Cancerous cachexia was coined in 1858 by Dr John Zachariah Laurence to describe chronic wasting associated with malignancy. Cancer cachexia is now defined as weight loss >5% over 6 months or ongoing weight loss >2% with a BMI of <20 kg/m2 or sarcopenia. Generations of oncologists have been taught to recognize and reverse cancer cachexia in patients as it results in inability to tolerate systemic treatment and poor survival outcomes. A neutralizing monoclonal antibody against growth differentiation factor 15, ponsegromab, has demonstrated to reduce cachexia symptoms compared with placebo albeit the median increase in body weight, the primary end point of the trial, was 2.81 kg over placebo at the highest dose.
The advent of targeted therapy has revolutionized patient outcomes and none more so than in the first-line (1L) treatment of ALK fusion–positive non–small cell lung cancer (NSCLC). The 3- and 5-year CROWN trial updates reported that lorlatinib (a third-generation ALK tyrosine kinase inhibitor [TKI])-treated patients with ALK+ NSCLC achieved 3- and 5-year progression-free survival (PFS) rates of 64% and 60%, respectively. Forty-four percent (n = 65) of lorlatinib-treated patients experienced weight gain of any Common Toxicity Criteria Adverse Event (CTCAE) grade. Grade 3 (≥20% increase in baseline weight) weight gain occurred in 30 of the 65 (46.2%) patients at a 3-year follow-up, which increased to 52.3% (34 of 65) at a 5-year follow-up.
Alectinib, a second-generation ALK TKI, achieved a 3-year PFS rate of 46.4% and a median PFS of 34.8 months as 1L treatment of advanced ALK+ NSCLC from the ALEX trial. Both alectinib and lorlatinib achieved significantly improved PFS against crizotinib. Since alectinib was approved for 1L treatment of advanced ALK+ NSCLC in 2017, it has been perceived to be well tolerated among next-generation ALK TKIs. Data suggested that both ALK TKIs are well-tolerated with the median relative dose intensity (RDI) of alectinib being 100% with a median duration of treatment (DOT) of 27.0 months from the ALEX trial, whereas the median RDI of lorlatinib was 99% with a median DOT of 57.0 months from the CROWN trial.
In 2023, de Leeuw et al reported that alectinib can cause sarcopenic abdominal obesity. Mean waist circumference increased by 9 cm (approximately 3.5 inches), and there was a relative 40% increase in abdominal obesity, defined as waist circumference ≥102 cm (40.1 inches) for males and ≥88 cm (34.6 inches) for females among a cohort of 46 Danish patients at a 1-year follow-up after starting alectinib.
In the article that accompanies this editorial, Sikkema et al followed up on the observations by de Leeuw et al and investigated the incidences and factors associated with alectinib-induced weight gain from 4 separate alectinib studies (three randomized trials—ALEX, J-ALEX, ALUR and one expanded access study). Patients' weights were not collected longitudinally in the ALEX trial, and any analysis of weight gain was based on investigators’ reported CTCAE grading of weight gain. Results from data analysis of 302 patients from the other three trials formed the bulk of the results reported. Not unexpectedly, weight gain as an adverse event was dramatically under-reported. For example, while 63.1% of patients in J-ALEX reached any CTCAE grade of weight gain (grade 1 to 3), actual report of weight gain as a CTCAE (any grade) was only 1%. Overall, the alectinib-induced weight gain was 0.48%/month (6% increase per year) and 0.31%/month (4% increase per year) over baseline for Japanese and Western patients, respectively. The longer a patient was on alectinib, the greater the weight gained regardless of baseline BMI when measured up to a 1-year study period. Given that 13.6% of the Japanese patients in J-ALEX had a BMI of <18.5 kg/m2, it is important to understand the context of weight gain and not attribute all weight gain as clinically detrimental. A grade 2 weight may be a welcomed outcome in a patient with cancer cachexia, but the same weight gain percentage may not hold true for a patient whose baseline weight is normal or overweight/obese. Both select RET TKIs, selpercatinib and pralsetinib, have also been reported to cause weight gain, and hence, TKI-induced weight gain may be more common than just limited to alectinib and lorlatinib.