LONDON CANCER NEWS DRUGS GROUP
Erlotinib re-challenge for the third or fourth-line treatment of NSCLC
London and South East Regional Medicines Information
September 2012
Background
A LCNDG rapid review was conducted in January 2012 for erlotinib third or fourth-line treatment
of NSCLC. Erlotinib is accepted for funding via the CDF in London for third or fourth-line
treatment of NSCLC. However, one of the LCNDG CDF criteria for erlotinib to be used in this
setting is that the patient has not previously received erlotinib or EGFR-TKI therapy. This
summary looks at the evidence surrounding re-challenging a patient with erlotinib for the third or
fourth-line treatment of NSCLC when the patient has previously received erlotinib or EGFR-TKI
therapy as an earlier line of treatment.
Published data
The original LCNDG review cited a phase III randomised control trial. Unfortunately, this
study does not state whether patients who had been previously treated with an EGFR
inhibitor were included in the trial. The American Society of Clinical Oncology clinical
practice guideline update states that erlotinib may be used as third-line therapy in patients
with NSCLC and a PS of 0 to 3 who have progressed on or following second-line
chemotherapy and have not received prior erlotinib or gefitinib (6).
Erlotinib after failure of gefitinib
A search of the literature identified two phase II studies, a small prospective study with 8
patients, and some retrospective studies.
Phase II studies
Cho B.C. et al. conducted a study with 21 patients who had generally received gefitinib as a
third-line therapy and showed progressive disease within 4 months of discontinuing gefitinib
(1). Erlotinib was administered as a fourth-line therapy to 10 patients, and the remaining 11
patients received erlotinib as a fifth-line therapy after treatment with irinotecan as fourth-line
chemotherapy.
The median age of the patients was 56 years (range 36–70 years). 47.6% of patients had an
ECOG performance status of 0–2. Patients received erlotinib 150mg daily. Responses in 21
assessable patients included 2 partial responses, 4 stable disease, and 15 progressive
disease, which gave an overall response rate of 9.5% (95% CI 3–22%) and a disease
control rate of 28.6% (95% CI 9.3–47.9%). Four of six gefitinib responders had progressive
disease whilst on erlotinib. Ten out of the 21 patients (47.6%) were refractory to both
tyrosine kinase inhibitors.
The most common adverse event was grade 1/2 skin rash, which affected 28.5% of patients.
Grade 3 skin rash occurred in one patient and grade 1 diarrhoea occurred in two patients.
One patient (4.8%) discontinued erlotinib as a result of grade 3 vomiting. Dose reduction
was required in one patient because of a grade 3 skin rash.
Zhou ZT. et al. also conducted a phase II study of erlotinib 150mg daily in 21 patients with
advanced or metastatic NSCLC who showed disease progression on gefitinib treatment (2).
The median age of the patients was 63 years (range 48–78). 66.7% of patients had an
ECOG performance status of 0–2. 9.5% of patients had received 1 prior chemotherapy
regimen, 61.9% of patients had received 2 prior chemotherapy regimens, and 28.6% had
received 3 prior chemotherapy regimens.
Out of the 21 patients, 2 (9.5%) had a partial response and 4 (19%) had stable disease,
giving an overall response rate of 9.5% (95% CI 5.5–19.6%), and a disease control rate of
28.5% (95% CI 16.4–58.7%). The two patients with partial response to erlotinib had both
obtained a partial response to gefitinib. In the four patients showing stable disease with
erlotinib, three patients had stable disease following gefitinib treatment and one patient had
progressive disease with gefitinib treatment.
The most common adverse event was grade 1/2 skin rash, which affected 75% of patients.
Grade 3 skin rash occurred in one patient and grade 1 diarrhoea occurred in 3 patients.
Retrospective analysis
Hata A. et al. conducted a retrospective analysis of 125 patients with relapsed NSCLC who
had been treated with erlotinib 150mg daily after gefitinib failure (3). 70% of patients had a
performance status of 0 or 1. 71 patients (57%) had previously responded to prior gefitinib
therapy. Out of 125 patients, 11 had a partial response to erlotinib and 44 patients had
stable disease, which gave an overall response rate of 9% (95% CI 5–15%) and a disease
control rate of 44% (95% CI 35–53%). Patients who achieved a partial response had
responded to prior gefitinib therapy. The median PFS was 2.0 months (95% CI 1.4–2.5
months) and the median overall survival time was 11.8 months (95% CI 6.4–16.0 months).
The most common adverse event was skin rash, which was reported in 101 patients (81%).
Interstitial lung disease was observed in four (3%) of the patients. No treatment-related
death was observed. Dose reduction or interruption was performed in 61 (49%) of patients
because of adverse events.
The authors report that following multivariate analysis, insertion of cytotoxic chemotherapies
between gefitinib and erlotinib treatment was associated with longer PFS.
Re-challenge with erlotinib
A search of the literature identified a retrospective study and a case report (5).
Retrospective study
Becker A. et al. conducted a retrospective study of 14 patients with stage IV NSCLC who
had initially responded to tyrosine kinase inhibitors but stopped at disease progression and
received platinum based chemotherapy. At renewed progression, patients were retreated
with an EGFR tyrosine kinase inhibitor (4).
The median age was 55 years (range 39–70 years). All except one patient were initially
treated with erlotinib. In one patient this was combined with sorafenib. In all cases, the
EGFR tyrosine kinase inhibitor used after the platinum based chemotherapy was erlotinib. In
three patients this was in combination with cetuximab.
After a median follow-up of 9 months, 86% of patients had either partial response (n = 5) or
stable disease (n = 7). Progressive disease was seen in 2 patients (14%). Two of the three
patients who also received cetuximab had progressive disease and one patient had a partial
response. Skin rash was commonly seen.
Case report
2
Following 4 weeks of initial erlotinib 150mg daily, a 70 year-old female with stage IV NSCLC
showed a complete response in her intracranial disease and a partial response in her lung
disease. After 12 months of erlotinib therapy, the lung tumour progressed. She received two
cycles of carboplatin and paclitaxel (which confirmed stable disease) but she refused further
cytotoxic chemotherapy due to severe treatment-related diarrhoea. She was re-challenged
with erlotinib and achieved a partial response after 4 weeks, although she also experienced
a grade 3 skin rash which didn’t require dose modification.
Summary
The evidence is weak and the ASCO clinical practice guideline states that patients may be
treated with erlotinib for third-line treatment of NSCLC if they have not received prior EGFR
inhibitors.
However, the evidence that is available suggests that re-challenge with erlotinib may result
in some level of benefit for a minority of patients but it should also be noted that erlotinib rechallenge is associated with a high risk of skin rash.
References
1) Cho B.C. et al. Phase II study of erlotinib in advanced non-small-cell lung cancer
after failure of gefitinib. Journal of clinical oncology. 2007; 25(18):2528–2533
2) Zhou ZT. et al. Erlotinib in advanced non-small-cell lung cancer after gefitinib failure.
Cancer chemotherapy and pharmacology. 2009; 64:1123–1127
3) Hata A. et al. Erlotinib after gefitinib failure in relapsed non-small cell lung cancer:
Clinical benefit with optimal patient selection. Lung cancer. 2011; 74:268–273
4) Becker A. et al. Retreatment with erlotinib: Regain of TKI sensitivity following a drug
holiday for patients with NSCLC who initially responded to EGFR-TKI treatment.
European journal of cancer. 2011; 47:2603–2606
5) Guo R. et al. Subsequent chemotherapy reverses acquired tyrosine kinase inhibitor
resistance and restores response to tyrosine kinase inhibitor in advanced non-smallcell lung cancer. BMC cancer. 2011; 11:90
6) Azzoli C.G. et al. American Society of Clinical Oncology Clinical Practice Guideline
update on chemotherapy for stage IV non-small-cell lung cancer. Journal of clinical
oncology. 2009; 27(36):6251-6266.
Details of search strategy:
1. EMBASE; ERLOTINIB/; 11881 results.
2. EMBASE; LUNG NON SMALL CELL CANCER/; 46079 results.
3. EMBASE; 1 AND 2; 5038 results.
4. EMBASE; *ERLOTINIB/; 2217 results.
5. EMBASE; *LUNG NON SMALL CELL CANCER/; 30588 results.
6. EMBASE; 2 AND 4; 1225 results.
7. EMBASE; 4 AND 5; 970 results.
8. EMBASE; 7 [Limit to: Human and English Language and (Year Published Last 5 Years)]; 591
results.
9. MEDLINE; erlotinib.ti,ab; 2421 results.
10. MEDLINE; CARCINOMA, NON-SMALL-CELL LUNG/; 27182 results.
11. MEDLINE; 9 AND 10; 954 results.
12. MEDLINE; *CARCINOMA, NON-SMALL-CELL LUNG/; 23622 results.
13. MEDLINE; 9 AND 12; 857 results.
14. MEDLINE; 13 [Limit to: English Language and Humans and (Year Published Last 5 Years)]; 632
results.
15. EMBASE; exp DRUG RECHALLENGE/; 739 results.
16. EMBASE; 7 AND 15; 1 results.
17. MEDLINE; rechallenge.ti,ab [Limit to: English Language and Humans]; 1449 results.
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18. MEDLINE; 13 AND 17 [Limit to: English Language and Humans]; 0 results.
19. EMBASE; 7 [Limit to: Human and English Language and (Clinical Trials Clinical Trial or Phase 1
Clinical Trial or
Phase 2 Clinical Trial or Phase 3 Clinical Trial or Phase 4 Clinical Trial)]; 297 results.
20. MEDLINE; 13 [Limit to: English Language and Humans and (Age Groups All Adult 19 plus years)];
351 results.
21. EMBASE; 19 [Limit to: Human and English Language and (Clinical Trials Phase 1 Clinical Trial or
Phase 2
Clinical Trial or Phase 3 Clinical Trial or Phase 4 Clinical Trial) and (Year Published Last 5 Years)];
128 results.
22. MEDLINE,EMBASE; Duplicate filtered: [13 [Limit to: English Language and Humans and (Age
Groups All Adult
19 plus years)]], [19 [Limit to: Human and English Language and (Clinical Trials Phase 1 Clinical Trial
or Phase 2
Clinical Trial or Phase 3 Clinical Trial or Phase 4 Clinical Trial) and (Year Published Last 5 Years)]];
479 results.
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