GRACE :: Lung Cancer

Angiogenesis, the Sequel: Does Cyramza (Ramucirumab) Make a Difference for Second Line Treatment?

The REVEL trial studied 1,200 non-small cell lung cancer patients to see if the drug Cyramza (ramucirumab) improved overall surival. The doctors had mixed feelings about the results.

REVEL Trial Overall Survival Curves

Zykadia for ALK Positive Lung Cancer: New Drug, New Hope

The doctors discuss the new FDA-approved drug for ALK positive lung cancer patients, Zykadia (ceritinib), including the dosage level, potential side effects and the ability of Zykadia to impact brain metastases.

Ceritinib: Highly Active Treatment Option for ALK-Positive NSCLC

Upcoming Tweet Chat July 17th: Help us define the benefit of online resources for cancer patients

tweet-chatWe have seen over the past decade that patient self-education and participation in their own care have been steadily increasing with availability of the Internet.  It has enabled patients and caregivers to look online for information as well as to connect with other people in the patient community who can provide both knowledge of available treatment options  and support. 

 We often hear that online educational resources and communities are helpful for patients and caregivers, but we actually know very little of how and how much beyond that basic statement.  While many note that their care has been improved, we still lack actual data about the benefits realized and the impact on health care.  We need to present and discuss some actual data to the oncology community to convey the potentially constructive impact of epatients, Janet Freeman-Daily (@JFreemanDaily) and I are hoping to work with others in the lung cancer/ #LCSM community to develop a survey that can help convert some of the anecdotal strands in patient stories and discussion forums into interpretable data that we might present to cancer specialists to help health care professionals become more receptive to epatients and the value of online resources.

At this point, our first step is to address the key topics to cover in developing such a survey. We would like to dedicate the upcoming #LCSM chat on July 17th (8 PM Eastern, 5 PM Pacific) to a crowd-sourced discussion of the most valuable questions to ask and results we should hope to report.  The chat will cover these central questions:


1)     How can we determine what the most useful  information is and where people are most successful in finding it?  

2)     How can we assess how HCPs receive/respond to information presented by patients & caregivers?

3)     Can we assess how this info is used in shaping care? Is there some way to learn if/how it improves outcomes?

4)     Will there be enough interest in this to expect many pts to participate? And how best to reach online pt community?

5)     How long a survey (time req’d) would be appropriate before it’s excessive?

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What Went Wrong? The Failure of MetMab with Tarceva in Advanced Non-Small Cell Lung Cancer

“Dead negative,” is how Dr. Nasser Hanna describes results of a phase 3 study that examined how patients with high MET expression did on the drug MetMab (onartuzumab).

OAM4971g: Overall Survival Results

Why T790M status matters: The new value proposition for repeat biopsies in acquired resistance

One of the ongoing questions in managing EGFR mutation-positive advanced NSCLC has been whether it should be routine to do repeat biopsies to look for new findings after a patient has developed acquired resistance to an EGFR tyrosine kinase inhibitor (TKI). Here are a few posts in which the topic has been covered:

Overall, many investigators in the field of EGFR have favored this, largely to get a better understanding of the mechanism of acquired resistance and to check for the oft-cited but rarely seen transformation to small cell histology.  For some of these investigators, it has made sense to favor rebiopsy because they may have had clinical trials specifically for patients with a specific mechanism of resistance, such as the T790M mutation on exon 20 that is seen in 60% of patients who develop acquired resistance to an EGFR TKI. But up until very recently, T790M status hasn’t been that important to know when it doesn’t lead to changes in how you manage patients.  While the lab-based work on the combination of Gilotrif(afatinib) and Erbitux (cetuximab) for acquired resistance to reversible EGFR TKIs like Tarceva (erlotinib) or Iressa (gefitinib) suggested that this combination would be particularly helpful for the subset of patients with a T790M mutation, the actual clinical study of the afatinib/cetuximab combination showed no difference in results between those patients with or without a T790M mutation.  

With no highly compelling answer to the question of “If I don’t have a clinical trial depending on it, what can I do with the information likely to be obtained from a repeat biopsy?”, this approach has largely remained limited to the research centers that have been focused on the research efforts in this arena; it has not penetrated as a common approach in routine management.  But I think that the results of some of the exciting trials with novel EGFR TKIs AZD9291 and CO1686 just presented at ASCO 2014 will change that.

Dr. Pasi Jänne from Dana Farber Cancer Institute in Boston presented the initial clinical results with AZD9291, a novel EGFR TKI with specific activity against T790M, in patients with an EGFR mutation and acquired resistance.  Over 200 patients were enrolled at a variety of dose levels, and the investigators did not restrict patients based on T790M status. Though responses were not limited to those patients with a T90M mutation, the response rate was three-fold higher — 64% vs. 22% — in the T790M-positive population. Moreover, the response rate was essentially the same whether patients had just been on another EGFR TKI right before AZD9291 or had been off of EGFR TKIs for a while. In contrast, the patients who were T790M-negative had a lower response rate of just 11% in those just switching from another EGFR TKI, compared with a 36% response rate in those who had been off of EGFR TKI therapy for a longer interval. This suggests that many of the responses seen in T790M mutation-negative patients were really just a “retreatment effect” that you might see as a very brief benefit from another EGFR TKI as well.   Along the same lines, the time before progression in T790M mutation-positive responding patients was far, far longer than the transient period of usually just a few weeks before progression then occurred in the T790M negative patients.

Dr. Lecia Sequist followed with her presentation on CO1686, another third generation EGFR TKI with lab-based demonstrated activity against the T790M mutation. This work is earlier in development and with smaller numbers than the results presented on AZD9291 by Dr. Jänne, but it demonstrated a similarly encouraging response rate of 58% in a population of patients with acquired resistance to EGFR TKI therapy that only included those with a T790M mutation. 

These two agents represent a major step forward in management of acquired resistance for acquired resistance to EGFR TKIs, and they are both moving forward focusing primarily or exclusively on the 60% of acquired resistance patients with a T790M mutation. As studies with these agents become more widely available very rapidly in the next year, we should expect to see a shift in practice patterns that now make it desirable, if not mandatory, to obtain a repeat biopsy once acquired resistance becomes apparent, in order to determine whether someone has a T790M mutation and is eligible to pursue one of these treatments, initially on a clinically trial and hopefully soon as an FDA-approved treatment.  In the process, we can expect to learn a lot more about what we might see during the evolution of a cancer on EGFR TKI treatment. 

We will also face a new challenge of what to do for the 40% of EGFR mutation-positive patients who develop acquired resistance but don’t have a T790M mutation. Let’s hope we can identify promising clinical research leads for them as well.

MET-Amplified Lung Cancer: A New Target for XALKORI?

Lung cancer patients with high MET amplification appear to do well on Xalkori (crizotinib), a drug that is approved for ALK positive patients.

CO1686 – 3rd Generation Drug for Acquired Resistance in EGFR Lung Cancer

Lung cancer patients with the EGFR mutation who had progressed on other drugs did well on a new drug in clinical trial, though one particular side effect concerns some.

CO-1686: Best Response in Phase 1 and early Phase 2 expansion cohort patients

AZD9291 for Acquired Resistance in EGFR Positive Lung Cancer

EGFR positive lung cancer patients who had seen cancer progression responded well to a new drug in an early clinical trial.

AZD9291: Response rate in T790M+ (central test)

Not all EGFR Activating Mutations are Created Equal: Time to Stop Pooling Them Together

It’s been a decade since EGFR gene mutations were first identified as highly correlated with a high probability of response to EGFR tyrosine kinase inhibitors (TKIs) like Iressa (gefitinib) and Tarceva (erlotinib), and more recently Gilotrif (afatinib).   We’ve learned that there are an array of EGFR mutations, and that the two most common ones, an exon 19 deletion or an L858R substitution on exon 21 (an exon is a specific expressed portion of a gene), each somewhere around 40-45% of  the EGFR mutations seen, are actually the ones consistently associated with a dramatic and often long-lasting response to EGFR TKIs. In contrast, the other 10-12% of EGFR mutations, most commonly on exon 18 or exon 20, are a heterogeneous group with a less clear benefit from EGFR TKIs.  

For about the last 5 years, the lung cancer community has reached a pretty clear consensus that the exon 19 deletions and exon 21, L858R substitutions represent so-called “activating mutations”, and patients with these specific mutations in their tumors are the ones that have, in trial after trial, been shown to have a markedly higher response rate (RR) and longer progression-free survival (PFS) with EGFR TKIs than with standard chemotherapy.  Over that time, they have been pooled together and largely presumed to be very comparable. More recent research presented at ASCO 2014, however, rekindles questions that go back many years and cast doubt on whether we should really pool these two mutations together. 

Back in 2006, two different publications came out — one from Boston’s Dana Farber Cancer Institute (on the top of the figure below), and another from New York’s Memorial Sloan-Kettering Cancer Center (bottom of figure below) — each independently reported that while both mutations were associated with very good responses to Iressa or Tarceva, the exon 19 patients seemed to do better, potentially in terms of both PFS and overall survival (OS).  

Exon 19 vs. Exon 21 2006

(click on image to enlarge)

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Does Gilotrif Help EGFR Positive Lung Cancer Patients?

An analysis of two large studies of EGFR lung cancer patients tried to determine if Gilotrif helped patients live longer.

Combined OS analysis: mutation categories

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