Rechallenge Pemetrexed-Based Chemotherapy Provides an Option for Initially Benefited Patients with Advanced Lung Adenocarcinoma
Pemetrexed, a chemotherapeutic agent often combined with platinum-based drugs such as cisplatin or carboplatin, is widely recommended as the standard first-line treatment for non-small cell lung cancer (NSCLC) patients without identified genetic mutations. This regimen has demonstrated a median survival of approximately 10.2 to 13.0 months and a 5-year survival rate of 13% to 15%. For patients with advanced lung adenocarcinoma, initial pemetrexed-based chemotherapy has been confirmed as an effective treatment, even in the absence of specific genetic biomarkers predicting its efficacy. Following induction chemotherapy, patients can continue with pemetrexed as a single-agent maintenance treatment, which has shown excellent patient tolerance and safety profiles in previous studies.
Recent reports suggest that rechallenging patients with pemetrexed, either alone or in combination with other agents, may be a feasible option for those who initially benefited from the treatment but later developed resistance to tyrosine kinase inhibitors. This approach is based on the hypothesis that pemetrexed-sensitive tumor cell clones may still exist and respond to rechallenge. Given the lack of standardized multiline treatment options for advanced NSCLC, this study aimed to evaluate the efficacy and safety of pemetrexed rechallenge in patients with locally advanced or metastatic lung adenocarcinoma who had previously benefited from first-line pemetrexed-platinum chemotherapy.
This retrospective study analyzed clinical data from 34 patients with advanced lung adenocarcinoma who received pemetrexed rechallenge between January 2012 and December 2017. The inclusion criteria were strict: patients had to have provided informed consent for chemotherapy, been diagnosed with locally advanced or metastatic non-squamous NSCLC (stage IIIB–IV), received pemetrexed rechallenge as second or further-line chemotherapy (at least two cycles), experienced therapeutic benefit (stable disease or partial response) from initial pemetrexed-platinum regimens, and had complete medical records. Patients with squamous lung cancer, disease progression, or those lost to follow-up were excluded.
Patients were followed from initial enrollment and monitored every two to three cycles until death, withdrawal of consent, or the study cutoff date. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Response data, including complete response, partial response, stable disease, and progressive disease, were evaluated using Response Evaluation Criteria in Solid Tumors (Version 1.1). The objective response rate was defined as the sum of complete and partial responses, while the disease control rate included complete response, partial response, and stable disease. Toxicity was assessed using the National Cancer Institute-Common Toxicity Criteria for Adverse Events (Version 4.0). Statistical analyses were performed using the Kaplan-Meier method, log-rank tests, and multivariate Cox analyses, with a significance level set at P < 0.05.
The study cohort consisted of 34 Chinese patients, with a median age of 58 years (range: 36–79 years). The majority were female (62%) and non-smokers (68%). All patients were diagnosed with adenocarcinoma and presented with stage IIIB/IV disease. At baseline, 56% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1, while 44% had an ECOG PS of 2–3. Comorbidities were present in 56% of patients, and all were taking concomitant medications such as anticoagulants and antihypertensives. Genetic testing revealed that 35% of patients had epidermal growth factor receptor (EGFR) mutations (exons 19 and 21), including one case with the T790M mutation, and 12% had EML4-ALK gene fusions.
Patients received pemetrexed and platinum doublets (cisplatin, carboplatin, or nedaplatin) as first-line therapy, with a median of five cycles. Nearly half (48%) underwent pemetrexed maintenance treatment, with a median of six cycles. The rechallenge regimens varied: 29% received pemetrexed as a second-line treatment, while 71% received it as third or further-line therapy. The rechallenge regimens included pemetrexed-carboplatin (32%), pemetrexed-cisplatin (26%), pemetrexed-nedaplatin (6%), pemetrexed-taxane (12%), and pemetrexed alone (24%). Additionally, 38% of patients received bevacizumab in combination with pemetrexed rechallenge. Maintenance pemetrexed was administered to eight patients, with a median of four cycles. All patients received oral folic acid and vitamin B12 injections to mitigate toxicity.
The median PFS after initial pemetrexed-based treatment (PFS1) was 12.7 months (range: 2.3–48.6 months), and the median treatment-free survival (TFS) was 15.5 months (range: 0.0–71.0 months). After a median follow-up of 30.8 months, the disease control rate for pemetrexed rechallenge was 82%. The median PFS for rechallenge was 9.35 months (range: 0.9–44.2 months), and the median OS was 42.2 months (range: 15.3–87.1 months). No significant differences in PFS or OS were observed between the various rechallenge regimens. Multivariate analyses identified PFS1 (≥10 vs. <10 months) and the line of rechallenge (second/third vs. ≥ fourth) as significant prognostic factors for PFS. Initial maintenance treatment and TFS (≥15 vs. <15 months) were significant predictors of OS.
The study demonstrated that pemetrexed rechallenge is a well-tolerated and effective strategy for patients with advanced lung adenocarcinoma who had previously benefited from pemetrexed-platinum chemotherapy. Patients with a PFS1 of ≥10 months, TFS of ≥15 months, and those receiving rechallenge as second or third-line therapy were identified as the most likely to benefit from this approach. Maintenance pemetrexed was also highlighted as a significant factor in improving OS.
In conclusion, rechallenge with pemetrexed-based chemotherapy offers a palliative option for advanced lung adenocarcinoma patients who initially responded well to pemetrexed-platinum regimens. This strategy may improve quality of life, prolong survival, and alleviate cancer-related symptoms, particularly for patients with favorable prognostic factors such as longer PFS1, TFS, and earlier lines of rechallenge therapy.
doi.org/10.1097/CM9.0000000000001511
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