Case Description

Mrs. T is a 60-year-old white woman living in St. Louis, Missouri. She is divorced and lives alone. She has one son, aged 32 years, and two young grandchildren, and she is currently employed full-time as an attorney. Mrs. T presents to her primary care physician with a persistent cough and weight loss of 20 lb, as well as vague aches and pains. She is otherwise healthy, has never smoked or used illicit drugs, and consumes <30 g/week of alcohol. She is allergic to animal dander and dust particles, for which she takes antihistamines. Her laboratory work up, including complete blood count and metabolic profile, is normal.

An initial chest X-ray shows a lesion in her left upper lung. Computed tomography (CT) scan of her chest and upper abdomen confirms a lesion in the upper lobe of her left lung (diameter 3.1 cm). A fine needle aspiration biopsy of the lesion is performed. Pathologic and immunohistochemical examination of the biopsy sample documents adenocarcinoma, c/w NSCLC.

Audio Commentary by Dr. Langer

A brain MRI scan is negative for brain metastases, but bone and PET/CT scans show multiple, disseminated bony metastases. Her Eastern Cooperative Oncology Group (ECOG) performance status is 1.

Decision Point 1: First-Line Therapy for Metastatic NSCLC

Which of the following would you choose for first-line therapy?

1. Paclitaxel, carboplatin, and bevacizumab
2. Gemcitabine, cisplatin, and bevacizumab
3. Vinorelbine, cisplatin, and cetuximab
4. Paclitaxel, carboplatin, and cetuximab
5. Pemetrexed and carboplatin
6. Any of the above

Discussion

Answer: (f) Any of the above would be appropriate first-line therapy for this patient.

Many combination chemotherapy regimens have been tested in the treatment of advanced/metastatic NSCLC. According to NCCN guidelines, patients with metastatic NSCLC and performance status 1 can be treated with platinum doublet combination chemotherapy alone, chemotherapy plus bevacizumab, or cetuximab plus vinorelbine and cisplatin.¹ Platinum-based doublets remain the backbone of treatment for NSCLC. In a recent phase III trial, the combination of cisplatin plus the antimetabolite pemetrexed, which inhibits several enzymes involved in the folate pathway, was found to have similar efficacy, plus better tolerability and more convenient administration, than cisplatin plus gemcitabine, as first-line treatment in patients with advanced/metastatic NSCLC.² In this trial, 1725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an ECOG performance status of 0 to 1 were randomized to treatment with cisplatin plus gemcitabine or cisplatin plus pemetrexed every 3 weeks for up to six cycles. Median overall survival was the same for the two groups (10.3 months). However, median overall survival was statistically superior for cisplatin plus pemetrexed in patients with adenocarcinoma (12.6 versus 10.9 months, P = .03), large-cell carcinoma (10.4 versus 6.7 months, P = .03), and non–squamous-cell histology (11.8 versus 10.4 months, P = .005), and inferior for patients with squamous-cell histology (9.4 versus 10.8 months, P = .05). Rates of grade 3 or 4 neutropenia (15.1% versus 26.7%, P <.001), anemia (5.6% versus 9.9%, P = .001), thrombocytopenia (4.1% versus 12.7%, P <.001), febrile neutropenia (1.3% versus 3.7%, P = .002), and alopecia (11.9% versus 21.4%, P <.001) were significantly lower in patients treated with cisplatin plus pemetrexed, whereas the rate of grade 3 or 4 nausea was higher (7.2% versus 3.9%, P = .004).

Among the newest agents approved for the first-line treatment of advanced/metastatic NSCLC is bevacizumab, a humanized recombinant monoclonal antibody that binds to and inhibits the activity of vascular endothelial growth factor (VEGF).^3,4 VEGF promotes endothelial cell growth and new blood vessel formation (angiogenesis); thus, bevacizumab inhibits these activities, which drive tumor growth. Bevacizumab has been approved, in combination with carboplatin and paclitaxel, for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic nonsquamous, NSCLC.⁵ In a phase III clinical trial, 878 chemotherapy-naive patients with stage IIIb or IV nonsquamous NSCLC and ECOG performance status of 0 or 1 were randomized to receive six cycles of paclitaxel plus carboplatin (PC), or PC plus bevacizumab; upon completion or discontinuation of chemotherapy, patients in the investigational arm continued to receive bevacizumab alone, until disease progression or unacceptable toxicity.⁶ The addition of bevacizumab to PC significantly increased median overall survival (12.3 versus 10.3 months, P = .003) and progression-free survival (6.2 versus 4.5 months, P <.001), and also significantly increased the response rate (35% versus 15%, P <.001). The rate of clinically relevant bleeding was significantly higher in the bevacizumab plus PC group (4.4% versus 0.7%, P <.001), and there were five deaths from pulmonary hemorrhage in this group. Other clinically important side effects with bevacizumab include arterial and venous thromboembolic events, gastrointestinal perforations and fistulas, wound healing complications, reversible posterior leukoencephalopathy syndrome, hypertension/hypertensive crisis, and proteinuria/nephrotic syndrome, but the incidence of these events is rare.³

In a recent phase III clinical trial, 1043 chemotherapy-naive patients with locally advanced, metastatic, or recurrent nonsquamous NSCLC were randomized to receive gemcitabine plus cisplatin (GC) or GC plus bevacizumab (7.5 or 15 mg/kg) every 3 weeks or until disease progression.⁷ Although the addition of bevacizumab to GC improved median progression-free survival compared with GC alone (HR 0.75, 95% CI 0.62–0.90; P = .002 for 7.5 mg/kg bevacizumab; HR 0.82, 95% CI 0.68–0.98; P = .03 for 15 mg/kg bevacizumab), it did not improve overall survival. While the intent of the study was not to compare the two doses of bevacizumab against each other, improvements in progression-free survival were noted when both low-dose (7.5 mg/kg) and conventional-dose (15 mg/kg) bevacziumab were compared with placebo. In an earlier randomized phase II study, in which patients with advanced NSCLC were treated with paclitaxel and carboplatin, with or without 7.5 mg/kg or 15 mg/kg bevacizumab, significant improvement in progression-free survival was observed only in the group that received chemotherapy plus 15 mg/kg bevacizumab, not in the group that received chemotherapy plus 7.5 mg/kg bevacizumab.⁸ This study was the foundation for the subsequent ECOG study, which demonstrated overall improvements in survival for bevacizumab plus chemotherapy compared with chemotherapy alone.⁶ Given these results, the standard practice in the United States has not changed, and bevacizumab is given at a dose of 15 mg/kg body weight, in combination with paclitaxel and carboplatin, every 3 weeks.

Audio Commentary by Dr. Langer

Another targeted therapy that has been tested in patients with NSCLC is cetuximab, a recombinant chimeric human/mouse monoclonal antibody that binds specifically to the extracellular domain of epidermal growth factor receptor (EGFR) and inhibits its activity.⁹ EGFR is a transmembrane receptor involved in cellular proliferation, survival, and differentiation.^10,11 Overexpression of EGFR has been found to occur in 40% to 80% of patients with NSCLC and has been associated with tumor formation, metastasis, resistance to chemotherapy, disease progression, and poor prognosis.^12,13 Cetuximab binding to EGFR on cells may trigger antibody-dependent complement medicated cytotoxicity.^10,11 A recent phase III clinical trial compared the safety and efficacy of cetuximab, in combination with cisplatin and vinorelbine (CV), with CV alone in 1125 patients with EGFR-detectable advanced NSCLC.¹⁴ The addition of cetuximab significantly increased median overall survival, both in the overall population (11.3 versus 10.1 months, P = .0441) and in whites (10.5 versus 9.1 months, P = .0025). The inclusion of cetuximab also tended to improve overall survival in patients with adenocarcinoma (12.0 versus 10.2 months, P = .0673) and in those with squamous cell histology (10.2 versus 8.9 months, P = .0556). To date, cetuximab has not been approved for the treatment of NSCLC, although it has started to receive compendia listing.

Audio Commentary by Dr. Langer

Case Continues

After learning about the side effects of bevacizumab, the patient declines this agent because of her worry about bleeding risk. Although she is willing to take cetuximab, her insurance company will not cover treatment of her disease with this agent, since its use has not been approved by the FDA for use in patients with NSCLC, although combinations including cetuximab have been included in NCCN guidelines.¹ She therefore starts treatment with pemetrexed and carboplatin. After four cycles, she has stable disease and still has a performance status of 1. She has an occasional cough and is still working full-time. She reports no toxicities on treatment.

Decision Point 2: Maintenance Therapy

How should her treatment proceed at this point?

1. Discontinue treatment and observe until further progression
2. Continue pemetrexed and carboplatin indefinitely until disease progression or excessive toxicities occur
3. Switch to pemetrexed monotherapy
4. Switch to docetaxel monotherapy
5. Switch to erlotinib monotherapy
6. Either a, c, d, or e

Answer: (f) The efficacy of maintenance therapy remains unclear, and current data suggest multiple options but no standard treatment. Therefore, it would not be inappropriate to either observe the patient without further treatment or to implement maintenance therapy, particularly with docetaxel or pemetrexed.^15,16 There are insufficient data to support the use of erlotinib, although a recent press release from Genentech, Inc and OSI Pharmaceuticals, Inc reported that the SATURN trial, which is evaluating maintenance erlotinib versus placebo in 889 patients with advanced NSCLC, found that erlotinib significantly enhanced progression-free survival.¹⁷ Continuing double combination therapy has not been shown to be beneficial.

Audio Commentary by Dr. Langer

A recent multicenter phase III trial comparing pemetrexed with best supportive care in 663 patients who had received platinum-based chemotherapy but had not progressed found that median progression-free survival (4.3 versus 2.6 months, P <.00001) and tumor response (51.7% versus 33.3%, P <.001) were significantly greater in the pemetrexed group, and that these differences were especially pronounced in patients with adenocarcinoma and nonsquamous histology.¹⁶ A subanalysis of patients with nonsquamous histology also suggested that pemetrexed has survival advantage in these patients.

Case Continues

The patient continues on pemetrexed monotherapy at a dose of 500 mg/^m2 IV every 3 weeks. She is still working and still has good performance status. At 21 months, however, she shows signs of disease progression with development of liver metastases.

Decision Point 3: Second-Line Treatment of Metastatic NSCLC

What is her best treatment option now?

1. Erlotinib
2. Docetaxel
3. Pemetrexed
4. Hospice care
5. c or d
6. a or b

Discussion

Answer: (f) Current NCCN guidelines recommend that patients with performance status of 0 to 2 who have experienced disease progression during or after first-line therapy should be treated with single-agent docetaxel, pemetrexed, or erlotinib.¹ Since the patient's disease progressed on a pemetrexed regimen for first-line treatment, it is not indicated for second-line treatment. In addition, erlotinib is particularly advantageous in patients, like Mrs. T, who have never smoked and in patients with adenocarcinoma.¹⁸ Since treatments are available, hospice care is not indicated at this time.

The efficacy of traditional second-line therapies in patients who received maintenance therapy is not clear, and optimum treatments have not been determined. Nevertheless, several second-line therapies have been assessed in patients with advanced NSCLC. For example, a phase III clinical trial showed that single-agent docetaxel as second-line agent improved survival and quality of life compared with vinorelbine or ifosfamide in patients who previously failed platinum-containing chemotherapy.¹⁹ In this trial, 373 patients were randomized to docetaxel (100 or 75 mg/m²) or vinorelbine or ifosfamide. The overall response rates for the two doses of docetaxel were significantly greater than those with vinorelbine or ifosfamide (10.8% versus 0.8%, P = .001, and 6.7% versus 0.8%, P = .036). Patients who received docetaxel had significantly longer time to progression and progression-free survival at 26 weeks. In another trial, docetaxel was associated with significantly greater time to progression (10.6 versus 6.7 weeks, P <.001) and median overall survival (7.0 versus 4.6 months, P = .047) than patients who received best supportive care.²⁰

To test the efficacy of pemetrexed monotherapy, this agent was compared with docetaxel as second-line therapy in patients with NSCLC.²¹ This phase III trial, in 571 previously treated patients, found that the overall response rates (9.1% versus 8.8%, P = .105), median progression-free survival (2.9 versus 2.9 months), median overall survival (8.3 versus 7.9 months, P = NS), and 1-year survival rates (29.7% versus 29.7%) for pemetrexed and docetaxel were equivalent.

Audio Commentary by Dr. Langer

Erlotinib is a small molecule tyrosine kinase inhibitor (TKI) specific for EGFR that has been shown effective in the treatment of advanced/metastatic NSCLC and has been approved by the FDA as monotherapy for treatment of locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.^22,23 In a phase III clinical trial, 731 patients with stage IIIB and IV NSCLC who had been treated with one or two previous chemotherapy regimens were randomized 2:1 to erlotinib or placebo/best supportive care.¹⁸ The erlotinib group achieved a significantly greater response rate (8.9% versus <1%, P <.001), as well as longer median time to progression (2.2 versus 1.8 months, P <.001) and median overall survival (6.7 versus 4.7 months, P <.001). Several patient subgroups were particularly responsive to erlotinib monotherapy, including women, patients of Asian descent, patients with adenocarcinoma, and patients who never smoked. In contrast, two phase III trials found that the addition of erlotinib to standard platinum-based chemotherapy regimens (PC or GC) in patients with previously untreated advanced or metastatic NSCLC did not improve response rate, overall survival, or progression-free survival.^24,25 In both trials, however, erlotinib improved overall survival in patients who never smoked.

The most frequently reported adverse effects associated with erlotinib monotherapy in patients with NSCLC are rash and diarrhea, but these are usually mild to moderate in intensity.²² Liver function test abnormalities, including elevated levels of alanine aminotransferase, aspartate aminotransferase, and bilirubin, have also been reported, but these elevations were mainly transient or associated with liver metastases. Other rare, but clinically important adverse effects of erlotinib observed in patients with NSCLC are pulmonary toxicities, including dyspnea, pneumonitis, and interstitial lung disease-like events; hepatoxicity, including hepatic failure and hepatorenal syndrome; and renal failure, including hepatorenal syndrome, acute renal failure, and renal insufficiency. Since erlotinib is metabolized primary in the liver, patients with hepatic impairment should be monitored closely during erlotinib treatment.

A recent phase II trial compared the efficacy of bevacizumab plus erlotinib with bevacizumab plus chemotherapy (docetaxel or pemetrexed), and chemotherapy alone as second-line treatment in 120 patients with nonsquamous NSCLC that had progressed during or after one platinum-based regimen.²⁶ Relative to chemotherapy alone, the risk of disease progression or death was 0.72 for bevacizumab plus erlotinib and 0.66 for bevacizumab plus chemotherapy, although neither difference was statistically significant. One-year survival rates were 57.4% for bevacizumab plus erlotinib, 53.8% for bevacizumab plus chemotherapy, and 33.1% for chemotherapy alone. Preliminary results of a phase III trial of 636 patients randomized to bevacizumab plus erlotinib or erlotinib alone showed that the addition of bevacizumab to erlotinib significantly enhanced progression-free survival (3.4 versus 1.7 months, P<.0001) and objective response rate (12.6% versus 6.2%, P = .008).²⁷

A second TKI, gefitinib, has also been tested in patients with advanced/metastatic NSCLC refractory to previous treatment. Although phase II clinical trials found that this agent was effective, a phase III trial demonstrated that the effect of gefitinib on overall survival was not significant.^28-30 A recent phase III clinical trial comparing gefitinib with docetaxel as second-line treatment in Japanese patients with NSCLC found that the two were equivalent in overall survival and progression-free survival, but that gefitinib was superior in objective response rate, quality of live measurements, and adverse events, suggesting that gefitinib may be effective in subsets of patients with NSCLC.³¹

The presence of mutant K-ras alleles has been found to predict lack of response to both erlotinib and gefitinib in patients with NSCLC.^32,33 In addition, higher response rates to both erlotinib and gefitinib have been associated with the presence of activating EGFR mutations and with high EGFR copy number.^34-38

A third small molecule TKI, vandetanib, which is specific for VEGF receptor-2 and EGFR, has also been tested in patients with previously treated advanced NSCLC. In a randomized phase II trial, vandetanib was compared with gefitinib in 168 patients with locally advanced or metastatic NSCLC who had progressed despite first- or second-line platinum based therapy.³⁹ Vandetanib showed a significant improvement in median progression-free survival when compared with gefitinib (11 versus 8.1 weeks, P = .025). A recent phase IIa dose-finding study showed that vandetanib monotherapy showed antitumor activity in 53 Japanese patients with previously treated advanced NSCLC.⁴⁰

Vandetanib has also been assessed in combination with chemotherapy. In one randomized phase II trial, 127 patients were randomized to treatment with vandetanib (100 or 300 mg/day) plus docetaxel (75 mg/m² every 21 days) or to placebo plus docetaxel.⁴¹ Median progression-free survival was significantly longer for vandetanib 100 mg/day plus docetaxel than for docetaxel alone (18.7 versus 12 weeks, HR = 0.64, P = .037), but not for vandetanib 300 mg/day plus docetaxel than for docetaxel alone (17 versus 12 weeks, HR = 0.83, P = .23). There were no significant between-group differences, however, in overall survival. Response to vandetanib may be associated with lower baseline VEGF concentrations.⁴²

A recent press release from AstraZeneca has reported preliminary results of three phase III trials of vandetanib in patients with advanced NSCLC.⁴³ In the ZODIAC trial, comparing the combination of vandetanib plus docetaxel with docetaxel alone in 1301 previously treated patients with advanced NSCLC, the addition of vandetanib significantly enhanced progression-free survival and objective response rate, as well as prolonging overall survival, but not significantly. In the ZEAL trial, comparing the combination of vandetanib plus pemetrexed with pemetrexed alone in 534 previously treated patients with advanced NSCLC, the addition of vandetanib significantly enhanced objective response rate and prolonged progression-free and overall survival, but not significantly. In the ZEST trial, which compared vandetanib with erlotinib in 1240 previously treated patients with advanced NSCLC, there were no significant between-group differences in progression-free and overall survival. This agent has not yet been approved by the FDA for the treatment of NSCLC. We are still awaiting the results of the phase III trial placebo-controlled trial evaluating this agent in patients whose disease has progressed after standard chemotherapy and EGFR TKI.

Case Continues

After learning about the potential benefits and side effects of erlotinib monotherapy, Mrs. T begins treatment with this agent. Although she develops a mild rash, she continues on erlotinib.

Conclusion

As described here, many chemotherapy regimens are now available as first-line, maintenance, and second-line treatments for patients with advanced/metastatic NSCLC. Among the newer agents approved for this indication are pemetrexed, which targets the folate pathway; bevacizumab, which targets VEGF; and erlotinib, which targets EGFR. In addition, cetuximab, which targets EGFR, has shown efficacy in these patients and is still being tested. Because of their targeted mechanisms of action, which generally do not overlap with older, conventional cytotoxics, these agents—in particular the monoclonal antibodies—can be combined with standard chemotherapy. However, they can introduce their own unique constellation of toxicities, and we the practicing physicians should be well versed in the recognition and management of these unique side effects.

References

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38. Zhu CQ, da Cunha Santos G, Ding K, et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol. 2008;26:4268-4275.


39. Natale RB, Bodkin D, Govindan R, et al. A comparison of the antitumour efficacy of ZD6474 and gefitinib (Iressa™) in patients with NSCLC: results of a randomized, double-blind phase II study. Lung Cancer. 2005;49:537.


40. Kiura K, Nakagawa K, Shinkai T, et al. A randomized, double-blind, phase IIa dose-finding study of vandetanib (ZD6474) in Japanese patients with non-small cell lung cancer. J Thorac Oncol. 2008;3:386-393.


41. Heymach JV, Johnson BE, Prager D, et al. Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer. J Clin Oncol. 2007;25:4270-4277.


42. Heymach JV, Hanrahan EO, Mann H, et al. Baseline VEGF as a potential predictive biomarker of vandetanib clinical benefit in patients with advanced NSCLC. J Clin Oncol. 2008;26:426s (abstr 8009).


43. Phase III studies show that vandetanib (ZACTIMA) brings clinical benefits to patients with lung cancer. AstraZeneca International, 19 November 2008. Available at: http://www.astrazeneca.com/pressrelease/5414.aspx. Accessed Dec. 1, 2008.