In the Literature

Selpercatinib Shows Durable Responses in Patients with Thyroid Cancer and RET Mutation

The safety and durability of responses to multitargeted inhibitors in thyroid cancer are at least partially limited by side effects. In all, 70% of patients with medullary thyroid cancer carry the RET mutation; RET fusions are rare in other types of thyroid cancer. The efficacy and safety of selective RET inhibition in patients with RET-altered thyroid cancer is unknown.

In a new phase 1/2 clinical trial, LIBRETTO-001, researchers evaluated the safety and efficacy of selpercatinib (Retevmo) in patients with medullary thyroid cancer and RET mutation or thyroid cancer and RET fusions (Wirth LJ, et al. N Engl J Med. 2020;383:825-835).

Selpercatinib is an ATP-competitive, highly selective, small-molecule RET-related kinase inhibitor, and is the first therapy approved by the FDA for the treatment of 3 types of cancer associated with RET alterations, including advanced or metastatic medullary thyroid cancer and advanced thyroid cancer with RET fusion (in addition to lung cancer with RET mutation).

LIBRETTO-001 was an open-label study with a total of 162 adolescent and adult patients with any solid tumor type harboring an activating RET alteration. The cohort of patients with thyroid cancer included those with medullary thyroid cancer and RET mutation who had previously received vandetanib (Caprelsa), cabozantinib (Cabometyx), or both; patients who did not receive either of these therapies, and those with thyroid cancer and RET fusion who had previously received treatment.

Selpercatinib was administered orally in 28-day cycles until disease progression, death, unacceptable adverse effects, or patient withdrawal from the study. Patients who were enrolled in the phase 1 dose-escalation portion of the study received selpercatinib ranging from 20 mg once daily to 240 mg twice daily. All patients enrolled in the phase 2 portion of the study received the recommended dose of 160 mg twice daily.

The primary end point of the trial was the objective response rate (ORR), including complete or partial response. Secondary end points included the duration of response, progression-free survival (PFS), and safety.

Among the 55 patients with medullary thyroid cancer and RET mutation who had previously received vandetanib, cabozantinib, or both, the ORR was 69%, including 9% complete responses and 60% partial responses. The 1-year PFS was 82% in that subset of patients.

In the 88 patients with medullary thyroid cancer and RET mutation who had not received previous therapy with vandetanib or cabozantinib, the ORR was 73%, including 11% complete responses and 61% partial responses. In this subset, the 1-year PFS was 92%.

Finally, among the smaller cohort of 19 patients with RET fusion–positive thyroid cancer who had previously received treatment, the ORR was 79%, including 5% complete responses and 14% partial responses. The 1-year PFS was 64% in this group.

Selpercatinib was generally well-tolerated, and the majority of the adverse events were low-grade. The most common grade 3 adverse events were hypertension (21%), increased alanine aminotransferase (11%), increased aspartate aminotransferase (9%), hyponatremia (8%), and diarrhea (6%).

The researchers concluded that the activity of selpercatinib was observed across all RET alterations and histologic types of thyroid cancer. They underscored that “the implementation of effective molecular screening strategies for patients with either germline or somatic RET mutation in nonfamilial medullary thyroid cancer will be essential in identifying patients who may benefit from RET inhibition.”

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Venclexta plus Azacitidine Improves Overall Survival in Patients with AML

The prognosis of older patients with acute myeloid leukemia (AML) has been poor, even after treatment with a hypomethylating agent. A previous phase 1b study of azacitidine (Vidaza) added to venetoclax (Venclexta) showed promising efficacy and duration of response in treatment-naïve patients with AML who were ineligible for chemotherapy.

In a new study, researchers report findings from a confirmatory clinical trial that evaluated the efficacy and safety of this combination regimen in treatment-naïve patients with AML who were ineligible for intensive induction therapy (DiNardo CD, et al. N Engl J Med. 2020;383:617-629).

The VIALE-A study was a multicenter, randomized, double-blind, phase 3 clinical trial of 433 patients with confirmed AML who were ineligible for intensive therapy because of comorbidities, aged ≥75 years, or both. The exclusion criteria included patients who had received previous treatment with a hypomethylating agent for an antecedent hematologic disorder.

Patients were randomized in a 2:1 ratio to azacitidine plus venetoclax (N = 286) or to azacitidine plus placebo (N = 145). All patients received a standard dose of azacitidine (75 mg2/kg subcutaneously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily in 28-day cycles. The primary end point was overall survival (OS). Secondary end points included composite complete remission.

With a median follow-up of 20.5 months, the median OS was 14.7 months in the azacitidine plus venetoclax arm versus 9.6 months in the azacitidine plus placebo arm (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P <.001).

Overall, 66.4% of the patients in the active combination arm achieved composite complete remission (complete remission or complete remission with incomplete hematologic recovery) compared with only 28.3% of the patients in the placebo arm. The treatment responses were also rapid and durable, with 43% of patients in the azacitidine plus venetoclax arm showing a response during the first cycle of treatment, and a median duration of remission of 17.5 months.

The combination of azacitidine plus venetoclax has a safety profile similar to that of each drug alone. The most common adverse events in both groups included hematologic and gastrointestinal events, and rates of adverse events were generally consistent between both treatment arms. However, higher rates of grade 3 neutropenia (42% vs 28%) and febrile neutropenia (42% vs 19%) were observed in the active combination arm compared with the azacitidine plus placebo arm.

“The combination of azacitidine plus venetoclax in this challenging patient population in this trial was an effective treatment regimen that led to significant improvements in the incidence of composite complete remission and overall survival,” the authors noted, emphasizing the importance of monitoring and managing myelosuppression in patients who are receiving this combination therapy.

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Advances in New Therapies Attributed to Reductions in Lung Cancer Mortality

The overall mortality for lung cancer has declined in the United States, but little is known about the mortality trends by lung cancer subtype, because death certificates do not record this information. To address this limitation in the data collection, the Surveillance, Epidemiology, and End Results (SEER) program has linked mortality records to incident cancer cases in all cancer types. Using SEER data, researchers from the National Cancer Institute assessed lung cancer mortality and linked deaths from lung cancer to incident cases in SEER cancer registries (Howlader N, et al. N Engl J Med. 2020;383:640-649). The analysis included SEER data from 2001 (the first year NSCLC was reliably identified) through 2016.

For this study, the researchers looked at data for 2 major histologic subtypes of lung cancer—non–small-cell lung cancer (NSCLC), which accounts for 76% of lung cancer in the United States, and small-cell lung cancer (SCLC), which accounts for 13%.

The results showed that in recent years, deaths from NSCLC decreased faster than the increase in incidence of NSCLC, and the decreases in death were associated with significant improvement in survival over a period of time that matched the approval of new targeted therapies for lung cancer.

Among men, deaths from NSCLC decreased by 3.2% annually between 2006 and 2013 and 6.3% annually between 2013 and 2016. By contrast, the incidence of NSCLC decreased gradually, by 1.9% annually, between 2001 and 2008, and by 3.1% annually between 2008 and 2016.

For women, incidence-based mortality decreased slowly, by 2.3% annually, between 2006 and 2014, and then at a faster rate of 5.9% annually between 2014 and 2016. By contrast, the incidence of NSCLC in women was flat between 2001 and 2006, before declining by 1.5% annually between 2006 and 2016.

The 2-year survival for men with NSCLC improved significantly over time, from 26% for patients diagnosed in 2001 to 35% for those diagnosed in 2014. By contrast, the 2-year survival for women diagnosed with NSCLC was higher for the same period (35% and 44%, respectively).

“The faster decreases in lung-cancer incidence among men than among women can be attributed to the relative differences in smoking prevalence according to sex,” the authors noted.

However, the analyses for SCLC showed that the decline seen in mortality resulted almost entirely from the decline in the incidence rate of SCLC, according to the researchers, which corresponds to the lack of new therapies for this patient population, as can be seen by the very limited treatment advances for SCLC over the same period. For example, among men with SCLC, the 2-year survival did not change over the study period from 2001 to 2016 (12% and 11%, respectively).

“We anticipate that incidence-based mortality methods will be valuable for evaluating trends in subtype-specific mortality in the future, as additional new lung-cancer treatments, as well as screening, are disseminated in the population,” concluded the researchers.

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