Reduced-Dose, MTD Erlotinib Outcomes Comparable In Advanced NSCLC

Non-small-cell lung cancer patients may derive survival benefit from erlotinib given below the maximum tolerated dose

medwireNews: Erlotinib therapy is effective at prolonging progression-free survival (PFS) in non-small-cell lung cancer (NSCLC) patients when given below the maximum tolerated dose (MTD), say researchers who believe reduced-dose treatment may be feasible for individuals unable to tolerate the standard regimen.

The team reviewed the outcome of 198 patients with advanced NSCLC testing positive for epidermal growth factor receptor (EGFR) L858R mutations or exon 19 deletions who received erlotinib therapy, 16% of whose treatment was initiated on a reduced-dose.

Patients who received the reduced dose, defined as 100 mg/day or lower, were older and had a poorer performance status than those given the MTD of 150 mg/day.

But PFS did not significantly differ between the reduced-dose and MTD patient groups, at a median of 9.6 versus 11.4 months, say Geoffrey Oxnard, from Dana-Farber Cancer Institute in Boston, Massachusetts, USA, and co-authors in Cancer.

And although there was a trend towards a higher rate of central nervous system progression in patients given the reduced dose versus the MTD, at 17.5% versus 7.8%, this did not reach significance.

The team notes that dose reductions were common and occurred early in the course of treatment; 49% of the 167 patients whose treatment was initiated at the MTD were using a reduced dose at time of progression and 80% of dose reductions occurred within 4 months.

When outcome was assessed by actual erlotinib dose being used at the 4-month checkpoint, median PFS did not significantly differ between patients who began treatment on the MTD but had a dose reduction, the patients who continued to use the MTD after 4 months and those who received a reduced erlotinib dose throughout, at 6.9, 9.8 and 8.9 months, respectively.

After a median follow-up of 24.2 months, 157 of the study participants had died, including 90% of those given reduced-dose erlotinib and 77% of the patients who began treatment on the MTD.

However, after adjusting for age, gender, brain metastases, performance status and other factors, initial erlotinib dose did not significantly predict overall survival.

“Although this study did not examine adverse effects at reduced doses, it has been demonstrated that lower doses of erlotinib lead to a decreased incidence of side effects such as diarrhea”, the researchers write. “Therefore, reduced-dose erlotinib is a reasonable alternative to the MTD that does not significantly compromise efficacy.”

Moreover, Geoffrey Oxnard et al believe that their results have “potential implications for the future development of targeted agents”, citing their literature review showing that 15 of the 30 nonhormonal, small-molecular or kinase inhibitors approved or granted breakthrough status by the US Food and Drug Administration were evaluated at the MTD or the maximum dose tested.

These agents became more likely to be developed at a dose below the MTD over time, an “evolving approach” which the researchers believe indicates there is “uncertainty regarding the efficacy of submaximal doses.”

“When the toxicities of MTD dosing are a concern, an investigation of small-molecule inhibitors at doses below the MTD is warranted”, they conclude, emphasizing that “[b]roadly, small-molecule inhibitors represent a class of therapeutics in which additional studies on the efficacy of lower doses are needed.”

References

Lampson BL, Nishino M, Dahlberg SE, et al. Activity of erlotinib when dosed below the maximum tolerated dose for EGFR-mutant lung cancer: Implications for targeted therapy development. Cancer 2016; Advance online publication 15 August. DOI: 10.1002/cncr.30270

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