Demographic, clinical, and treatment profile of patients on second-line therapy in nonsquamous mutation-positive nonsmall cell lung cancer

Median follow-up of patients is 14 months. Patients receiving gefitinib had better response rates’ complete response partial response (CR + PR) compared with nongefitinib group, 60/113 (53%) versus 18/74 (24%) when used in second line in EGFR mutation positive, metastatic NSCLC. Among nongefitinib group (n = 74), pemetrexed platinum doublet had better response rate (CR + PR), 16/58 (28%) compared to other agents 2/16 (12%). Median PFS and OS of entire cohort of patients are 5.9 months and 13 months, respectively. Gefitinib group had significantly better PFS (7.4 months vs. 4.4 months, P = 0.001) and OS (14 months vs. 9.7 months, P = 0.03) compared to nongefitinib group.

Response to therapy (CR + PR) was significantly associated with improved PFS (10.8 vs. 3.9 months, P = 0.001) in gefitinib as well as in nongefitinib group (6.2 months vs. 3.8 months, P = 0.007). Similarly, OS was significantly improved in both gefitinib (21.4 months vs. 8.9 months, P = 0.01) and nongefitinib group (11.7 months vs. 8.8 months, P = 0.03) for patients with good response to therapy. None of the other prognostic factors such as age, sex, performance status, EGFR mutation status, smoking, and tobacco use had a significant impact on outcome, except gefitinib group had better survival among nonsmokers [Table 2].

Impact of prognostic factors in gefitinib and nongefitinib group on median progression-free survival and median overall survival - log rank test (pair-wise over each stratum)

Patients receiving gefitinib had diverse but mostly low-grade toxicity compared to nongefitinib group such as diarrhea, rash, paronychia, pruritus, anorexia, fatigue, and dry skin [Table 3]. Among chemotherapy group, neutropenia was the most common toxicity including life-threating febrile neutropenia (5.5%). After progression from second-line therapy, 87/187 (46%) went on to receive third-line agents. Weekly paclitaxel (100 mg/m2) was the most common regimen (43/87, 49%) followed by docetaxel (15/87) and gefitinib (10/87).

Toxicity recorded among patients receiving gefitinib versus nongefitinib therapy, as per Common toxicity criteria v4.03

Discussion

First-line pemetrexed platinum doublet and TKIs are both approved as a standard of care in metastatic nonsquamous NSCLC.[2] [3] However, upfront TKI has shown significant benefit in improving PFS when used upfront compared to chemotherapy in EGFR mutation-positive NSCLC.[3] [4] [5] [6] [7] [8] [9] [10] [11] Despite the use of TKIs or pemetrexed doublet, almost all patients subsequently suffer disease progression and become eligible to receive second-line therapy with respect to age, performance status, and comorbidities. TKIs are a valid second-line option for patients who progressed on first-line chemotherapy and harbor EGFR classical mutation. Similarly, patients who progressed on first-line TKI, merit systemic chemotherapy where pemetrexed is more rational choice compared to docetaxel in nonsquamous NSCLC, having similar outcomes with reduced toxicities.[17] We report outcomes and toxicities of physician choice second-line agents who progressed after first-line TKIs or pemetrexed platinum doublet with or without maintenance pemetrexed in patients with EGFR mutation-positive advanced metastatic nonsquamous NSLC exclusively from the Indian subcontinent.

In the initial studies, gefitinib in unselected patients produces response rate of 15%–20%-after progression on 1–2 lines of platinum-based chemotherapy.[18] [19] Gefitinib when compared with docetaxel as second-line therapy in randomized Phase II/III trial did not show any improvement in PFS and OS in unselected patients.[20] [21] [22] [23] However, post hoc subset analysis showed better response rate (42% vs. 21%) and PFS with gefitinib in EGFR mutation-positive subset of NSCLC.[24] Similarly, our study demonstrated superior response rates in selected EGFR classical mutation NSCLC with gefitinib compared to chemotherapy (53% vs. 24%, P = 0.03) which translated into improved PFS (7.4 months vs. 4.4 months, P = 0.001) and OS (14 months vs. 9.7 months, P = 0.03) as second-line therapy.

Several randomized Phase III trial has now compared gefitinib with nonpemetrexed doublet in first line and shown better response rates (60%–84% vs. 30%–47%) and PFS.[7] [8] [9] [10] [11] LUX-Lung 3 is the only randomized Phase III trial which has compared TKI (afatinib) with the standard of care pemetrexed platinum doublet, without maintenance, and shown significantly improved PFS of 11.6 months versus 6.9 months.[12] Our study, with second-line gefitinib, consolidates the evidence that TKIs after progression from first-line chemotherapy retains its drug sensitivity and provides a better outcome in EGFR mutation-positive NSCLC compared to any other second-line chemotherapy.

Hanna et al. reported largest randomized trial of pemetrexed versus docetaxel in second-line NSCLC, where pemetrexed has shown modest response rates of 9%- with PFS of 2.9 months and OS of 8.3 months which was clinically equivalent to docetaxel albeit with reduced toxicities.[17] Our study produced much better response rates (28%) with PFS and OS of 4.4 months and 9.7 months, respectively, with pemetrexed platinum doublet second-line therapy. This discordant outcome can be explained by the fact that all patients in our study receiving pemetrexed platinum doublet in second line were platinum naive and have not been exposed to any chemotherapeutic agent before. Moreover, as against Hanna et al., majority of our patients have received pemetrexed platinum doublet (58/74) compared to pemetrexed alone, being platinum naive.

Majority of our patients who received second-line pemetrexed doublet had prior received gefitinib in first line as per the provision of Phase III randomized trial and had shown better response rate and PFS in first line.[14] Similar to Hanna et al., where better response to second-line chemotherapy, was demonstrated in the same cohort of patients who had complete or PR to first-line agents, in our study better response to second-line pemetrexed doublet could also be attributed to higher response produced by first-line gefitinib (65% vs. 43%) in EGFR mutation-positive NSCLC.[14] [17] This further contributes to the fact that response to first-line agents is strong prognostic and predictive factor of outcome with second-line agents. Pemetrexed doublet in our study produced <5 class="i" xss=removed>et al., where single agent pemetrexed was used.[12] [17]

Rash, diarrhea, fatigue, pruritus, and paronychia are the most common toxicities seen with gefitinib while nongefitinib chemotherapy had higher hematological toxicities. In nongefitinib group, while 78%-had received pemetrexed platinum doublet, remaining patients received weekly paclitaxel, pemetrexed, docetaxel, and gemcitabine, thus making the overall comparator (nongefitinib group) heterogeneous when compared to second-line gefitinib. As physician choice was exercised to select patients and chemotherapeutic agents, selection bias cannot be ruled out with PS 2–3 patients receiving single-agent chemotherapy compared to pemetrexed doublet otherwise. After progression from second-line agents, 46%-patients also received third-line agents, mainly weekly paclitaxel. Hence, impact of third line chemotherapy on OS cannot be completely nullified.

Conclusion

Among exclusive EGFR mutation-positive NSCLC, our study is the first to report outcomes of gefitinib versus physician choice chemotherapy as second line among patients from Indian subcontinent. Favorable response rate after second-line agents is one of the strongest prognostic factors for overall outcome. TKIs after progression on first-line chemotherapy improves response rates, PFS, and OS compared to chemotherapy in EGFR mutation-positive NSCLC.

Conflict of Interest

There are no conflicts of interest.

References

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Publication History

Article published online:
17 June 2021

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