Tuesday, June 9, 2015

ASCO: Knowledge Part I - Phase 1 Immunotherapy studies

While at the ASCO meeting I viewed a large number of posters  and listened to sessions reporting on the  results of new immunotherapy treatments.  Here are four  in the initial stages of testing that  caught my eye.  

Poster  Board:  #95    First ­in ­human  phase I/II  dose­ escalation  study  of  IMAB027  in  patients  with  recurrent  advanced  ovarian  cancer  (OVAR):  Preliminary  data  of  

phase  I  part. 
Ugur  Sahin,  MD

This study was done in a group of women (median age 64 years) that had been highly pretreated, meaning they had multiple ( 4 +) prior treatments for their disease. This Phase I/II study ( safety and dosage levels)  used IMAB027 is the first-in-class monoclonal antibody (mAB) directed against claudin 6 (CLDN6), a cancer stem cell marker. Claudin-6 is expressed in 55% of ovarian cancers. The 12 women in the study were all claudin 6+. There were some adverse events recorded but the majority were grade 1-2 (the lower the grade the less severe the adverse effect). The first signs of clinical activity were observed. 

Conclusions: This is the first clinical study to show effects of a therapy targeting CLDN6. Based on these preliminary Phase I data, IMAB027 may present a safe and well tolerated treatment option for women with recurrent, advanced OC. This warrants further clinical evaluation of IMAB027

Poster  Board:  #116  Phase 1 study of  IMGN853,  a  folate  receptor  alpha  (FRα )targeting  antibody­ drug conjugate (ADC) in  patients (Pts) with epithelial ovarian cancer (EOC)
and other  FRα ­positive  solid  tumors
Hossein  Borghaei,  DO,  MS

This Phase 1 trial included 23 women with platinum resistant epithelial ovarian cancer , 11 women with endometrial cancer as well as 1 cervical, 4 non-small cell lung cancer and 5 renal cancer patients. The study was done to determine safety, pharmacokinetics (PK – how the drug moves through the body), tolerated dose, and evidence of activity of IMGN853 in ovarian cancer or other FRa-positive solid tumors. 
“IMGN853 (mirvetuximab soravtansine) is a folate receptor α-targeting anti-body drug conjugate (ADC ) comprising a FRα-binding antibody and potent maytansinoid, DM4.”  
 In other words,  IMGN853 binds to Folate Receptor α on cancer cells and is internalized; the DM4 ( a tubulin-acting agent) is released through the degradation of the antibody and it disrupts cell division and causes cell death. Two different schedules were used (A) once every 3 weeks and (B) Days 1, 8, and 15, every 4 weeks. The adverse effects were mostly grade 1 or 2.  Initial results show partial and complete clinical response as well as  CA-125 response. In A schedule, 11 of 44 patients showed complete response(CB), 4/44 showed partial response(PR)  and 5 showed stable disease (SD) . Using schedule B,  5/15 showed CR, 1 PR, 4 SD. 

"Conclusion: With both schedules,IMGN853 demonstrates encouraging clinical activity in heavily pretreated patients during dose escalation with a manageable AE profile. A RP2D has been identified for schedule A, while schedule B continues dose finding."

The following results were presented in a session called
Intersection of  Mutanome and the Immunome on Monday afternoon.

Avelumab  (MSB0010718C), an anti­PD­L1 antibody, in  patients  with  previously  treated,  recurrent  or  refractory  ovarian  cancer:  A  phase Ib, open-­label  expansion  trial.                        
Mary  L.  Disis

Slide on Avelumab from Dr Disis' presention

Avelumab  (MSB0010718C) is a human anti-PD-L1 IgG1 antibody.  PD-1 is a programmed death -1 receptor and PD-L1 is it’s ligand ( protein) are targets that can help to reactivate  a person’s immune system.
The patients enrolled in this Phase 1b study were not chosen based on PDL-1 expression. All patients had recurrent ovarian cancer and had multiple prior treatments. 52% of the patients reported adverse effects mostly fatigue, nausea, chills and diarrhea . Of the 23 patients currently enrolled and followed for 2-8 months,  4 patients showed best overall response, 11 had stable disease and 4 had a shrinkage of their tumor of >30%. During the presentation it was reported that patients who had smaller tumor burdens had a better response.

"Conclusions: These data represent the largest reported dataset of patients with recurrent ovarian cancer treated with anti-PD-L1 therapy. Avelumab demonstrated an acceptable safety profile and is clinically active in this heavily pretreated ovarian cancer pt population."

Antitumor activity and safety of pembrolizumab in patients (pts) with  PD-­L1 positive advanced ovarian  cancer: Interim results from a phase Ib study                              
Andrea  Varga,  MD

Slide from Dr Varga's presentation

This was the second of two presentations on anti-PDL-1 immunotherapy treatments that I heard. Pembrolizumab is a monoclonal antibody against PD-1 and blocks the interaction of PD-L1 and PD-L2 . It also removes any blockage by the cancer cells of the body’s T-cells. T-cells are part of your body’s immune response to cancer. This study unlike the previous study with Avelumab was with women who were determined to be PD-l+. They received 10mg/kg of Pembrolizumab every two weeks. Twenty-six patients (median age 56) were enrolled.  Over 80% had prior treatments. There were no grade 4 or 5 adverse effects. Reported effects include fatigue, anemia  and loss of appetite. One patient had complete response, 2 had partial response and 6 had stable disease. 23% of the patients had experienced a decrease in their targeted lesions.

"Conclusions: PD-1 blockade with pembrolizumab is well tolerated and has antitumor activity in pts with advanced ovarian cancer. This preliminary signal for clinical efficacy will be further investigated."

Note:To learn more about pembrolizumab ( Keytruda) , which is approved for melanoma visit https://www.keytruda.com/melanoma/how-keytruda-works/index.xhtml

These handful of studies are just the tip of the iceburg when it comes to targeted immunotherapy treatments for gynecologic cancers. I look forward to hearing the results of future Phase II and III studies.  

In the next post I will write about the session I heard on Managing Ovarian Cancer in the Older Patient.

Every Day is a Blessing!

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