPTiM analysis, talimogene laherparepvec continued to result in improved longer-term efficacy versus GM-CSF and remained well tolerated. The final analysis also confirms that talimogene laherparepvec was associated with durable CRs that were associated with prolonged survival.

This is one of those studies that gets on my nerve.  We wouldn't have expected GM-CSF to do much better than it did!!!!  But, I guess it shows what T-VEC can do on its own.

And finally, this:

Intratumoral Immunotherapy-Update. Hamid, Ismail, Puzanov.  Oncologist.  2019 Nov 29.

Intratumoral immunotherapies aim to trigger local and systemic immunologic responses via direct injection of immunostimulatory agents with the goal of tumor cell lysis, followed by release of tumor-derived antigens and subsequent activation of tumor-specific effector T cells. In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV-10 and toll-like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa-Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types. Talimogene laherparepvec (T-VEC), a genetically modified herpes simplex virus type 1-based oncolytic immunotherapy, is the first oncolytic virus approved by the U.S. Food and Drug Administration for the treatment of unresectable melanoma recurrent after initial surgery. In patients with unresectable metastatic melanoma, T-VEC demonstrated a superior durable response rate (continuous complete response or partial response lasting greater than/= to6 months) over subcutaneous GM-CSF (16.3% vs. 2.1%). Responses were seen in both injected and uninjected lesions including visceral lesions, suggesting a systemic antitumor response. When combined with immune checkpoint inhibitors, T-VEC significantly improved response rates compared with single agent; similar results were seen with combinations of checkpoint inhibitors and other intratumoral therapies such as CAVATAK, HF10, and TLR9 agonists. In this review, we highlight recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on T-VEC in the treatment of advanced melanoma as a model for future solid tumor indications.

IMPLICATIONS FOR PRACTICE: This review provides oncologists with the latest information on the development of key intratumoral immunotherapies, particularly oncolytic viruses. Currently, T-VEC is the only U.S. Food and Drug Administration (FDA)-approved oncolytic immunotherapy. This article highlights the efficacy and safety data from clinical trials of T-VEC both as monotherapy and in combination with immune checkpoint inhibitors. This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T-VEC, the only U.S. FDA-approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T-VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.

For those interested, here's a direct link to the abstract above:  Intratumoral Immunotherapy-Update 2019.

So - there you have it. NOW!!!  We need direct head-to-head comparisons of some of these other intralesionals (PV-10, CAVATAK, etc.) to T-VEC.  I also think it is clear that generally, intralesional therapy COMBINED with anti-PD-1 is the way to go - whether you are Stage III or IV.   But, that's just me...

Thanks, ratties.  You change the world! - c

8 comments:

  1. I have several question . I am stage 3c. You may have posted and I would appreciate your direction to those posts.
    Regarding CLND, your last comment was' time to move on' meaning in your mind that debate is settled? and what did you settle on? I am not being obtuse but I am not going to interpret anything anyone says.

    As regards 5 year survival study, Keynote -001, isn't there therapies that involves more than one drug or am I wrong about that? If so what are their survivability outcomes?

    your blog is a tremendous help BTW. my docs don't seem to communicate nor do they as a rule give me all the info I need to make descisons. in my case CLND is on the decision tree and right now it seems like I will have to flip a coin to decide yeah or neah.

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  2. Use the search bubble at the top left of the page. It is your friend. Here is a link to tons of data on CLND:
    https://chaoticallypreciselifeloveandmelanoma.blogspot.com/search?q=CLND

    All recent data has come to the conclusion reported in this 2019 article: "Performance of CLND provides prognostic information but is not associated with a survival benefit. Clinical variables can predict a positive CLND in patients who may be at high risk of recurrence." Meaning - sentinel node biopsy makes a difference because your stage is defined and thereby your therapy options are identified. CLND does not lengthen your life. When you add all the data that NEO-adjuvant care is providing the impact is even greater to me. Given all the things we need to study and learn about that we do not know re melanoma and the time and effort that has been spent examining the value (or not) of CLND - my quote was " given the advances in melanoma therapy, it is probably time to move on!"

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  3. RE KEYNOTE-001 - from the report:
    'KEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months and 38.6 months, respectively"

    This post from October of this year - https://chaoticallypreciselifeloveandmelanoma.blogspot.com/2019/10/ipinivo-combo-5-year-overall-survival.html notes the following:

    "At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group. Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group."

    Again, the search bubble is your friend!

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  4. This primer that covers melanoma and its treatments may be helpful for you to get an overview:

    https://chaoticallypreciselifeloveandmelanoma.blogspot.com/2017/08/melanoma-intel-primer-for-current.html

    The ipi/nivo combo is FDA approved for Stage IV and Stage III patients with unresectable disease - in other words not for stage III patients who have had their disease removed by surgery or radiation. There are adjuvant studies ongoing in Stage III patients where the nivo is being compared to the ipi/nivo combo that I think will end up in getting the combo approved - though that is just my thought and I cannot say when that approval would occur. I don't know if those studies are still enrolling or not. Luckily, both anti-PD-1 products are FDA approved for adjuvant care as are some of the BRAF/MEK combo's (for those who are BRAF positive).

    Hope this helps.

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  5. My oncologist gave me the NCCM Guidelines v.3.2019 Subcutaneous Melanonama with some hand drawn lines pointing to Nivo and asking me when the surgeon will do the CLNB. She made some general comments on immunotherapy and how I would live a long time to come.

    The surgeon on the other hand spoke against CLND.

    I am a guy, on my own , trying to decipher the jargon whilst not trying to be too big a horses's ass to people whose judgement I must rely on to save my life. I don't see myself directly challenging the oncologist with the surgeon's opinion.

    I get it, its big business, and bureaucratic. and no one that I have encountered so far appears indifferent. But it is treacherous terrain and wrong decisions can be disastrous. In my brief sojourn into Cancerland there have been a lot of miscoummications and misdirections from the pros.

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  6. Finally, you need to be sure you are seeing a melanoma specialist...or at least a local onc who takes care of many melanoma patients. It can make all the difference in the care you attain and therefore the outcome of that care.

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  7. If your onc is still advocating CLND for a melanoma patient - you need a new oncologist. Just my 2 cents but I would be out the door. It is your life. The best advocate you have is you. It is a shame it has to be that way. But - it is.

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  8. Another thought - You may find some great advice and support from the folks on this forum: https://melanoma.org/legacy/find-support/patient-community/mpip-melanoma-patients-information-page

    Hang in there. Melanoma world is incredibly foreign at first....but eventually the language begins to make sense. I wish you my best. Ask more questions as you have the need.

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