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Dr Pennell

Dr Pennell

Dr Pennell

Real Hope for Small Cell Lung Cancer Treatments from ASCO 2015

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Guest post by Dr. Nate Pennell, a board certified medical oncologist at the Taussig Cancer Center at the Cleveland Clinic. He specializes in the treatment of thoracic malignancies with a focus on lung cancer. Dr. Pennell’s research interests include clinical trials using novel therapies, with a goal of facilitating the movement of new treatments from the laboratory to the clinic. Follow him on Twitter at @n8pennell.

As the dust settles from a very exciting ASCO meeting in Chicago, it is time to reflect on some of the developments in the field of small cell lung cancer (SCLC). The SCLC session is historically the session at ASCO that no one wants to attend, where failed phase 3 trials are the rule and we are constantly reminded that treatments for SCLC haven’t changed in three decades. But 2015 was different for a welcome change, and as Dr. Cathy Pietanza noted in her pre-ASCO post on this topic, we did indeed hear exciting data.

Oh sure, we got our fair share of failed trials. Dr. Alessandro Morabito presented the Italian phase 3 STAD-3 trial comparing usual dose cisplatin and etoposide chemotherapy to “toxicity-adjusted” chemotherapy in extensive stage SCLC patients, which escalated the dose of chemotherapy in patients who did not have significant side effects in the hope that more is better. More was not better, and higher doses of chemotherapy only resulted in more side effects without any differences in survival. The only positive from this trial may be that we can finally put to rest the idea that higher doses of chemotherapy make a difference in this disease and move on.

However, progress was made in both translational and clinical research. Dr. Afshin Dowlati’s group in Cleveland identified a significant potential new target in SCLC called RICTOR which was amplified in 17% of SCLC patients, which may predict for benefit from drugs targeting mTORC1/2. Such drugs are available and trials are planned for this group of patients. Other studies continued to help shape our understanding of the genetics of SCLC, although simple targets are much less common than in non-small cell lung cancer.

The most exciting development was in immunotherapy, which I must admit I was skeptical about prior to the meeting. Two trials were presented, one testing the PD-1 inhibitor Keytruda (pembrolizumab) in patients with PDL-1-positive extensive SCLC, and one testing both the PD-1 inhibitor Opdivo (nivolumab) alone and in combination with Yervoy (ipilumumab) in SCLC not selected by PDL-1 positivity. In the KEYNOTE-028 trial, Dr. Patrick Ott showed that pretreated PDL-1+ SCLC had a 35% response rate with pembrolizumab! Of course, only 28% of patients screened were PDL-1+ so this was a select group, but as Dr. Orr pointed out, this was a “proof of concept” trial to show that the drug worked at all, not intended to restrict the drug in the future to only a small group of patients. The median duration of responses was longer than 6 months and many patients continued to respond well past that point.

The Checkmate-032 study presented by Dr. Scott Antonia was even more exciting, showing that pretreated SCLC patients, a notoriously hard group to help, had a 15% response rate to nivolumab alone and a 33% response rate to the combination of nivo and ipilumumab, with most of the responses ongoing at the time of the presentation. This was NOT restricted to PDL-1+ patients, opening the door to a potentially very effective combination for these patients. One note of caution was a low incidence of serious autoimmune disorders including one fatal case of myasthenia gravis which may have been induced by the immunotherapy.

Now that we know these drugs can work, larger trials testing them in SCLC patients should be the top priority for the field in my opinion. Hopefully this is just the start of a more hopeful era for SCLC patients, and in coming years we will continue to see more trials like the latter two and fewer like the STAD-3 trial.


Dr Pennell

New Hope for EGFR Mutant NSCLC with Acquired Resistance to Tarceva (including T790M!)

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I am sorry to say that there were few surprises or earth-shatteringly positive results at this year’s ASCO meeting in Chicago (unless you count my button-shattering belly expansion from too many pizza lunches and dinners). However, in my mind there was one presentation that stood out above the others in terms of real hope for a particularly frustrating subset of lung cancer patients, namely those with EGFR activating mutations that develop resistance to Iressa (gefitinib) or Tarceva (erlotinib). The presentation was the initial results of a phase II trial combining afatinib (Tomtovok; BIBW 2992) with the anti-EGFR antibody cetuximab in TKI-resistant NSCLC patients.

This is a very frustrating group to treat. They tend to be younger, and most have never smoked or for only a short while, and they tend to respond wonderfully to TKIs like Tarceva. However, most patients will eventually go on to progress despite the TKI, and the reasons behind this progression have been a very active area of research. We know that about 50% of them, for example, will develop a second EGFR mutation in exon 20 called the T790M mutation.

There have been a number of strategies tested to overcome this resistance. The two major strategies have been to use a better TKI, such as the irreversible inhibitors BIBW 2992 and HKI 272, or to add a second drug to the TKI that inhibits a parallel pathway. One example of this strategy is the trial testing the addition of a MET inhibitor (ARQ 197) to Tarceva, which is now open all over the globe.

However, to date none of these strategies have proven to be particularly effective. One disappointing example was the LUX LUNG 1 study, which randomized patients who had failed chemotherapy and then progressed after benefit from a first-generation TKI (enriching the group for EGFR mutant cancers) to either afatinib or placebo. The goal of this study was to test if the irreversible TKI (afatinib) could overcome resistance by itself. Unfortunately, this trial failed to show a survival benefit from afatinib over placebo as a single agent. There were also only 7.4% of TKI-resistant patients who responded to afatinib.

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Dr Pennell

The Evolving Role of Molecular Markers in the Management of Non-Small Cell Lung Cancer

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The Importance of Identifying Molecular Markers in Non-Small Cell Lung Cancer

To understand the importance of molecular markers in the current and future treatment of lung cancer, one should first understand how lung cancer was classified up until the beginning of this decade. Pathologists would look at a sample of a patient’s lung tumor under a microscope, and then make a judgment of whether the cells represented small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Although that is an oversimplification, for all practical purposes, that is what oncologists cared about when it came to choosing treatment. If the diagnosis was NSCLC, then oncologists treated the patient with platinum doublet chemotherapy using one of many standard regimens that were felt to be equally effective. Unfortunately we knew that these regimens only worked in a certain proportion of patients, but we had no way to predict ahead of time who would benefit and who would not.

At the same time pathologists and molecular biologists have know for some time that NSCLC is not really just one disease, but rather a constellation of many diseases that all share the distinction of starting in the lung. For example, major subtypes such as adenocarcinoma, squamous cell carcinoma, and large cell carcinoma were often reported in pathology reports but did not influence treatment choice. Since 2004 we have taken this one step farther, asking pathologists to tell us not just that the lung cancer is non-small cell but also that it is non-squamous cell, for purposes of safety with Avastin (bevacizumab) and efficacy with Alimta (pemetrexed), but that is the topic for another chapter.

As our understanding of the molecular basis of cancer has grown, we have developed a number of new molecularly-targeted agents with promise in the treatment of lung cancer. However, targeted drugs tend to have limited or no effect on cancers that lack the “target” of the drug, creating a need for markers to guide us.

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Dr Pennell

An Overview of Molecular Markers in Lung Cancer

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Introduction to Molecular Markers

A molecular marker is an identifiable molecular characteristic (usually DNA, RNA, or protein) in a patient or a tumor that can be used to provide prognostic or predictive information about the cancer or about a particular treatment. A prognostic marker is one which indicates a better or worse outcome irrespective of treatment. For example, a mutation in the KRAS gene has been widely regarded as a poor prognostic molecular marker (see below), but does not necessarily guide us in selecting therapy for a particular patient. In contrast a predictive marker indicates a better or worse chance of an outcome for a specific treatment. Identifying this type of marker is a major goal of translational research and forms the basis of “personalized medicine”, which is simply saying that you may be able to determine ahead of time which treatment will or will not work in a specific patient.

In this chapter, I will try and describe the most common molecular markers being investigated in lung cancer, including some tests that are already being used in practice today. Continue reading


Dr Pennell

Who Benefits from Third-line Treatment for Advanced NSCLC?

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