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Physicians' Education Resource®, LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

These PER Pulse™ Recaps are not approved for AMA PRA Category 1 Credit™.

Acknowledgment of Commercial Support

This activity is supported by educational grants from Boehringer Ingelheim and Genentech.

Advances in Targeted Therapies: Non-Small Cell Lung Cancer
PER Pulse™ Recap


PER Pulse™ Recap
The Advances in Targeted Therapies series is an online CME activity that includes expert interviews accompanied by a series of clinical vignettes focusing on non-small cell lung cancer (NSCLC), breast cancer, and colorectal cancer.

Medical Writer: Kim Farina, PhD
These PER Pulse™ Recaps are not approved for AMA PRA Category 1 Credit™.

PER Pulse™ Recap

Advances in Targeted Therapies

The Advances in Targeted Therapies series is a collection of online publications that focuses on therapeutic agents interfering with cancer cell proliferation and spread by inhibiting signaling pathways, inducing apoptosis, or stimulating the immune system. This activity will focus on non-small cell lung cancer (NSCLC), breast cancer, and colorectal cancer, and will include expert interviews accompanied by a series of clinical vignettes that enable participants to apply the information presented in the interviews.

Module 1: Lung Cancer
Advances in Targeted Therapies: Non-Small Cell Lung Cancer
New Options for EGFR-Mutated Non-Small Cell Lung Cancer

In the following interviews, Drs. Suresh Ramalingam and Lecia Sequist discuss new options for EGFR-mutated NSCLC.

Dr. Ramalingam reviewed findings from two major trials that evaluated the safety and efficacy of erlotinib and afatinib, and led to the approval of these drugs in the United States for the treatment of epidermal growth factor receptor (EGFR)-mutated NSCLC. Approximately 15% of patients with NSCLC, primarily adenocarcinoma of the lung, present with EGFR mutations. In 2013, two drugs were approved by the FDA for the first-line treatment of patients with EGFR-mutated lung cancer. The first was erlotinib, a tyrosine kinase inhibitor (TKI) agent previously approved for advanced-stage NSCLC with or without EGFR mutation, based on the results of the BR-21 trial that showed survival benefit when compared with placebo. The EURTAC trial evaluated the efficacy of erlotinib in chemotherapy-naïve patients with EGFR-mutation-positive, advanced NSCLC. Patients were randomized to receive erlotinib or combination chemotherapy. The primary endpoint of the trial was progression-free survival (PFS). A statistically significant and clinically meaningful improvement in PFS was observed in patients treated with erlotinib, with a hazard ratio of 0.36 and a tolerability profile consistent with previously conducted studies. No clinically significant difference was observed in overall survival (OS), which was attributed to the high percentage of frontline chemotherapy to erlotinib cross-over treatment during the trial. PFS benefit did not translate into OS. Based on the results of the study, erlotinib was approved in 2013 with the indication of first-line treatment of patients with metastatic NSCLC with EGFR mutation.

Afatinib, an irreversible EGFR inhibitor, was the second drug approved by the FDA in 2013 for first-line use in EGFR-mutation-positive lung cancer, along with a companion diagnostic test. Afatinib binds to the EGF receptor in an irreversible manner with a covalent bonding and differs slightly from erlotinib biochemically. Afatinib showed activity in patients with disease progression who had been previously treated with erlotinib and had promising results in the pivotal LUX-Lung 3 phase III NSCLC trial. LUX-Lung 3 randomized patients to either afatinib or combination cisplatin/pemetrexed chemotherapy. Patients in the afatinib group showed a clinically meaningful and statistically significant improvement, and had higher response rates (RRs) when compared with the control group.

Although both erlotinib and afatinib were approved for the treatment of EGFR-mutated NSCLC, their indications differ. Afatinib is indicated specifically in the treatment of patients with advanced NSCLC who express exon 19 or exon 21 (ie, L858R) EGFR mutations. This was based on the results of a randomized phase III trial, where those two populations of patients showed significant improvement in PFS (median 13.6 months), and was considered one of the best observed improved rates in patients with EGFR mutation. It was also noted that afatinib was associated with a higher rate of toxicity in the form of diarrhea, skin rash, and mucositis. It is unknown how erlotinib and afatinib would compare with each other in the treatment of EGFR-mutated tumors, but trials to evaluate those objectives are under way. Until that time, the choice of treatment should depend on the individual patient, the available options (with consideration given to the level of toxicity in the available agents), patient preference, and the physician’s clinical judgment and comfort level in using the therapies and managing their toxicities.

Dr. Sequist discussed the similarities and differences between the recently approved frontline therapies for EGFR-mutation-positive NSCLC, erlotinib and afatinib.

For several years (especially since the publication of the IPASS data in 2009), it has been recommended that patients with EGFR-mutation-positive lung cancer be treated with an EGFR inhibitor early in their course of treatment, preferably as first-line therapy. Finally, in 2013, two EGFR inhibitor therapies were approved specifically for the treatment of EGFR-mutation-positive NSCLC. Erlotinib (a drug with prior approval) received approval specifically for first-line use in EGFR-mutation-positive disease, and afatinib, a drug without prior approval, was also approved for the same indication. The two drugs differ slightly, in that erlotinib is a reversible first-generation EGFR inhibitor that is specific for EGFR. In contrast, afatinib is an irreversible inhibitor that covalently binds to EFGR for the lifetime of the receptor. Afatinib is a panHER inhibitor also affecting HER2.

Although there are no definitive data that directly compare erlotinib and afatinib, both drugs have been evaluated against standard chemotherapy in the frontline and showed favorable results. The EURTAC trial compared erlotinib versus chemotherapy, and the LUX-Lung 3 trial evaluated frontline afatinib versus frontline chemotherapy with cisplatin/pemetrexed. In both trials, the EGFR inhibitors elicited better RR and prolonged PFS for patients compared with chemotherapy. In addition, the results of the LUX-Lung 3 study indicated better quality of life for patients in the erlotinib arm compared with patients who received chemotherapy. When considering which drug to choose for a patient with an EGFR mutation, Dr. Sequist stated that the choice is not clear because no head-to-head comparisons of the two drugs are available; therefore, both drugs are options for patients with an EGFR mutation. Looking across trials, the median PFS for first-line erlotinib is approximately 9 to 10 months in most trials. In the one randomized trial performed with afatinib, the median observed PFS was 11 months for all patients and 13 months for patients with the common mutations, L858R, or deletion 19 mutations.

Furthermore, the toxicity profiles may be slightly different in these drugs and vary from patient to patient. "I have treated many patients with both drugs, and I can say in my experience they are more similar than they are different," said Dr. Sequist. She explained, however, that because of its irreversible nature and broader target range, afatinib can have higher rates of skin toxicities such as paronychia and stomatitis, and higher rates of diarrhea. “In my experience it does take a little bit more proactive management to nip symptoms in the bud, and careful education of patients about managing these side effects.” Dr. Sequist usually starts patients on prophylactic antibiotic medication (eg, minocycline) prior to initiating therapy with afatinib. She concluded, "I do think both options are very promising for patients with EGFR mutations, and you could really choose either one."

Overcoming Resistance to EGFR TKIs: Focus on the T790M Resistance Mutation

Drs. Ramalingam and Sequist discussed strategies to overcome lung cancers that have developed resistance to EGFR TKIs).

Unfortunately, as effective as first-line EGFR inhibitors are for patients with EGFR-mutation-positive NSCLC, these therapies are not curative. Resistance to TKIs eventually occurs in most patients within 1 to 1.5 years of treatment initiation.

Several factors play a role in tumor cells becoming resistant to EGFR TKIs, but the most common mechanism is believed to be the mutation of T790M within exon 20. This is a secondary resistance mutation within the EGFR that alters the conformation of the receptor so that the original treatment (ie, erlotinib, afatinib, gefitinib) can no longer penetrate and bind to the receptor tyrosine kinase binding pocket. Therefore, the EGFR is reactivated and cancer cells continue to grow.

Over the years, several drugs have been studied to potentially resensitize cells and obtain tumor regression. Initially, encouraging results were observed with second-generation EGFR inhibitors such as neratinib, afatinib, or dacomitinib, but the enthusiasm was short-lived after completion of clinical trials in resistance settings. Efforts are under way to discover more optimal ways to manage patients with resistance to TKIs.

Combination afatinib/cetuximab

One strategy being tested in a large cohort of patients is combination therapy with afatinib and cetuximab, an anti-EGFR monoclonal antibody. Preclinical data suggest that afatinib plus cetuximab may be active in patients who have developed resistance to EGFR TKIs. In a phase Ib trial, over 100 patients with EGFR-mutation-positive NSCLC who had progressed on gefitinib or erlotinib received afatinib plus cetuximab. The study concluded with a promising approximate objective response rate (ORR) of 30% and a median PFS of 5.5 months. Larger randomized trials are ongoing to verify these outcomes. According to Dr. Sequist, this combination may be a challenging long-term solution based on the extensive incidence of skin toxicity observed, attributed to the known safety profiles of both agents and their tendencies to cause high rates of skin toxicity. She commented, “Nonetheless, some patients have been on it a long time, for 1 year or more. One of the most difficult things to get through when your patients are on afatinib plus cetuximab is the skin toxicity."

Third-generation EGFR

Drs. Ramalingam and Sequist discussed what they view as one of the most promising events on the horizon, namely, the introduction of third-generation EGFR inhibitors for the treatment of patients with EGFR TKI resistance. Two new drugs that are in early-stage development appear specific for the T790M mutation mechanism: AZD9291 and CO-1686.

Preliminary phase I data from an ongoing study with AZD9291 were reported recently at the ESMO 2013 meeting. These data demonstrated activity in the context of T790M-associated resistance: 50% of patients who were resistant to TKIs showed a positive response (confirmed and unconfirmed) to this agent. At the time the data were presented, only 18 patients had been treated; yet, the results of the study were considered promising.

Preliminary results from a phase I study of CO-1686 were presented at the 2013 World Conference on Lung Cancer and showed a high degree of activity in patients with EGFR-mutated NSCLC with the T790M mutation (67% partial response; n = 9). Both AZD9291 and CO-1686 are under evaluation in ongoing trials with larger cohorts, and based on the positive preliminary outcomes, the results are highly anticipated in the industry. “We wait with a high degree of enthusiasm to see how the results will turn out, and if preliminary results of phase I trials of these compounds are any indication, I think we are in for a very effective treatment strategy for our patients,” remarked Dr. Ramalingam.

Dr. Sequist pointed out that because these experimental drugs target mutated EGFR, but not wild-type EGFR, they are associated with lower rates of skin, intestinal, or oral toxicities than have been observed with earlier classes of EGFR inhibitors. “The toxicity profile is quite different,” said Dr. Sequist, “and it is because of this that I think we will be able to get to higher doses that have a better chance of actually impacting resistant cancer cells. Early reports presented at recent scientific meetings confirm positive responses in a number of patients to both third-generation therapies that were previously resistant to EGFR inhibitors. “It is definitely something to keep your eye on coming out over the next couple of years,” Dr. Sequist concluded.

Guidelines for Molecular Testing in Lung Cancer

Drs. Ramalingam and Sequist discussed guidelines for molecular testing in lung cancer.

Molecular testing is an essential part of treating patients with lung cancer today. It is no longer an exclusive procedure to be done during consult at a major hospital, but a part of routine diagnostics testing that should be offered at every oncology office nationwide. It is supported in guidelines from several professional societies such as the College of American Pathologists (CAP), International Association for the Study of Lung Cancer (IASLC), and the National Comprehensive Cancer Network (NCCN).

IASLC, in collaboration with CAP and the Association for Molecular Pathology, recently issued evidence-based guidelines for molecular testing of patients with lung cancer. The guidelines recommend that patients with adenocarcinoma of the lung should be tested for EGFR mutations and anaplastic lymphoma kinase (ALK) gene translocation, in order to better identify therapies targeted toward these abnormalities. Dr. Sequist commented that these molecular abnormalities are unlikely to be present in histologies other than adenocarcinoma (eg, squamous cell), while the percentage of patients with adenocarcinoma and an EGFR mutation is commonly high. In fact, she said that over 50% of nonsmokers and potentially 20% of former smokers are at risk of EGFR mutations. This renders testing for EGFR mutation and ALK translocation vital in the treatment planning stages for patients with adenocarcinoma.

Various methods can be utilized to test for EGFR mutation, but the most common involve sequencing or PCR-based techniques where specific hotspot mutations known to be associated with response to treatment are identified. ALK rearrangement is best detected by the standard and FDA-approved fluorescence in situ hybridization (FISH) test, an immunology-based, break-apart assay that detects chromosomal rearrangement of the EML4-ALK fusion gene.

Historically, clinical parameters such as smoking history, histology, or ethnicity have been relied upon to determine whom to test for EGFR or ALK mutations. The guidelines clearly state, however, that while clinical parameters are useful, they should not be considered the sole determinants of whether to perform molecular testing on a particular patient. Therefore, the recommendations are clear that any patient with advanced-stage disease of nonsquamous histology should be tested for EGFR mutation and ALK translocation, regardless of his or her clinical risk factors. For patients with locally advanced or early-stage disease, testing can be individually considered depending on the course of treatment, perhaps in a clinical trial setting that may specifically benefit from collection of that information.

Dr. Ramalingam also touched upon the recommendations’ handling of concerns regarding the optimal duration of time for availability of test results. The consensus is that a 10-business-day-turnaround time is acceptable. The guidelines suggest that institutions that are unable to provide testing results within this recommended time frame consider seeking an external testing laboratory to do so, in order to initiate the optimum evidence-based treatment in a timely manner.

New screening methods, such as immunohistochemistry (IHC) detection of the ALK protein, are under way but are not yet standardized. Dr. Sequist anticipated that multiplex testing, where multiple abnormalities are simultaneously tested, is the way of the future. Presently, targeted therapies are being developed for various genes (eg, BRAF, HER2 mutations or amplifications, MET amplifications, and RET translocations). “At some point there are going to be so many tests that are important for patients that it is going to be hard to do them one-off and then another and then another,” remarked Dr. Sequist. “It is a much more efficient use of time, money, and tissue to do them all at once, just like with a comprehensive metabolic panel where the entire panel is run at once.” She predicts that the same will be true of genetic tumor testing. "We are going to run the whole panel, get the results at once, and then make decisions regarding care."

Clinical Vignettes Q: For a patient with metastatic lung adenocarcinoma, how would you approach EGFR and ALK testing with regard to smoking history?
  1. I would test regardless of smoking history.
  2. I would test only former and never-smokers.
  3. I would test only never-smokers.
Dr. Ramalingam explained that current guidelines recommend testing all patients with metastatic lung adenocarcinoma for EGFR and ALK, regardless of smoking history. Restricting testing to nonsmokers or light smokers could result in overlooking a substantial number of patients expressing EGFR and/or ALK mutations.

Q: Your patient with metastatic lung adenocarcinoma wishes to begin treatment immediately and does not want to wait for EGFR mutation test results. You initiate chemotherapy with pemetrexed and carboplatin. Two days before the beginning of the second cycle, the EGFR test reveals a sensitizing exon 19 deletion. How would you proceed?
  1. Continue chemotherapy, reserve erlotinib for disease progression
  2. Continue chemotherapy, add erlotinib
  3. Stop chemotherapy, switch to erlotinib
Dr. Ramalingam's approach is to initiate and to continue with chemotherapy when the patient is too symptomatic to await the results of genetic testing. In his practice, patients are typically administered 2 to 4 cycles of chemotherapy (as long as the treatment is being tolerated well), and a TKI is initiated as maintenance therapy. This is based on the observation that for patients with EGFR mutations receiving chemotherapy, the response rate is higher when treated with a TKI agent. He summarized, "If you are already committed to chemotherapy, if the patient is tolerating well, give up to a maximum of 4 cycles, and then switch to a TKI."

According to Dr. Sequist, the decision to add a TKI while patients continue on chemotherapy after testing positive for an EGFR mutation is situational and patient-dependent. One consideration would be to evaluate how the patient is tolerating the current treatment. For patients with low tolerance to their current chemotherapy regimen, switching to a new potentially effective treatment may be advantageous. On the other hand, if the patient is tolerating and responding to chemotherapy (gauged after restaging), she suggests continuation with 4 to 6 cycles of frontline platinum-based chemotherapy and switching to a TKI as maintenance therapy. A third option is to give erlotinib as a second-round treatment after progression. She cautioned, however, that with the knowledge that EGFR-mutation-positive adenocarcinomas are highly sensitive to EGFR TKIs, waiting until cancer progression may not be optimal. Often, cancer progression can be indolent and detected early, but from time to time, rapid progression occurs, and it can deprive patients of the chance to receive a potentially efficacious alternative treatment.

Q: How would you treat a patient with ALK-positive NSCLC who experiences widespread progressive disease on frontline crizotinib?
  1. Discontinue crizotinib, begin platinum-doublet chemotherapy
  2. Begin treatment with a second-generation ALK inhibitor
  3. Enroll in a clinical trial with an HSP90 inhibitor
Dr. Ramalingam’s approach to subsequent treatments depends on the degree of progression. In the case where progression is slow, minimal increase is observed during scans (eg, only 1 or 2 sites of progression), and stable disease is noted otherwise, local therapy (eg, radiation) is administered, and treatment with crizotinib would continue. This strategy can help extend the use of targeted therapies while keeping the disease under overall control.

For a patient with rapidly progressing disease, however, Dr. Ramalingam recommends enrollment in a clinical trial for a second-generation ALK inhibitor, if one is available. If not, he explained, the standard approach is to discontinue crizotinib and initiate chemotherapy (ie, platinum-based for platinum-naïve patients or single-agent chemotherapy for patients who have received platinum). “Pemetrexed works effectively in ALK-positive patients, so that would be my choice of therapy, either alone or in combination with a platinum compound,” he advised.

Dr. Sequist said that any of the response choices could apply. Several active treatments are being studied for ALK-positive patients who are resistant to crizotinib. Therefore, an option could be to locate a clinical trial based on the patient’s geographic location or willingness to travel. If clinical trial participation is not feasible, chemotherapy is a good option for this population of patients. Although clinicians tend to have more experience with EGFR-resistant patients, the decision to add chemotherapy as a secondary agent versus discontinuing the use of crizotinib and switching treatment to chemotherapy can have uncertain consequences. In general, patients with EGFR- and ALK-positive NSCLC who become resistant to the targeted therapy tend to suffer from disease flare once the targeted drug is discontinued.

Dr. Sequist explained that although TKI-resistant cancer cell growth is evident in these patients, there is likely a large number of underlying cancer cells that remain TKI-sensitive. Withdrawing the TKI allows this larger population of cells to grow, leading to disease progression and a much sicker patient. "So the evolving paradigm, which is still being investigated in prospective studies, is to keep the inhibitor, like crizotinib, on and add chemotherapy; the same goes for EGFR patients, as well," recommended Dr. Sequist.

Q: How would you proceed with a newly diagnosed, fit patient with metastatic, EGFR wild-type, KRAS wild-type, ALK-negative lung adenocarcinoma?
  1. Paclitaxel/carboplatin plus bevacizumab, if eligible
  2. Pemetrexed/carboplatin with or without maintenance therapy
  3. Test for other oncogenic drivers (eg, ROS1, BRAFV600E)
Dr. Ramalingam’s approach would be to initiate a combination chemotherapy regimen, once the patient has tested negative for EGFR and ALK mutations. Some centers have more extensive testing methods to identify less-common events such as ROS, RET, and other oncogenes such as HER2, while patients are tested for EGFR and ALK. In the event that one of the rare mutations is identified, treating with an appropriate targeted strategy as part of a clinical trial would be favorable. Otherwise, the recommended approach would be to initiate platinum-based combination chemotherapy. And based on predominant nonsquamous histology and no history of bleeding, a standard practice would be the addition of bevacizumab to chemotherapy for eligible patients. Another treatment option is the combination of pemetrexed with platinum, with pemetrexed as maintenance therapy. Furthermore, based on the ECOG 4599 trial, a rational approach is to begin bevacizumab with combination chemotherapy as first-line treatment, and continue with bevacizumab as maintenance therapy after 4 to 6 cycles of chemotherapy. In summary, for EGFR- and ALK-negative lung adenocarcinoma, platinum-based chemotherapy with bevacizumab (for appropriate patients) is the recommended approach.

Dr. Sequist suggests that when a patient tests negative for the common driver mutations (EGFR, ALK, and KRAS), testing for other rare driver mutations would provide insight into the disease and prepare the clinician in considering alternative treatment options, such as clinical trials. Withholding chemotherapy while waiting for the broad panel test results is not an approach endorsed by Dr. Sequist. This is based on the notion that a positive test result for a rare mutation may justify the patient’s referral to a clinical trial, most of which require prior treatment with chemotherapy.

The question of what the best chemotherapy might be is yet unanswered. What has become clear in recent years is that combining two treatments is not indicative of the same efficacy ratio. The ECOG 4599 study revealed that adding bevacizumab to carboplatin/paclitaxel improved outcomes when compared with chemotherapy alone. Subsequently, pemetrexed-based chemotherapy was used to treat adenocarcinoma. It was assumed at that time that adding bevacizumab to pemetrexed therapy would improve the result, but this was not observed across various clinical trials. To date, there is no definitive answer as to which is a better regimen for this population of patients. The decision whether to select a paclitaxel/ bevacizumab or a pemetrexed-based regimen, or any other active regimes should be based on the side-effect profile of the agents and fitness level of the patient. As frontline treatment, Dr. Sequist tends to use cisplatin/pemetrexed, carboplatin/pemetrexed, or carboplatin/pemetrexed with bevacizumab. A taxane-based regimen is also an acceptable choice.


Physicians' Education Resource®, LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

This activity is not approved for AMA PRA Category 1 Credit™.

This activity is supported by educational grants from Boehringer Ingelheim and Genentech.

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