At the 2014 Multidisciplinary Symposium in Thoracic Oncology in Chicago, Jyoti D. Patel, MD, associate professor in Medicine-Hematology/Oncology at the Feinberg School of Medicine at Northwestern University, led a breakout session on how to manage the toxicities associated with the molecular therapies used to treat patients with lung cancers.

The nuances of providing this care effectively can be complex but Patel’s premise was simple: Addressing toxicities promptly is vital because the treatment regimens used for lung cancer require tight compliance. “We hope our patients will be taking these medications for a year or more. They must be willing to take them every day,” she said. “But when toxicities are severe, the effects can interfere with activities of daily living and when that happens, treatment adherence can be drastically affected.”

Though the care of lung cancer patients requires specific expertise in oncology that takes years to develop, Patel suggested that colleagues remember their earliest days as physicians, too. “We need to put on our internal medicine hats again,” she said. “That means being proactive to counsel and educate our patients ourselves.”

Patel’s practice relies heavily on toxicity appointments with a physician, not a mid-level provider, to maintain patient compliance. The physician reviews each patient’s symptoms, toxicities, and medication adherence: “That's when we might cover anecdotal points like limiting hot water exposure, using a humidifier, or choosing a thick, oil-based skin cream [versus a water-based lotion] to help with rashes.” The intent is to discover and address toxicities before treatment adherence is affected. Dosing, of course, may need to be adjusted and can also be done at this appointment.

Patel reviewed EGFR inhibitor—associated toxicity in erlotinib, afatinib, and cetuximab. She noted that papulopustular rash and diarrhea are their most common side effects. With severe skin cracking and fissures, her practice recommends brief bleach soaks to prevent infection, zinc creams and, for heels and fingertips, silver nitrate, zinc oxide and cyanoacrylate glue (skin glue or Krazy Glue).

, can cause GI upsets within 2 to 5 days of starting treatment. It can also cause visual effects at 2 weeks; both these side effects typically resolve on their own. Crizotinib can also cause peripheral edema at 2 to 3 months, which generally does not resolve on its own. Rare but serious toxicities include pneumonitis and neutropenia.

Patel also discussed crizotinib’s potential to cause hypogonadism, noting that testosterone levels may drop to levels that affect patient quality of life within weeks. She urged colleagues to monitor testosterone levels in all male patients on crizotinib and to refer them for endocrine care as appropriate.

She also addressed crizotinib’s tendency to cause bradycardia, noting that 11% of patients in trials experienced this adverse effect (AE). Patel recommended discontinuing crizotinib until the patient’s heart rate returns to 60 bpm or greater. Also, be prepared to adjust or discontinue other medications as needed, as well as to adjust the crizotinib dose itself, she advised.

Finally, Patel discussed ceritinib. “In studies, nearly 60% of patients needed a dose reduction to be able to continue with it,” she said. “When we start patients on ceritinib, we really need to see them every week initially.” Given that 10% of patients needed to discontinue ceritinib due to AEs [mainly pneumonia, pneumonitis, and decreased appetite], she advised colleagues to monitor patients’ liver function tests at least monthly and reduce their doses as soon as toxicities emerge.

To close, Patel reminded colleagues that these toxicities are often insidious and usually don’t correlate with laboratory findings and, to return to her internal medicine analogy, require frequent referrals across multiple disciplines. “In general, lung cancer patients are very motivated to take the drugs we prescribe,” she said. “Unfortunately, they may not be able to if we can't manage the associated toxicities.”

	Patel JD. Tips for treating toxicities from targeted therapies. Presented at: 2014 Multidisciplinary Symposium in Thoracic Oncology; October 30—November 1, 2014; Chicago, IL.

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Jyoti D. Patel, MD, provides insight into managing the toxicities associated with molecular therapies used to treat patients with lung cancers.

Expert Advises on Managing Side Effects of Targeted Lung Cancer Therapies

The PD-1 immune checkpoint inhibitor nivolumab (Opdivo) achieved an objective response rate (ORR) of 15% (95% CI, 8.7- 22.2) with a median duration of response that was not yet reached at an 11-month follow-up for patients with advanced, refractory non-small cell lung cancer (NSCLC).

The data were presented at the 2014 Multidisciplinary Symposium in Thoracic Oncology, where lead author Suresh S. Ramalingam, MD, professor and director of medical oncology, Winship Cancer Institute of Emory University, called the study findings encouraging.

"There are currently no effective treatment options for patients with refractory squamous cell lung cancer after their disease has progressed through 2 prior therapies," he said at the symposium. "Historically, these patients have had ORRs of 2%-8% and median overall survival (OS) of about 5 months so, even though we have not yet reached the median duration of response [in this study], the signs are very promising."

ORR was the primary endpoint of this study, known as Checkmate-063. The study was designed for patients who had failed 2 or more systemic treatments (n = 117). Notably, 65% of patients (n = 76) had previously failed 3 or more treatments. Seventy-six percent of patients were within 3 months of completion of their most recent therapy.

Patients in the study were treated with nivolumab as a single agent at 3 mg/kg by intravenous infusion every 2 weeks until disease progression or treatment discontinuation. Responders were further characterized by duration of response. Secondary endpoints included investigator-assessed ORR, and exploratory endpoints were overall survival (OS), progression free survival (PFS), and efficacy by PD-L1 expression status. 

With approximately 11 months of minimum follow up, the ORR was 15% (95% CI, 8.7, 22.2) as assessed by an independent review committee (IRC) using RECIST 1.1 criteria. The median duration of response was not reached. The estimated 1-year survival rate was 41% (95% CI, 31.6-49.7) and the median OS was 8.2 months (95% CI, 6.05-0.91). This compares favorably with the previously demonstrated 1-year survival rate of 5.5% to 18% for patients with third-line squamous cell NSCLC, noted Ramalingam.

An additional 26% of patients had stable disease for a median duration of 6 months (95% CI, 4.73-10.91), demonstrating a disease control rate (defined as ORR + stable disease) of 41%. For patients with quantifiable PD-L1 expression, responses were observed independent of PD-L1 status.

Adverse events (AEs) of all types and grades occurred in 74% of patients; however, 85% of patients were able to receive at least 90% of their planned dose intensity. Grade 3-4 drug-related AEs were reported in 17% of patients. The most common (greater than or equal to 2%) Grade 3-4 AEs were fatigue (4.3%), pneumonitis (3.4%), and diarrhea (2.6%). Discontinuations due to drug-related AEs of any grade occurred in 12% of patients. Two drug-related deaths (1 hypoxic pneumonia, 1 ischemic stroke) occurred in patients with multiple comorbidities and progressive disease.

Among the 15% of patients who responded to nivolumab, the response was durable and remained ongoing in 76% of patients. Additionally, the authors noted that nivolumab was well tolerated with a manageable safety profile, and showed clinical activity in patients who were both PD-L1-positive and PD-L1-negative.

In recognition of the urgent need for therapies for squamous NSCLC, the study authors pointed out a phase III trial is currently under way comparing the OS of nivolumab to docetaxel for squamous NSCLC. At this point, 4 phase III trials are evaluating nivolumab as monotherapy in patients with NSCLC: 3 in previously treated patients and 1 in the frontline setting.

The study has already garnered attention within the oncology community, with the thoracic symposium accepting results from the phase II Checkmate-063 study as a late-breaking abstract, to highlight its rapidly developing data.

, immunotherapy discussant Vassiliki Papadimitrakopoulou, MD, a professor at MD Anderson Cancer Center, described results from the Checkmate-063 study as the most promising of 5 immunotherapy studies presented at the symposium.

"The study looking at nivolumab monotherapy for squamous NSCLC is quite unprecedented," Papadimitrakopoulou said. "It shows promise for a group of patients who are not able to be served by any existing therapies. And it gives us a signal where to focus our further studies in this important area."

	S.S. Ramalingam, J. Mazieres, D. Planchard et al. Phase II study of nivolumab (Anti-PD-1, BMS-936558, ONO-4538) in patients with advanced, refractory squamous non-small cell lung cancer. Presented at: 2014 Multidisciplinary Symposium in Thoracic Oncology; October 30-November 1, 2014; Chicago, IL. Abstract Number: LB2.

The PD-1 immune checkpoint inhibitor nivolumab achieved an ORR of 15% with a median duration of response that was not yet reached at a median 11-month follow-up for patients with advanced, refractory NSCLC. 

Phase II Study Shows Promising Efficacy for Nivolumab in Advanced NSCLC

First-line afatinib (Gilotrif) improved overall survival (OS) by about 1 year in patients with advanced non—small cell lung cancer (NSCLC) whose tumors harbor EGFR exon 19 deletions according to results from the LUX-Lung 3 and the LUX-Lung 6 phase III randomized trials. The data were presented at the 2014 Multidisciplinary Symposium in Thoracic Oncology.

The study authors believe that these survival data warrant a major shift among clinicians. “In our opinion, first-line afatinib should become the standard of care for EGFR Del19 patients,” lead author Lecia V. Sequist, MD, said at the symposium. “The questions have been answered regarding its effectiveness for this mutation,” added Sequist, medical oncologist, associate professor, Massachusetts General Hospital, Harvard Medical School.

Afatinib is approved in many countries globally, including the United States, where it is indicated for previously untreated patients with metastatic NSCLC harboring common EGFR mutations (Del19 and L858R).

Both the LUX-Lung 3 and the LUX-Lung 6 trials shared the same design and methodology. Following testing for an EGFR mutation, patients with stage IIIB/IV EGFR-positive NSCLC were randomized 2:1 to receive oral afatinib (40 mg daily) or up to six cycles of chemotherapy. LUX-Lung 3 chemotherapy was pemetrexed/cisplatin and LUX-Lung 6 chemotherapy was gemcitabine/cisplatin. Randomization was stratified by mutation type (Del19/L858R/other) for both trials, with 89% of patients in each trial having either Del19 or L858R. Only 11% of patients had uncommon mutations.

The LUX-Lung 3 also stratified patients (n = 345) by race (Asian/non-Asian). Non-Asian patients were recruited mainly from Europe, South America and Australia. LUX-Lung 6 (n = 364) consisted of Asian patients, primarily Chinese.

The primary endpoint of both studies was progression-free survival, which previously reported data showed both trials met. OS, disease control rate (DCR), patient reported outcomes (PRO) and objective response rate (ORR) were secondary endpoints for both studies.

Median follow up for OS was 40.9 months in LUX-Lung 3 and 33.7 months in LUX-Lung 6. The hazard ratios (HR) for OS were 0.78 (95% CI 0.58-1.06; 

 = .109) versus pemetrexed/cisplatin and 0.83 (95% CI, 0.63-1.09; 

 = .176) versus gemcitabine/cisplatin. Results within the mutation subgroups were consistent between both trials.

In the analysis of common mutations, OS improved in EGFR Del19 patients regardless of their race. The afatinib versus chemotherapy data by population group are as follows:

		LUX-Lung 3, global population: median of 33.3 months with afatinib versus 21.1 months with chemotherapy (HR = 0.54; 95% CI, 0.36-0.79)

		LUX-Lung 6, Asian population: median of 31.4 months with afatinib versus 18.4 months with chemotherapy (HR = 0.64; 95% CI, 0.44-0.94)

		LUX-Lung 3, Non-Asian population: median of 33.6 months with afatinib versus 20.0 months with chemotherapy (HR = 0.45; 95% CI, 0.21-0.95; 

However, there was no significant difference in the OS of patients who had L858R mutations between afatinib and chemotherapy. Sequist and her colleagues believe that, despite the lack of clear differentiating factors between the regimens, afatinib remains a treatment option for EGFR L858R patients.

Sequist et al also drew another important conclusion from the LUX-Lung 3 and LUX-Lung 6 trials: “We also believe that, going forward, we can no longer look at patients with these two mutations together [in the same study]. We need to look at them separately because the Del19 and L858R mutations react quite differently.”

Sequist L, Wu Y, Schuler M, et al. Overall survival (OS) with afatinib versus chemotherapy in patients (Pts) with advanced non-small cell lung cancer (NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations (EGFR mut): results of LUX-Lung 3 (LL3) and LUX-Lung 6 (LL6). Presented at: 2014 Multidisciplinary Symposium in Thoracic Oncology; October 30-November 1, 2014; Chicago, IL. Abstract 9.

First-line afatinib (Gilotrif) improved overall survival (OS) by about 1 year in patients with advanced nonâ€“small cell lung cancer (NSCLC) whose tumors harbor EGFR exon 19 deletions according to results from the LUX-Lung 3 and the LUX-Lung 6 phase III randomized trials.

Afatinib Extends OS by Approximately 1 Year in Subgroup of NSCLC

 Biopsies were found to be the most costly tool used in lung cancer diagnosis, and may be performed too frequently based on negative test results and adverse events, according to a Medicare claims analysis presented at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology.

The analysis looked at utilization rates and estimated the Medicare costs of the lung cancer diagnostic workups of patients with an abnormal chest CT scan. The retrospective study used a random sample from the 5% of the Medicare Claims Database (2009-2011).

“This study provides a baseline of current costs for the lung cancer diagnostic workup prior to the introduction of major lung cancer screening programs. Biopsy costs comprise a significant proportion of the overall cost of diagnosing lung cancer,” lead author Tasneem Lokhandwala, PhD, MS, a data analyst at Xcenda in Palm Harbor, Florida, said at the symposium. “Reducing the number of patients who are referred for lung biopsies has the potential to decrease Medicare costs and ultimately improve patient outcomes.”

The study population consisted of patients aged 65-74 years who had an abnormal CT scan between July 1, 2009 and December 31, 2010 (n = 8,979). Patients were excluded if they had been diagnosed with cancer, pneumonia, atelectasis or tuberculosis in the 6 months preceding the abnormal CT scan or if they were not continuously Medicare-eligible during the entire study period, which included a 12-month follow-up. The mean patient age was 69.3 years, 86.5% of patients were Caucasian, and 43.6% were male.

Of the study population, 13.9% (n = 1,249) of patients were diagnosed with lung cancer during a 12-month period. The median time to diagnosis was 11 days. Diagnostic tests included chest x-rays (54.4% of patients; n = 4,886), CT scans (32.9% of patients; n = 2,958), PET scans (0.5% of patients; n = 47), and lung biopsy (19.4% of patients; n = 1,744).

The analysis included estimated Medicare costs for each type of diagnostic test. The average cost of a chest x-ray was $19, a CT scan was $184, and a PET scan was $624. Costs were calculated by analyzing claims with a CPT code for each specific service.

Biopsy claims were notably more complex: the average cost was $14,634, including all costs associated with that procedure. “This approach enabled the capture of other services and adverse events associated with a biopsy,” said Lokhandwala.

Of the 1,744 patients who received a lung biopsy, 19.3% (n = 336) experienced a biopsy-related adverse event (those included were hemorrhage, pneumothorax and respiratory failure requiring mechanical ventilation). The average cost of a biopsy with adverse events was approximately four times higher than a complication-free biopsy ($37,745 compared to $8,869).

Overall, the total diagnostic costs for the study population were $38.3 million. Of the total workup costs, $16.5 million (43.1%) was accounted for by negative biopsies.

“These results show that we need to develop more precise risk stratification tools to better identify patients who require referrals for lung biopsy. Doing so has the potential to reduce costs and improve patient outcomes,” Lokhandwala said. “Additionally, clinicians should consider noninvasive testing methods first and we should also increase our focus on developing less invasive tests.”

According to the National Comprehensive Cancer Network lung cancer screening guidelines, clinicians should use low-dose CT of the chest followed by a PET scan to identify patients for lung biopsy. This analysis indicated that many patients who ultimately had a negative lung cancer diagnosis underwent unnecessary biopsies, including biopsy-related adverse events.

	Lokhandwala T, Dann R, Johnson M, et al. Costs of the Diagnostic Workup for Lung Cancer - A Medicare Claims Analysis. Presented at: 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology; October 30-November 1, 2014; Chicago, Illinois. Presentation Number: 103.

Biopsies were found to be the most costly tool used in lung cancer diagnosis, and may be performed too frequently based on negative test results and adverse events.

Darcy Lewis

Articles

Expert Advises on Managing Side Effects of Targeted Lung Cancer Therapies

Phase II Study Shows Promising Efficacy for Nivolumab in Advanced NSCLC

Afatinib Extends OS by Approximately 1 Year in Subgroup of NSCLC

Reducing Lung Biopsies May Cut Costs, Improve Patient Outcomes