News on MPDL3280A (anti PD-L1) 2013 ASCO (UPDATED ESMO)

[Maia]

Promising news on MPDL3280A (Roche Genentech), an immunotherapeutic drug that targets PD-L1 gene protein.
(This if for you, Dianne052506... hang in there! : )

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Promising drug prevents cancer cells from shutting down immune system

31 May 2013 19:19:03 yale.edu

An investigational drug that targets the immune system’s ability to fight cancer is showing promising results in Yale Cancer Center (YCC) patients with a variety of advanced or metastatic forms of the disease. Updated data from this Phase 1 clinical trial are being formally presented at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. Yale Cancer Center is one of the lead trial sites. The abstract was made public by ASCO in advance of the meeting.

The drug, known as MPDL3280A and manufactured by Roche Genentech, is designed to prevent a cancer cell’s mutated and overexpressed PD-L1 gene protein from putting the immune system to sleep. The overexpressed PD-L1 protein turns off the immune system’s T-cells by binding to its PD-1 and B7.1 proteins. In doing so, it disguises itself and evades detection and destruction by the body’s immune response.

This new drug is the latest advance in the burgeoning field of immunotherapy, which aims to boost the body’s immune system to fight the foreign pathogens of cancer. By blocking the cancer tumor’s PD-L1 protein, MPDL3280A frees the immune system to do its job. This PD-L1 targeted antibody was specially engineered to increase safety and efficacy over earlier immunotherapy agents.

Yale oncologists report that the efficacy of MPDL3280A was evaluated in 140 patients with locally advanced or metastatic solid tumors who had exhausted other means of therapy. Tumor shrinkage was observed in patients with non-small cell lung cancer, melanoma, kidney cancer, colorectal cancer, and gastric cancer. Yale oncologists say ongoing, durable responses were observed in nearly all patients who responded to the drug. Overall, 29 out of 140 patients (21 percent) experienced significant tumor shrinkage, and the highest number of responses were in patients with lung cancer and melanoma.

MPDL3280A was generally well tolerated, they say, with few immune-related adverse events. Some patients were continuing to respond more than a year after starting treatment.

“We have been very impressed by the response in seriously ill patients whose cancer had metastasized. So far, almost none of those who showed tumor shrinkage have gotten worse, which is extraordinary,” said lead author Roy Herbst, M.D., professor of medicine and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven. “Immunotherapy treatment is providing new hope for cancer patients,” he added.

Further studies will be needed, including randomized clinical trials, to confirm the safety and effectiveness of MPDL3280A, and to develop methods to determine whether a patient will indeed respond to the anti-PD-L1 drug.

http://news.yale.edu/2013/05/31/promisi ... une-system

[Maia]

The abstract:

A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors.

Sub-category: Immunotherapy and Biologic Therapy

Category: Developmental Therapeutics - Immunotherapy

Meeting: 2013 ASCO Annual Meeting

Abstract No: 3000

Citation: J Clin Oncol 31, 2013 (suppl; abstr 3000)

Author(s): Roy S. Herbst, Michael S. Gordon, Gregg Daniel Fine, Jeffrey Alan Sosman, Jean-Charles Soria, Omid Hamid, John D. Powderly, Howard A. Burris, Ahmad Mokatrin, Marcin Kowanetz, Maya Leabman, Maria Anderson, Daniel S. Chen, F. Stephen Hodi; Yale University, New Haven, CT; Pinnacle Oncology Hematology, Scottsdale, AZ; Genentech, Inc., South San Francisco, CA; Vanderbilt-Ingram Cancer Center, Nashville, TN; Institut Gustave Roussy, Villejuif, France; The Angeles Clinic and Research Institute, Los Angeles, CA; Carolina BioOncology Institute, Huntersville, NC; Sarah Cannon Research Institute, Nashville, TN; Genentech Inc., South San Francisco, CA; Dana-Farber Cancer Institute, Boston, MA

Abstract:

Background: Tumor PD-L1 mediates cancer immune evasion. Therefore, inhibition of PD-L1 binding represents an attractive strategy to restore tumor-specific T-cell immunity.MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1.
Methods: A study was conducted with MPDL3280A administered IV q3w in pts with locally advanced or metastatic solid tumors, including 3+3 dose-escalation and expansion cohorts. ORR was assessed by RECIST v1.1 and includes u/cCR and u/cPR.
Results: As of Jan 10, 2013, 171 pts were evaluable for safety. Administered doses include ≤1 (n=9), 3 (n=3), 10 (n=35), 15 (n=57) and 20 mg/kg (n=67). Pts in the dose-escalation cohorts did not experience DLTs. No MTD was identified. Pts had received MPDL3280A for a median duration of 127 days (range 1-330). 39% of pts reported G3/4 AEs, regardless of attribution. AEs of special interest included hepatitis, rash and colitis. No G3-5 pneumonitis was observed. MPDL3280A PK was linear at doses ≥1 mg/kg. 122 pts enrolled prior to Jul 1, 2012 were evaluable for efficacy. RECIST responses were observed in multiple tumor types including NSCLC, RCC, melanoma, CRC and gastric cancer. An ORR of 21% (25/122) was observed in nonselected solid tumors, including several pts who demonstrated tumor shrinkage within days of initiating treatment. Additional pts had delayed responses after apparent radiographic progression (not included in the ORR). Some responders demonstrated prolonged SD prior to RECIST responses. The 24-week PFS was 44%. Pts with PD-L1–positive tumors (from archival samples) showed an ORR of 39% (13/33) and a PD rate of 12% (4/33). In contrast, patients with PD-L1–negative tumors showed an ORR of 13% (8/61) and a PD rate of 59% (36/61). As of the cutoff date, all responses are ongoing or improving. Updated data will be presented.
Conclusions: MPDL3280A was well tolerated, with no pneumonitis-related deaths. Durable responses were observed in a variety of tumors. PD-L1 tumor status appears to correlate with responses to MPDL3280A. PK supports q3w dosing at 15 mg/kg or fixed-dose equivalent.
Clinical trial information: NCT01375842.

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“This therapy has the potential to be used in almost every tumor type,” Herbst said in an interview. “It’s just the tip of the iceberg so far. We’re still figuring out exactly what the right biomarker is going to be to predict the most responsive population.”

"In a biomarker analysis, responses were better among patients with higher levels of PD-L1 expression. The response rate among PD-L1-positive patients was 36% (13 of 36 patients), compared with 13% (9 of 67 patients) who were PD-L1-negative."

More data in: Early Results Robust for New PD-L1 Immunotherapy Agent

[vickitwo]

Maia, Like I have said before, you are a gem. Thanks for providing the information that you do. Hope your daughter is doing better.

[Maia]

You're welcome, Vicki!
And yes, she's doing better (it was not a worsening of her epilepsy but toxicity from the anticonvulsant med she's taking! I should share what happened to us, maybe could be useful. But we're still working on it). You're so sweet, thank you : )

[Maia]

Other presentation:

Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic CRC, gastric cancer (GC), SCCHN, or other tumors.

Subcategory: Colorectal Cancer
Category: Gastrointestinal (Colorectal) Cancer
Meeting: 2013 ASCO Annual Meeting
Session Type and Session Title: General Poster Session, Gastrointestinal (Colorectal) Cancer
Abstract Number: 3622


Citation: J Clin Oncol 31, 2013 (suppl; abstr 3622)

Author(s):

Josep Tabernero, John D. Powderly, Omid Hamid, Michael S. Gordon, George A. Fisher, Fadi S. Braiteh, Lawrence E. Garbo, Gregg Daniel Fine, Marcin Kowanetz, Bruce McCall, Xiaodong Shen, Daniel S. Chen, Holbrook Edwin Kohrt; Vall d'Hebron University Hospital, Barcelona, Spain; Carolina BioOncology Institute, Huntersville, NC; The Angeles Clinic and Research Institute, Los Angeles, CA; Pinnacle Oncology Hematology, Scottsdale, AZ; Stanford University, School of Medicine, Stanford, CA; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; New York Oncology Hematology/US Oncology, Albany, NY; Genentech, Inc., South San Francisco, CA; Genentech Inc., South San Francisco, CA

Abstract

Background: PD-L1 has been reported to be expressed broadly in human cancer and can lead to inhibition of anti-tumor T-cell responses. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Pts with a broad range of tumors were examined in an expansion study with MPDL3280A.
Methods: Pts with locally advanced or metastatic tumors received MPDL3280A administered IV q3w. Pts were treated for up to 1 y. Response was assessed by RECIST v1.1.
Results: As of Jan 10, 2013, 20 pts with tumor types other than NSCLC, RCC and mM were evaluable for safety and treated at doses of 0.01-20 mg/kg (≤1 [n=3], 3 [n=1], 10 [n=3] and 20 mg/kg [n=13]). Median pt age was 67 y (range 26-80 y), 100% were PS 0-1, 90% had prior surgery and 45% had prior radiotherapy. 95% of pts received prior systemic therapy. Pts received MPDL3280A treatment for a median of 96 days (range 22-330). The incidence of all G3/4 AEs, regardless of attribution, was 50%. No G3-5 pneumonitis or diarrhea was reported. Confirmed RECIST responses were observed in several tumor types, including CRC, GC and SCCHN. Additionally, antitumor activity (tumor shrinkage that has not yet met criteria for a RECIST response) has been observed in sarcoma and lymphoma. Analysis of biomarker data from archival tumors revealed that all pts reported to have RECIST response had baseline tumors that were PD-L1 positive. Updated data will be presented.
Conclusions: Treatment with MPDL3280A was well tolerated, with no pneumonitis-related deaths. Rapid responses were observed in pts with CRC, GC and SCCHN. PD-L1 tumor status appears to correlate with responses to MPDL3280A. These data suggest that PD-L1 is a conserved mechanism for mediating tumor immune escape across a range of tumor types. MPDL3280A may be broadly active as anti-cancer therapy in PD-L1–expressing tumors, supporting further investigation. Clinical trial information: NCT01375842.

[usopen]

Thank you Maia. You are so caring, upbeat, intelligent.....i won't go on and on (but i could), because I don't want to embarrass you (I can tell you are humble, too).
Ok, I'll stop.

I, too, have been thinking about you and your daughter.

My nightly ritual is to light a (flameless) candle and dedicate it to someone. Tonight it will be for you and your family, also for your dear friend.
(I have been WAY too focused on myself, and this makes me focus on others).

Take good care.

Joan

[Maia]

Oh Joan... just thank you

[SkiFletch]

Wow, that's an impressive response. Hope it keeps up

[mackswife]

Maia - I don't know how you find all of this fabulous information, but I thank you for the effort you put into it, and for your generosity is sharing it with us. For me, these posts of yours are like drinking a refreshing glass of HOPE! Blessings to you and yours,

Pattie

[concernedrelative]

For some starting the heavy research lift on these topics, hope this helps. Early days for my understanding but this area seems to be THE only exciting stuff coming out of this ASCO for mCRC.

http://www.landesbioscience.com/journal ... MM0226.pdf

Targeting PD-1/PD-L1 interactions for cancer immunotherapy

[Maia]

Pattie, thanks! : )

Concerned, that is a very good article that clarifies information about the difference between PD-1 and PD-L1. Wish I could explain it well, for those interested in the drugs tha Roche-Genentech, Bristol-Myers and Merck are developing.

PD-1 and PD-L1 belong to a same 'pathway', in cancer biology. Some tumours take that route to throw off the agents of the immune system. "PD-1" is "something", a receptor, on activated T cells (if you want, PD-1 is part of the immune system). "PD-L1" is "something", a ligand (that's why the "L"), on the tumour cells (is you want, PD-L1 is part of the 'cancer'). That's why you can get a tumour sample tested to see if it has a high PD-L1 expression. On the other hand, we all have PD-1 receptors.
So. There is an immunotherapy drug that targets PD-L1 on cancer cells (which use the programmed death ligand to thwart attacks from immune cells that express PD-1); this is Genentech-Roche (MPDL320A or MPDL3280A, the one we're discussing in this thread). And there are others that target PD-1 on immune cells ; those are Bristol-Meyer nivolumab (BMS-936559, aka MDX1106; this was the big star of ASCO 2013 with the good results for melanoma) and Merck's lambrolizumab (MK-3475; with good results for melanoma too).
There are different arguments favouring both, drugs that target PD-1 and PD-L1, but I guess everyone reading this, myself included, is exhausted by now. LOL

[Maia]

Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic CRC, gastric cancer (GC), SCCHN, or other tumors.

Subcategory: Colorectal Cancer
Category: Gastrointestinal (Colorectal) Cancer
Meeting: 2013 ASCO Annual Meeting
Session Type and Session Title: General Poster Session, Gastrointestinal (Colorectal) Cancer
Abstract Number: 3622

Citation: J Clin Oncol 31, 2013 (suppl; abstr 3622)

Author(s):

Josep Tabernero, John D. Powderly, Omid Hamid, Michael S. Gordon, George A. Fisher, Fadi S. Braiteh, Lawrence E. Garbo, Gregg Daniel Fine, Marcin Kowanetz, Bruce McCall, Xiaodong Shen, Daniel S. Chen, Holbrook Edwin Kohrt; Vall d'Hebron University Hospital, Barcelona, Spain; Carolina BioOncology Institute, Huntersville, NC; The Angeles Clinic and Research Institute, Los Angeles, CA; Pinnacle Oncology Hematology, Scottsdale, AZ; Stanford University, School of Medicine, Stanford, CA; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; New York Oncology Hematology/US Oncology, Albany, NY; Genentech, Inc., South San Francisco, CA; Genentech Inc., South San Francisco, CA

Abstract

Background: PD-L1 has been reported to be expressed broadly in human cancer and can lead to inhibition of anti-tumor T-cell responses. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Pts with a broad range of tumors were examined in an expansion study with MPDL3280A.
Methods: Pts with locally advanced or metastatic tumors received MPDL3280A administered IV q3w. Pts were treated for up to 1 y. Response was assessed by RECIST v1.1.
Results: As of Jan 10, 2013, 20 pts with tumor types other than NSCLC, RCC and mM were evaluable for safety and treated at doses of 0.01-20 mg/kg (≤1 [n=3], 3 [n=1], 10 [n=3] and 20 mg/kg [n=13]). Median pt age was 67 y (range 26-80 y), 100% were PS 0-1, 90% had prior surgery and 45% had prior radiotherapy. 95% of pts received prior systemic therapy. Pts received MPDL3280A treatment for a median of 96 days (range 22-330). The incidence of all G3/4 AEs, regardless of attribution, was 50%. No G3-5 pneumonitis or diarrhea was reported. Confirmed RECIST responses were observed in several tumor types, including CRC, GC and SCCHN. Additionally, antitumor activity (tumor shrinkage that has not yet met criteria for a RECIST response) has been observed in sarcoma and lymphoma. Analysis of biomarker data from archival tumors revealed that all pts reported to have RECIST response had baseline tumors that were PD-L1 positive. Updated data will be presented.
Conclusions: Treatment with MPDL3280A was well tolerated, with no pneumonitis-related deaths. Rapid responses were observed in pts with CRC, GC and SCCHN. PD-L1 tumor status appears to correlate with responses to MPDL3280A. These data suggest that PD-L1 is a conserved mechanism for mediating tumor immune escape across a range of tumor types. MPDL3280A may be broadly active as anti-cancer therapy in PD-L1–expressing tumors, supporting further investigation. Clinical trial information: NCT01375842.

The ASCO poster presentation for that one. Observe Figure 6 (Anti-tumour activity in CRC)

[Maia]

Update from ESMO (European Society for Medical Oncology) conference, sept 27 - oct 1st 2013. It's for non-small cell lung cancer but very promising, anyway.
About

PD-L1 Inhibitor Delivers Rapid, Durable Responses in Advanced NSCLC

Published Online: Sunday, September 29, 2013

A phase I study has shown remarkable and durable responses with the engineered monoclonal antibody MPDL3280A (MPDL) in metastatic non-small cell lung cancer (NSCLC), including tumors with squamous and adenocarcinoma histology. This immunotherapy, which inhibits PD-L1, had more robust responses in smokers who typically have a poorer response to therapy than nonsmokers with NSCLC.

“We are at the beginning of a new era. After 30 years of research in immunotherapy for lung cancer, bingo, we have one that one works, and it works in smokers,” said lead author Jean-Charles Soria, MD, Institut Gustav Roissy, Paris, France, in presenting the results at the European Cancer Congress (ECC) 2013 held September 27-October 1 in Amsterdam, Netherlands.

“This is the first study to suggest a potential relationship between smoking history and response to inhibiting PD-L1/PD-1 pathway—a pathway that is instrumental in enabling cancer cells to escape detection in by the immune system. In this study, smokers responded much better than nonsmokers. The data are preliminary, but the trends are extremely promising,” Soria said.

- See more at: http://www.onclive.com/conference-cover ... WAUni.dpuf