HAE MATOLOGICAL CANCER

Initial pirtobrutinib data show promise
U RO LOGICAL CANCE R
Benefit with enfortumab vedotin confirmed

Despite the activity of covalent BTK inhibitors in different B-cell malignancies, the development of resistance or intolerance
eventually leads to treatment discontinuation in up to 40% of patients. Pirtobrutinib is a highly selective, reversible BTK inhibitor
with equal potency against wild-type and C481-mutated BTK, a common cause of resistance in malignancies including chronic lymphocytic leukaemia (CLL). Now, data from the first-in-human trial of this agent indicate its efficacy in B cell malignancies.
The BRUIN phase I/II study involved patients with CLL or small lymphocytic lym- phoma (SLL; n = 170), mantle cell lymphoma (MCL; n = 61), Waldenström macroglobulinae- mia (WM; n = 26) or other B-cell lymphomas (n = 66) who had received a median of three previous therapies, including a covalent BTK inhibitor in 76%. Efficacy was observed at all dose levels tested (25–300 mg pirtobrutinib daily); 200 mg daily was selected as the recommended phase II dose.

The majority of adverse events (AEs) were grade 1–2 (87% of events). The most
common grade ≥3 AE was neutropenia (in 10% of patients). None of the 18 patients who discontinued a previous BTK inhibitor owing
to cardiovascular toxicity or haemorrhage had
In December 2019, the FDA granted accel- erated approval to the nectin-4-targeted antibody–drug conjugate (ADC) enfortumab vedotin for patients with previously treated advanced-stage urothelial carcinoma based on data from a single-arm study. Now,
a phase III trial has revealed that enfortumab vedotin is associated with improved overall survival (OS) in these patients.

In this trial, 608 patients who previously received an anti-PD-1/PD-L1 antibody and a platinum-containing regimen were randomly assigned (1:1) to receive enfortumab vedotin or physician’s choice of chemotherapy.
Median OS and progression-free survival were longer with the ADC: 12.9 versus 9.0 months (HR 0.70, 95% CI 0.56–0.89;
P = 0.001) and 5.6 versus 3.7 months
(HR 0.62, 95% CI 0.51–0.75; P < 0.001),
respectively. Overall response rate (ORR) and complete response rate were also higher with the ADC: 40.6% and 4.9%, respectively, versus 17.9% and 2.7% (P < 0.001). Of note, the ORR and complete response rate that led to the accelerated approval of enfortumab vedotin were 44% and 12%, respectively.

MELAN OMA
The incidence of grade ≥3 treatment- related adverse events (TRAEs) was similar with the ADC and chemotherapy: 51.4% versus 49.8%. TRAEs of special interest associated with enfortumab vedotin include rash (of any grade in 43.9% of patients and
of grade ≥3 in 14.5%) and peripheral neurop- athy (46.3%, grade ≥3 in 3.7%); 9.6% and 30.6% of patients receiving chemotherapy had any grade rash or peripheral neuropathy, respectively. Seven patients receiving the ADC and three receiving chemotherapy
died from TRAEs.
These results and those from studies of other ADCs, such as sacituzumab govitecan, indicate that this class of agents could become key in the treatment of urothelial carcinoma. Indeed, the combination of enfortumab vedotin plus pembrolizumab received
FDA Breakthrough Therapy designation for the first-line treatment of patients with advanced-stage disease in February 2020.
Diana Romero

ORIGINAL ARTICLE Powles, T. et al. Enfortumab vedotin
in previously treated advanced urothelial carcinoma. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2035807 (2021)
a recurrence of such toxicities.

The overall response rates (ORRs) among
BRAF-mutant ctDNA predicts outcomesthe efficacy-evaluable patients with CLL or SLL, MCL, WM, or other B cell lymphomas were 63%, 52%, 68% and 33%, respectively. Most of these were partial responses, except for 14 complete responses in the
MCL group and 4 minor responses in the WM group. Among patients with CLL or SLL,
MCL or WM who had previously received a covalent BTK inhibitor, the ORRs were 67% (75% for those harbouring C481 mutations and 60% for those without), 52% and 69%, respectively. After a median follow-up duration of 6 months, 88% and 57% of patients with CLL or SLL, or MCL remained on treatment.
These data indicate that treatment with pirtobrutinib might provide clinical benefit in patients with B cell malignancies resistant to covalent BTK inhibitors. Longer follow-up results are awaited, as well as those from
planned phase III studies in CLL, SLL and MCL.
ORIGINAL ARTICLE Mato, A. R. et al. Pirtobrutinib in relapsed
or refractory B-cell malignancies (BRUIN): a phase 1/2 study.
Lancet 397, 892–901 (2021)
Diana Romero

Circulating tumour DNA (ctDNA) is an appeal- ing source of biomarkers that has the potential to improve patient management in a range
of disease settings; however, data from large cohorts of patients are currently limited.
Now, an analysis of samples from two clinical trials provides further evidence that BRAF mutations present in ctDNA can be used to predict clinical outcome.

Patients with unresectable or metastatic BRAF-mutant (V600E or V600K) melanoma received the BRAF inhibitor trametinib with or without the MEK inhibitor dabrafenib as part of the COMBI-d or COMBI-MB trials.
In a preplanned biomarker analysis, samples obtained during these trials were analysed for BRAFV600E/K mutations.
Pretreatment and 4-week on-treatment plasma samples were available from 345 (82%) and 224 (53%) patients, respectively, enrolled in COMBI-d. BRAFV600 mutations were detect- able in baseline samples from 93% of patients. Analysis revealed a strong negative correlation between baseline BRAFV600-mutant ctDNA copy number and overall survival (OS): patients with
≥64 BRAFV600-mutant ctDNA copies/ml had
a median OS duration of 13.4 months versus
35.1 months for those with <64 copies/ml
(HR 2.23, 95% CI 1.73–2.87; P < 0.0001).

Similarly, among patients with paired samples available, 201 (90% of paired samples) had detectable BRAFV600-mutant ctDNA at baseline, which decreased to 121 patients (60%),
at week 4. Undetectable BRAFV600-mutant ctDNA at this timepoint was associated with an improved OS (median 28.2 months ver- sus 14.6 months; HR 0.56, 95% CI 0.40–0.79;
P = 0.0009). Both findings were independently predictive after adjusting for other variables.

These observations were confirmed in an analy- sis of samples from 38 patients with metastatic melanoma with CNS metastases enrolled in arm A of COMBI-MB. These data provide robust evi-
dence for a predictive role of BRAFV600 mutations in ctDNA in patients with advanced-stage melanoma. Prospective validation is eagerly LOXO-305 awaited.
Peter Sidaway
ORIGINAL ARTICLE Syeda, M. M. et al. Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study. Lancet Oncol https://doi.org/10.1016/S1470-2045(20) 30726-9 (2021)

258 | MAY 2021 | VOLUME 18 www.nature.com/nrclinonc