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NSCLC: Advances Made in Refining Targeted Therapies

Laino, Charlene

doi: 10.1097/01.COT.0000359111.52060.99

ORLANDO, FL—When it comes to the treatment of non-small cell lung cancer (NSCLC), targeted therapies aimed at those patients most likely to benefit took center stage here at the ASCO Annual Meeting.

A randomized Phase III study showed that maintenance therapy with the multitargeted antifolate pemetrexed may help to extend the lives of patients with advanced and metastatic disease, particularly those with non-squamous cell histology.

Other noteworthy research showed that dual-targeted maintenance therapy with erlotinib and bevacizumab may help to delay progression in patients with advanced NSCLC.

Another study showed that genetic screening of NSCLC patients for epidermal growth factor receptor (EGFR) mutations may help to identify those who will benefit from treatment with gefitinib.

A fourth study showed that vandetanib, an investigational agent that targets EGFR and vascular endothelial growth factor receptor (VEGFR), may extend progression-free survival times in patients with advanced NSCLC.

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Adding pemetrexed to best supportive care as maintenance treatment extended overall survival times by about three months, compared with best supportive care alone, reported Chandra P. Belani, MD, the Miriam Becker Professor of Medicine at Penn State Hershey College of Medicine and Deputy Director of the Penn State Cancer Center.



Preliminary study results, presented at last year's ASCO meeting, showed that patients given pemetrexed were significantly less likely to have disease progression than those given optimal supportive care alone (Ciuleanu et al, ASCO 2008 Abstract 8011). While there was a trend toward improved overall survival rates in the pemetrexed group of patients, the difference did not reach statistical significance at that time, Dr. Belani said.

With longer follow-up, patients randomized to pemetrexed survived a median of 13.4 months, compared with 10.6 months for controls. This corresponded to a significant 21% lower risk of dying in the pemetrexed arm.



In the study, funded by Lilly, 663 patients with Stage IIIB/IV NSCLC that had not progressed after four cycles of platinum-based chemotherapy were randomized to either pemetrexed (500 mg/m2 on Day 1) or placebo, in 21-day cycles. Both groups also received the best supportive care with vitamin B12, folic acid, and dexamethasone.

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Histology Predicts Response

“When looked at by tumor histology (a prespecified analysis), the benefit was limited to non-squamous cell tumors,” Dr. Belani said.

Overall, patients with non-squamous cell histology given pemetrexed survived a median of 15.5 months vs 10.3 months for those given placebo. In contrast, pemetrexed did not extend survival in patients with squamous-type NSCLC.

The incidence of Grade 3/4 toxicities was generally low, Dr. Belani said, although patients given pemetrexed were significantly more likely to experience Grade 3/4 fatigue (5% vs. 1% in the placebo group) and neutropenia (3% vs. 0%). There were no treatment-related deaths.

The results will change clinical practice, Dr. Belani predicted, adding that clinicians will need to take histology into account when deciding on treatment.

Commenting on the findings, Bruce E. Johnson, MD, Director of the Lung Cancer Program at Dana-Farber Cancer Institute, told OT that treating patients based on histology is part of “a paradigm shift toward evidence-based medicine” in NSCLC.

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Erlotinib + Bevacizumab

In another advance for patients with advanced NSCLC, researchers found that the addition of the EGFR inhibitor erlotinib to bevacizumab as maintenance therapy after initial treatment with chemotherapy and bevacizumab significantly improved disease-free survival times, compared with use of bevacizumab alone.

“Bevacizumab is a core component of the treatment of advanced non-small cell lung cancer, and we've shown here that we can delay progression with the addition of another targeted agent, erlotinib,” Vincent A. Miller, MD, Associate Attending Physician in the Thoracic Oncology Service at Memorial Sloan-Kettering Cancer Center, reported in his late-breaking presentation.

The median time to disease progression was 4.76 months for patients who received bevacizumab plus erlotinib, compared with 3.75 months in patients who received bevacizumab and placebo.

The Phase IIIb study was stopped prematurely on the recommendation of the independent data safety monitoring board earlier this year, after a pre-planned interim analysis demonstrated that combining bevacizumab and erlotinib significantly extended the time to progression. The ASCO report was the first time that the details were released.

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Hazard Ratio Critical

The study, funded by Genentech, involved 1,160 patients with locally advanced, recurrent, or metastatic NSLCL.

After four cycles of first-line chemotherapy plus bevacizumab, the 769 patients whose disease had not progressed were randomized to bevacizumab and erlotinib or bevacizumab plus placebo.

Although the combination targeted treatment only delayed progression by about one month, Dr. Miller said that “what is really important for the clinician and the patient is the hazard ratio for progression, 0.72 in favor of the combination treatment. The survival advantage continues to be there throughout the curve, not just at one point in time.”

At three months, for example, about 68% of patients given bevacizumab and erlotinib were free of disease, compared with 53% of patients on bevacizumab plus placebo. At six months, the corresponding figures were 40% and 28.

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‘Living Longer vs Living Better’

The issue raised by both these studies is whether maintenance therapy results in the patient “living longer or living better,” said the Discussant for the Belani and Miller studies, Nasser H. Hanna, MD, Associate Professor in the Division of Hematology/ Oncology at Indiana University Simon Cancer Center.



While targeted agents are generally gentler than chemotherapy, they too can cause adverse effects, he said. In the pemetrexed study, “there was no reported difference in quality-of-life deterioration between the pemetrexed and placebo arms.”

Since the life expectancy of patients with advanced NSCLC is very short, even mild drug-related toxicities are not trivial, he noted.

As for the bevacizumab/erlotinib study, “improved progression-free survival alone is [not that] meaningful unless it also results in a decrease in cancer symptoms or complications, or an improvement in quality of life,” Dr. Hanna continued.

The bottom line: “There are some patients who would benefit from [maintenance therapy], but it is definitely not all patients, as many would be overtreated unnecessarily,” he said.

For some patients, a strategy of active surveillance, with supportive care to relieve symptoms as needed, might be more appropriate.

Dr. Miller said that his team is now conducting biomarker analyses to identify patients who are most likely to benefit from combination treatment with erlotinib plus bevacizumab.

That makes a lot of sense, given that another study presented at the meeting showed that EGFR mutation status is a strong predictive biomarker for response to treatment with the EGFR inhibitor gefitinib, said ASCO Immediate Past President Richard L. Schilsky, MD, Professor of Medicine and Associate Dean for Clinical Research at the University of Chicago.

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EGFR Mutation Status

As reported by Masahiro Fukuoka, MD, Professor of Medical Oncology at Kinki University School of Medicine in Osaka, patients with EGFR mutations benefitted more when treated with the gefitinib than when treated with carboplatin and paclitaxel.

Patients who tested negative for EGFR mutations, on the other hand, had better outcomes when treated with carboplatin-paclitaxel chemotherapy, he said.

“EGFR mutation was a strong predictive biomarker for a differential progression-free survival and overall response rate with gefitinib versus carboplatin/paclitaxel in this clinically selected first-line setting, indicating that a molecularly defined population will benefit most from first-line gefitinib. A patient who is positive for EGFR mutations should be started on targeted therapy, while patients who are negative for these mutations should be started on conventional chemotherapy.”



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Biomarker Analysis

Dr. Fukuoka and colleagues performed biomarker analyses using data from the First Line IRESSA Versus Carboplatin/ Paclitaxel in Asia (IPASS) study, a Phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small cell lung cancer in Asia.

The 1,217 Asians in the study were either never-smokers or ex-light smokers and had adenocarcinoma histology.

Previous findings showed that Asians who were never-smokers or ex-light smokers and had adenocarcinoma histology benefitted more from gefitinib than from carboplatin/paclitaxel chemotherapy (Mok T et al: ESMO 2008, Abstract LBA2).

Specifically, the 12-month progression-free survival rate was 25% for patients treated with gefitinib, compared with 7% for those treated with carboplatin/paclitaxel.

For the new analysis, EGFR mutation status was determined for 437 patients: 261 were mutation-positive.

Among the mutation-positive patients, the median progression-free survival time was 9.5 months with gefitinib therapy versus 6.3 months with conventional chemotherapy.

In this subgroup, 73.5% of gefitinib-treated patients progressed versus 86% of patients who received carboplatin-paclitaxel. This corresponded to a significant, 52% lower risk of progression with gefitinib than with conventional chemotherapy, Dr. Fukuoka said.

Among mutation-negative patients, the median progression-free survival time was 1.5 months with gefitinib versus 5.5 months with chemotherapy. A total of 96.7% of patients treated with gefitinib progressed versus 82.4% of those treated with conventional chemotherapy. This corresponded in a significant, 2.85-fold higher risk of progression with gefitinib compared with carboplatin-paclitaxel.

In response to a question from the audience, Dr. Fukukoa said that median overall survival has not yet been reached, but that the patients will continue to be followed.

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Two Diseases

The findings suggest “that NSCLC should be thought of as two diseases depending on EGFR mutation status,” Dr. Schilsky said.

Discussant George R. Simon, MD, Director of Thoracic Oncology at Fox Chase Cancer Center, said that the study firmly establishes sensitizing EGFR mutations as the best predictors of response to gefitinib. Dr. Simon also presented data that suggested that findings can be extended to erlotinib.

“Every effort should be made to determine the EGFR mutational status in patients with NSCLC,” he said. Patients who are mutation-positive will benefit from gefitinib or erlotinib, and if mutation status is not known, “chemotherapy is the way to go.”

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Vandetanib in ZODIAC Trial of 1,381 Patients Not Responding to First-Line Treatment

The once-daily oral agent vandetanib is unique in that it targets both EGFR and VEGFR signaling, said Roy S. Herbst, MD, PhD, Chief of Thoracic Medical Oncology at the University of Texas M. D. Anderson Cancer Center.

EGFR inhibition affects tumor cell growth, while VEGFR blockade affects angiogenesis. Dr. Herbst presented results of the randomized double-blind placebo-controlled Phase III ZODIAC (Zactima in Combination with Docetaxel in Non-Small Cell Lung Cancer) trial of 1,391 patients with Stage IIIB/IV NSCLC who had not responded to first-line chemotherapy.



The patients were randomized to either vandetanib (100 mg/day) plus docetaxel (75 mg/m2) or the same dose of docetaxel plus placebo, every 21 days, for a maximum of six cycles.

The combination of vandetanib and docetaxel resulted in a statistically significant improvement in the primary endpoint of progression-free survival time, Dr. Herbst reported. The median progression-free survival time was 17.3 weeks in the vandetanib arm vs 14 weeks in the placebo group.

At a median follow-up of 12.8 months, the objective response rate was 17% in the vandetanib group vs 10% in the placebo arm, also a significant difference.

The time to deterioration of symptoms, based on the Functional Assessment of Cancer Therapy-Lung Cancer Subscale, also was significantly longer in the vandetanib arm, he said. “When we looked at the symptom index, patients felt better.”

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Endpoints Debated

There was a trend toward overall survival time in the vandetanib arm, but the difference did not reach significance. “We'll look at data as they mature and hopefully see significance later this year. But this is a positive trial; it met its endpoint, which was progressive-free survival,” Dr. Herbst stressed.

The adverse-event profile was consistent with that observed in other studies of vandetanib for the treatment of NSCLC, he said.

Adverse events more commonly reported by patients in the vandetanib group than by patients in the docetaxel-only arm were diarrhea (42% vs 33%), rash (42% vs 24%), and neutropenia (32% vs 27%).

Adverse events less commonly reported by patients in the vandetanib group were nausea (23% vs 32%), vomiting (16% vs 21%), and anemia (10% vs 15%).

“We didn't see more bleeding in the lung [with vandetanib], which was our major concern,” Dr. Herbst said.

Other experts said they would await the overall survival data before drawing any firm conclusions.

“The results are somewhat promising. We'll have to wait and see,” Dr. Johnson said.

Study Discussant Martin J. Edelman, MD, Professor of Medicine at the University of Maryland Greenebaum Cancer Center, agreed, saying that overall survival is an objective endpoint, while progression-free survival is a subjective endpoint. More importantly, he said, studies of targeted therapies are showing that distinct populations of patients, based on histology or mutation status, benefit from these agents.

The subset of patients most likely to benefit from vandetanib has yet to be identified, Dr. Edelman said.

AstraZeneca, which funded the study, plans to apply for FDA approval of vandetanib in near future.

© 2009 Lippincott Williams & Wilkins, Inc.
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