GRACE :: Lung Cancer

Lung Cancer

Dr. Goldman

Why Carboplatin, Pemetrexed and Pembrolizumab Have Become My New Go-to Regimen for First-Line Non-Squamous NSCLC Treatment

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Why carboplatin, pemetrexed and pembrolizumab have become my new go-to regimen for first-line non-squamous NSCLC treatment.

By Jonathan W. Goldman, MD


Metastatic non-small cell lung cancer (NSCLC) treatment has generally improved by optimizing care for “slices of the pie”—pieces of a pie chart representing all of lung cancer patients. Initially, mutation-based treatment led the way; 10% of lung cancers were identified as EGFR-mutant and treated with appropriate tyrosine kinase inhibitors. Subsequently, thinner and thinner slices of the population, each 1-7% of NSCLC patients, have been described and their cancers targeted. More recently, immunotherapy entered the picture, but again the greatest benefit of this therapy was limited to the 20-25% of patients that were PD-L1 positive. Despite all of these advances, we still had at least half of patients receiving more than 10-year-old chemotherapy as their initial treatment.

We now have preliminary evidence that this may be changing. Langer, et al reported in November 2016 (Lancet Oncology) the phase 2 KEYNOTE-021-G1 cohort of non-squamous NSCLC patients treated with the standard, carboplatin and Alimta (pemetrexed), alone or with the PD-1 inhibitor, Keytruda (pembrolizumab). Previous attempts to add to a platinum-doublet had generally provided marginal benefits at best (for example, with Avastin [bevacizumab] or Erbitux [cetuximab]). In contrast, the 021G trial suggested massive benefits, at least as far as response rate (RR) and progression free survival (PFS).

The 021G trial was a moderate-sized phase 2 trial with 123 patients split between the two arms. With Keytruda added to chemotherapy, the response rate increased from 29 to 55%, and importantly this benefit was irrespective of PD-L1 status (above or below a 1% PD-L1 cutoff). PFS was also significantly improved from 8.9 to 13.0 months with a hazard ratio of 0.53, which represents a decrease in the risk of cancer progression by almost half. Many of the trials leading to new drug approvals especially in an unselected cohort report hazard ratios of 0.75 or 0.80, so the benefit in 021G is staggering. The overall survival curves were overlapping at the time of the initial report, and if they suggested a possible survival benefit when updated at the 2017 ASCO Annual Meeting, there was still no statistically significant difference. This lack of a clear survival benefit is certainly at least in part due to crossover at the time of progression from the chemotherapy alone arm to get Keytruda or another immunotherapy (32% within the study and 74% if you count receiving an immunotherapy agent at any point, on or off the trial).

Furthermore, the toxicity associated with the addition of Keytruda was generally manageable, although moderate to severe toxicity (grade 3 or higher) was increased from 28 to 41%. Primarily, these were hematologic toxicities, including anemia and low blood counts, which oncologists are very comfortable managing. Stereotypical immunotherapy toxicities (such as pneumonitis, colitis or hepatitis) were reported at rates similar to previous experience with single-agent PD1 or PDL1 inhibitor therapy. Nevertheless, Keytruda was discontinued due to toxicities in 10% of patients, including in 1 patient with grade 3 pneumonitis, and doctors and patients will need to be on the lookout for such complications.

Many investigators and thought leaders were surprised when the FDA granted priority review for the front-line Keytruda-chemotherapy combination in January 2017. While lung cancer drug approvals had come from phase 2 or even phase 1 data before, that had consistently been for targeted therapy in areas of unmet need. However, just a few months later, on May 10, 2017 the FDA provided accelerated approval based on the RR and PFS benefits reported from KEYNOTE-021-G1. This does require verification in confirmatory trials including the KEYNOTE-189 trial, which mirrors the 021G trial but in a larger, phase 3 format.

This approval further shocked the lung cancer community. It certainly put standard treatment pathways and clinical trials, both open and in planning, in to disarray. However, from the FDA standpoint, how could you say no to a doubling in the response rate and a 50% decrease in the risk of progression? From the patient standpoint, there is now a novel treatment option that applies to the majority of patients. This is an event to celebrate.

There have been several lines of criticism of this combined treatment modality. The clearest is that if the overall survival curves remain overlapping, it may be advantageous to use chemotherapy and immunotherapy sequentially instead of concurrently. However, it seems likely that if the impressive RR and PFS advantages of concurrent therapy are real, they will translate into a survival advantage. It is also important to remember that patients can worsen rapidly during front-line therapy and never have the opportunity to benefit from a second-line treatment. If a survival advantage is not seen in the small phase 2 trial, it seems likely to be demonstrated in the larger phase 3 trial.

Another criticism of the concurrent approach is the associated medical and financial toxicity. Some presume that most patients will be benefiting from either the chemotherapy or the immunotherapy, and that by giving everything together, we are exposing patients to needless drug toxicity and society to unsustainable costs. One could respond, firstly, we do not know exactly how chemotherapy and immunotherapy may be interacting and there may be synergism beyond the efficacy of the individual parts. (Some hypothesize that tumor cell death via chemotherapy releases antigens that prime an immune response, which is then amplified into an immune effector response by immunotherapy.) Secondly, the toxicity profile as seen in the 021G trial shows that concurrent administration of chemotherapy and PD-1 blockade is tolerable for most patients. Thirdly, we have used expensive triplet regimens before (the best example being carboplatin, Alimta and Avastin) but at least with the 021G triplet there is evidence for major benefit.

In the end, we are all awaiting the confirmatory phase 3 trials of chemoimmunotherapy across many of the PD1 and PDL1 inhibitor drug-development pipelines. In the meantime, I applaud the FDA’s provisional approval and I am happy to be able to provide this as an option for my patients. I have heard some doctors state that they will reserve the triplet for patients that “need a response.” I have never met a patient who did not feel that he or she needed a response, and therefore the 021G triplet is my new go-to first-line regimen for non-squamous NSCLC patients without targetable mutations.


Dr. Goldman joins GRACE from UCLA Medical Center in Santa Monica, where he specializes in Hematology and Oncology.  He serves as Assistant Professor of UCLA Hematology & Oncology, Associate Director of Drug Development and Director of Clinical Trials in Thoracic Oncology.  


 

 

 

 


Denise Brock

Targeted Therapies Patient Forum September 2017 Speaker Highlight – Shirish M. Gadgeel, MD

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***Speaker Highlights***

for full faculty bio’s, please visit our FACULTY page


 Learn about Shirish M. Gadgeel, MD

 

Dr. Shirish Gadgeel is Co-Leader of the Thoracic Oncology Team in the Comprehensive Cancer Center at Michigan Medicine at the University of Michigan as of May 2017. He also has been appointed Associate Director for Cancer Care (ADCC) at Networking and Affiliated Centers.

Prior to joining Michigan Medicine Dr. Gadgeel was the co-leader of the Molecular Therapeutics Program of the Karmanos Cancer Institute (KCI).

Dr. Gadgeel has conducted and participated in many lung cancer specific trials and has also been a principal investigator of a Southwest Oncology Group trial, S0528 and NCI protocol 7389. He has engaged in many epidemiologic studies in the field of lung cancer, publishing on features of lung cancer in African-Americans and young patients. He is currently the principal investigator of multi-PI R21 to identify ‘driver’ genetic alterations in African-American lung cancer patients.  


Here is the first part of Dr. Gadgeel’s discussion from last year’s Targeted Therapies Patient Forum in Aurora, Colorado.  

 

Please feel free to offer comments and raise questions in our Discussion Forums.


Targeted Therapies in Lung Cancer Patient Forum

September 16, 2017

Presented by the Global Resource for Advancing Cancer Education in collaboration
with the Cleveland Clinic Cancer Center

See below for our growing list of topics and presenters!  

Register at cancerGRACE.org | Agenda is subject to change

8:30 – 10:00 am        The Many Faces of Progression
Dr. Nathan Pennell Cleveland Clinic Cancer Center The Role of Local Therapy
Dr. Shirish Gadgeel Karmanos Cancer Center, Wayne State University Biopsies & Re-biopsies
Dr. Karen Reckamp, City of Hope
10:30 – noon       
The Question of Clinical Trials
Dr. Alice Shaw Massachusetts General Hospital The Crossroads: Local Therapy, Chemo, Targeted Therapy, or Immunotherapy? 
Panel Discussion with Drs. Pennell, Gadgeel, Reckamp, and Shaw, and patients Matt Hiznay (ALK) and Sara Whitlock (RET). Moderator: Dr. H. (Jack) West

BREAKOUT SESSIONS

1:00 – 2:30 pm     
 
Presentations by Lung Cancer Sub-type
*Available treatment options 
*Acquired resistance: How do you pick your next treatment? 
ALK/ROS Dr. Alice Shaw, Dr. Shirish Gadgeel, & Matt Hiznay, ALK patient
EGFR Dr. Nathan Pennell, Dr. H. (Jack) West, & John Cherol, EGFR patient
MET/RET/BRAF Dr. Karen Reckamp, Dr. Vamsidhar Velcheti (Cleveland Clinic Cancer Center), & Sara Whitlock, RET patient

BREAKOUT SESSIONS

2:50 – 4:00 pm     
 
Managing the Costs of Cancer Care
James P. Stevenson, MD Cleveland Clinic Cancer Center
Patient to Patient Mentoring
Kathryn Sefcek, MHA 4th Angel Mentoring Program
Avoiding Fake News & Finding Trustworthy Cancer Info Online
Dr. H. (Jack) West Swedish Cancer Institute & Founder of cancerGRACE
Janet Freeman-Daily ROS1 patient, #LCSM Twitter Chat co-moderator, Cure Today contributor, Gray Connections blogger

 Please feel free to offer comments and raise questions in our Discussion Forums.

 GRACE would like to thank the following companies for their support of this forum:

B-I for web           
Guardant

 

 


Denise Brock

Targeted Therapies Patient Forum September 2017 Speaker Highlight – John Cherol

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***Speaker Highlights***

for full faculty bio’s, please visit our FACULTY page


 Learn about John Cherol, EGFR patient

 

John Cherol was diagnosed in January 2016 with Stage IV EGFR+ lung cancer at the age of 28. He started Gilotrif (afatinib) and acquired resistance after 14 months. Luckily a blood test showed he developed the t790m mutation and he started Tagrisso in April of this year. He’s also been treated for nine brain mets with Gamma Knife at the Cleveland Clinic.

John is a graduate of Youngstown State University with a bachelor’s degree in computer forensics.  He currently works as a Senior Cyber Security Analyst in Pittsburgh, PA. He got engaged shortly after his diagnosis to his fiancé, Kristine, who he met in 2014. They’re actively planning their September 9th wedding and a honeymoon to Iceland. Thanks to targeted therapy, John has been able to continue some of the hobbies he loves most like camping and kayaking. He hopes to help change the face of lung cancer and enjoy many more evening walks with Kristine and their rescue dog Liam.

 

 


 

Please feel free to offer comments and raise questions in our Discussion Forums.


Targeted Therapies in Lung Cancer Patient Forum

September 16, 2017

Presented by the Global Resource for Advancing Cancer Education in collaboration
with the Cleveland Clinic Cancer Center

See below for our growing list of topics and presenters!  

Register at cancerGRACE.org | Agenda is subject to change

8:30 – 10:00 am        The Many Faces of Progression
Dr. Nathan Pennell Cleveland Clinic Cancer Center The Role of Local Therapy
Dr. Shirish Gadgeel Karmanos Cancer Center, Wayne State University Biopsies & Re-biopsies
Dr. Karen Reckamp, City of Hope
10:30 – noon       
The Question of Clinical Trials
Dr. Alice Shaw Massachusetts General Hospital The Crossroads: Local Therapy, Chemo, Targeted Therapy, or Immunotherapy? 
Panel Discussion with Drs. Pennell, Gadgeel, Reckamp, and Shaw, and patients Matt Hiznay (ALK) and Sara Whitlock (RET). Moderator: Dr. H. (Jack) West

BREAKOUT SESSIONS

1:00 – 2:30 pm     
 
Presentations by Lung Cancer Sub-type
*Available treatment options 
*Acquired resistance: How do you pick your next treatment? 
ALK/ROS Dr. Alice Shaw, Dr. Shirish Gadgeel, & Matt Hiznay, ALK patient
EGFR Dr. Nathan Pennell, Dr. H. (Jack) West, & John Cherol, EGFR patient
MET/RET/BRAF Dr. Karen Reckamp, Dr. Vamsidhar Velcheti (Cleveland Clinic Cancer Center), & Sara Whitlock, RET patient

BREAKOUT SESSIONS

2:50 – 4:00 pm     
 
Managing the Costs of Cancer Care
James P. Stevenson, MD Cleveland Clinic Cancer Center
Patient to Patient Mentoring
Kathryn Sefcek, MHA 4th Angel Mentoring Program
Avoiding Fake News & Finding Trustworthy Cancer Info Online
Dr. H. (Jack) West Swedish Cancer Institute & Founder of cancerGRACE
Janet Freeman-Daily ROS1 patient, #LCSM Twitter Chat co-moderator, Cure Today contributor, Gray Connections blogger

 Please feel free to offer comments and raise questions in our Discussion Forums.

 GRACE would like to thank the following companies for their support of this forum:

B-I for web           
Guardant

 

 


Denise Brock

Targeted Therapies Patient Forum September 2017 Speaker Highlight – Janet Freeman Daily

Share

***Speaker Highlights***

for full faculty bio’s, please visit our FACULTY page


 Learn about Janet Freeman-Daily, ROS1 patient, #LCSM Twitter Chat co-moderator, Cure Today contributor, Gray Connections blogger

 

Janet Freeman-Daily is a writer, science geek, and lung cancer patient/activist. She received a diagnosis of advanced non-small cell lung cancer in May 2011 which became metastatic despite chemotherapy and radiation.  After learning about genomic testing and precision medicine in online patient communities, she joined a clinical trial for ROS1-positive lung cancer and has had no evidence of disease for over four years.

After twenty years in aerospace systems engineering, Janet is now a full-time patient activist who translates the experience and science of lung cancer treatment and research to improve outcomes and quality of life for lung cancer patients. She co-moderates the Lung Cancer Social Media (#LSCM) Chat on Twitter as @JFreemanDaily, blogs at grayconnections.net, and is one of the leaders of the Global ROS1 Initiative. She has spoken at events and on videos for lung cancer advocacy organizations, hospitals and cancer research centers, oncology conferences, President’s Cancer Panel workshops, and the National Cancer Institute. 

 


 

To see more Janet Freeman-Daily on GRACE, please visit this link
Please feel free to offer comments and raise questions in our Discussion Forums.


Targeted Therapies in Lung Cancer Patient Forum

September 16, 2017

Presented by the Global Resource for Advancing Cancer Education in collaboration
with the Cleveland Clinic Cancer Center

See below for our growing list of topics and presenters!  

Register at cancerGRACE.org | Agenda is subject to change

8:30 – 10:00 am        The Many Faces of Progression
Dr. Nathan Pennell Cleveland Clinic Cancer Center The Role of Local Therapy
Dr. Shirish Gadgeel Karmanos Cancer Center, Wayne State University Biopsies & Re-biopsies
Dr. Karen Reckamp, City of Hope
10:30 – noon       
The Question of Clinical Trials
Dr. Alice Shaw Massachusetts General Hospital The Crossroads: Local Therapy, Chemo, Targeted Therapy, or Immunotherapy? 
Panel Discussion with Drs. Pennell, Gadgeel, Reckamp, and Shaw, and patients Matt Hiznay (ALK) and Sara Whitlock (RET). Moderator: Dr. H. (Jack) West

BREAKOUT SESSIONS

1:00 – 2:30 pm     
 
Presentations by Lung Cancer Sub-type
*Available treatment options 
*Acquired resistance: How do you pick your next treatment? 
ALK/ROS Dr. Alice Shaw, Dr. Shirish Gadgeel, & Matt Hiznay, ALK patient
EGFR Dr. Nathan Pennell, Dr. H. (Jack) West, & John Cherol, EGFR patient
MET/RET/BRAF Dr. Karen Reckamp, Dr. Vamsidhar Velcheti (Cleveland Clinic Cancer Center), & Sara Whitlock, RET patient

BREAKOUT SESSIONS

2:50 – 4:00 pm     
 
Managing the Costs of Cancer Care
James P. Stevenson, MD Cleveland Clinic Cancer Center
Patient to Patient Mentoring
Kathryn Sefcek, MHA 4th Angel Mentoring Program
Avoiding Fake News & Finding Trustworthy Cancer Info Online
Dr. H. (Jack) West Swedish Cancer Institute & Founder of cancerGRACE
Janet Freeman-Daily ROS1 patient, #LCSM Twitter Chat co-moderator, Cure Today contributor, Gray Connections blogger

 Please feel free to offer comments and raise questions in our Discussion Forums.

 GRACE would like to thank the following companies for their support of this forum:

B-I for web           
Guardant

 

 


Denise Brock

Targeted Therapies Patient Forum September 2017 Speaker Highlight – Alice Shaw MD, PhD

Share

***Speaker Highlights***

for full faculty bio’s, please visit our FACULTY page


 Learn about Alice Shaw, MD, PhD, Massachusetts General Hospital

 

Alice T. Shaw is the Director of the Center for Thoracic Cancers and the Paula O’Keeffe Endowed Chair of Thoracic Oncology at Massachusetts General Hospital.  She is also an Associate Professor of Medicine at Harvard Medical School. She received her A.B. in Biochemistry from Harvard and her M.D. and Ph.D. degrees from Harvard Medical School.  She did her residency in Internal Medicine at Massachusetts General Hospital and completed a fellowship in Hematology/Oncology at Dana-Farber/Massachusetts General Hospital.  She completed her postdoctoral work in the laboratory of Dr. Tyler Jacks at MIT.   

In addition to caring for patients with lung cancer, Dr. Shaw also performs clinical and translational research.  Her clinical research focuses on a variety of different molecularly-defined subsets of non-small cell lung cancer (NSCLC). Her translational research focuses on elucidating mechanisms of resistance to targeted therapies.  Based on her research, she has helped to develop numerous FDA-approved targeted therapies for patients with oncogene-driven NSCLC, and her current efforts focus on developing novel combinatorial strategies aimed at overcoming drug resistance.

Dr. Shaw has been awarded a number of research grants, including grants from the Damon Runyon Cancer Research Foundation, the Burroughs Wellcome Fund, the V Foundation for Cancer Research, Uniting Against Lung Cancer, the National Foundation for Cancer Research, SU2C/AACR/ACS, and the NIH/NCI.  In 2014 she was elected as a member to the American Society of Clinical Investigation.  She is a standing member of the FDA Oncologic Drugs Advisory Committee and she recently joined the LUNGevity Foundation Scientific Advisory Board. 


 

 

To see more Alice Shaw, MD, PhD, on GRACE, please visit this link
Please feel free to offer comments and raise questions in our Discussion Forums.


Targeted Therapies in Lung Cancer Patient Forum

September 16, 2017

Presented by the Global Resource for Advancing Cancer Education in collaboration
with the Cleveland Clinic Cancer Center

See below for our growing list of topics and presenters!  

Register at cancerGRACE.org | Agenda is subject to change

8:30 – 10:00 am        The Many Faces of Progression
Dr. Nathan Pennell Cleveland Clinic Cancer Center The Role of Local Therapy
Dr. Shirish Gadgeel Karmanos Cancer Center, Wayne State University Biopsies & Re-biopsies
Dr. Karen Reckamp, City of Hope
10:30 – noon       
The Question of Clinical Trials
Dr. Alice Shaw Massachusetts General Hospital The Crossroads: Local Therapy, Chemo, Targeted Therapy, or Immunotherapy? 
Panel Discussion with Drs. Pennell, Gadgeel, Reckamp, and Shaw, and patients Matt Hiznay (ALK) and Sara Whitlock (RET). Moderator: Dr. H. (Jack) West

BREAKOUT SESSIONS

1:00 – 2:30 pm     
 
Presentations by Lung Cancer Sub-type
*Available treatment options 
*Acquired resistance: How do you pick your next treatment? 
ALK/ROS Dr. Alice Shaw, Dr. Shirish Gadgeel, & Matt Hiznay, ALK patient
EGFR Dr. Nathan Pennell, Dr. H. (Jack) West, & John Cherol, EGFR patient
MET/RET/BRAF Dr. Karen Reckamp, Dr. Vamsidhar Velcheti (Cleveland Clinic Cancer Center), & Sara Whitlock, RET patient

BREAKOUT SESSIONS

2:50 – 4:00 pm     
 
Managing the Costs of Cancer Care
James P. Stevenson, MD Cleveland Clinic Cancer Center
Patient to Patient Mentoring
Kathryn Sefcek, MHA 4th Angel Mentoring Program
Avoiding Fake News & Finding Trustworthy Cancer Info Online
Dr. H. (Jack) West Swedish Cancer Institute & Founder of cancerGRACE
Janet Freeman-Daily ROS1 patient, #LCSM Twitter Chat co-moderator, Cure Today contributor, Gray Connections blogger

 Please feel free to offer comments and raise questions in our Discussion Forums.

 GRACE would like to thank the following companies for their support of this forum:

B-I for web           
Guardant

 

 


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