Ariana Pelosci 

In patients with resectable colorectal cancer, findings from circulating tumor (ct)DNA assays may help identify which patients with colorectal cancer will benefit most from the use of adjuvant chemotherapy, according to findings from the observational GALAXY study presented during the 2022 Gastrointestinal Cancers Symposium.

Patients with high-risk stage II disease and ctDNA-positive status at 4 weeks experienced a 6-month DFS rate of 100% (95% CI, 100%-100%) with adjuvant chemotherapy vs 53.8% (95% CI, 24.8%-76.0%) without. In stage III disease, those rates were 89.2% (95% CI, 78.7%-94.7%) and 32.0% (95% CI, 15.2-50.2), respectively. For stage IV disease, adjuvant chemotherapy use in patients with positive ctDNA status resulted in 6-month DFS rates of 72.7% (95% CI, 49.1%-86.7%) vs 28.3% (95% CI, 16.2-41.6) for those without.

“Our study shows that stratifying post-surgical treatment decisions using the assay can identify patients likely to benefit from ACT [adjuvant chemotherapy] across all stages,” Masahito Kotaka, MD, PhD, from Gastrointestinal Cancer Center, Sano Hospital, said during the presentation.

This study that is a part of the CIRCULATE-Japan platform protocol in patients with resectable CRC was undertaken to determine if ctDNA-based molecular residual disease (MRD) status could be a viable risk-assessment strategy for adjuvant therapy selection post-surgery. Personalized tumor-informed ctDNA assays were collected at 4, 12, 24, 36, 48, 72, and 96 weeks after surgery.

A total of 1564 patients were enrolled to GALAXY between June 5, 2020, and April 30, 2021, of whom 1040 were included in the current analysis (Outcome cohort). After excluding ineligible patients, investigators further divided the cohorts into patients who were ctDNA positive (n = 183), known as the Clearance cohort, and ctDNA negative (n = 531) 4-weeks post-surgery.

The Outcome cohort was majority male in both the positive and negative groups (51% vs 62%; 

 <.01), with stage III cancer occurring most frequently (36% vs 48%). Patients with negative vs positive ctDNA were more likely to harbor 

 <.01) or have microsatellite instability (MSI)–high tumors (12% vs 3%; 

 <.001). The Clearance analysis cohort was majority male (54% vs 72%; 

 <.001) cancer in patients who received adjuvant chemotherapy versus those who did not, respectively. Only 1 patient had stage I and 2 patients had low-risk stage II disease along with ctDNA-positive status.

With a median follow-up of 11.4 months in the overall population of patients with stage I to IV disease, 6- and 12-month disease-free survival (DFS) rates were 96.5% (95% CI, 95.0%-97.5%) and 92.7% (95% CI, 90.4%-94.5%) for those with ctDNA-negative status 4-weeks post-operative. Those with ctDNA positivity had significantly worse outcomes, with corresponding DFS rates of 62.8% (95% CI, 55.4%-69.2%) and 47.5% (95% CI, 39.3%-55.2%; HR, 10.9; 95% CI, 7.8-15.4; 

 <.001; sensitivity for recurrence, 63.6%). Limiting the analysis to patients with stage II to IV disease indicated that 6- and 12-month rates of DFS favored the negative vs positive cohorts at 97.8% (95% CI, 96.3%-98.7%) vs 73.0% (95% CI, 63.9%-80.2%) and 95.2% (95% CI, 92.6%-96.9%) vs 55.5% (95% CI, 44.8%-65.0%), respectively (HR, 13.3; 95% CI, 8.0-22.2; 

 <.001; sensitivity for recurrence 67.6%).

The multivariate analysis found that the highest risk of recurrence for patients with stage II to III cancer was correlated with 4-weeks post-surgery ctDNA positive vs negative status (HR, 15.3; 95% CI, 8.6-27.2; 

Investigators then performed an analysis which excluded patients who recurred within 12 weeks of surgery, called the Dyanmics analysis cohort (n = 838), to evaluate the predictive effect of ctDNA on this population. The 6-month DFS rate for those with ctDNA-negative status at the 4-week time point and negative status at the 12-week point was 100% vs 98.0% with negative/negative ctDNA (HR, 0.8; 95% CI, 0.27-2.15; 

 = .60), 62.5% for negative to positive ctDNA (HR, 9.2; 95% CI, 3.0%-28.4%; 

 <.001), and 58.3% for positive/positive (HR, 15.8; 95% CI, 5.7%-44.2%; 

Cumulative clearance of ctDNA at 6 months after surgery was higher amongst those who received adjuvant chemotherapy vs no chemotherapy, at rates of 68% vs 10%, respectively (HR, 9.3; 95% CI, 4.6-18.9; 

 <.001). A multivariate analysis of patients with stage II to IV disease showed the risk of recurrence was significantly between those with and without adjuvant chemotherapy (HR, 5.6; 95% CI, 3.2-9.7; 

 mutant vs wild-type status (HR, 2.0; 95% CI, 1.3-3.1; 

The 12-month DFS rate for those who received adjuvant chemotherapy and had high-risk stage II cancer was 88.9% (95% CI, 43.3%-98.4%) vs 46.2% without (95% CI, 19.2-69.6%; HR, 9.4; 95% CI, 1.1-79.1; 

 = .04). In stage III disease, the 12-month DFS rates were 68.3% (95% CI, 53.4%-79.2%) vs 24.0% (95% CI, 9.8%-41.7%), respectively (HR, 8.8; 95% CI, 3.9-19.5; P <.001). For stage IV, corresponding rates were 53.7% (95% CI, 28.4%-73.6%) vs 22.3% (95% CI, 11.2%-35.7%; HR, 2.4; 95% CI, 1.1-5.2; 

In the ctDNA-negative cohort treated with adjuvant vs no chemotherapy, patients were 50% male, had performance status of 0 (92% vs 81%, respectively; 

 = .001), and had stage III cancer (83% vs 41%; 

<.001). Those treated with adjuvant chemotherapy had 6- and 12-month DFS rates of 98.6% (95% CI, 95.7%-99.5%) and 96.2% (95% CI, 92.1%-98.2%) compared with 97.5% (95% CI, 95.0%-98.7%) and 94.7% (95% CI, 90.5%-97.1%) for those with chemotherapy (HR, 1.3; 95% CI, 0.5-3.6; 

“ctDNA-guided adjuvant strategy will further be established by ongoing randomized VEGA and ALTAIR studies and will be presented in the future conferences,” Kotaka concluded.

Kataka M, Shirasu H, Wantanbe J, et al. Association of circulating tumor DNA dynamics with clinical outcomes in the adjuvant setting for patients with colorectal cancer from an observational GALAXY study in CIRCULATE-Japan. 

. 2022;40(suppl 4):9. 10.1200/JCO.2022.40.4_suppl.009

Articles

The observational GALAXY study has shown that using a ctDNA assay may help identify which patients with colorectal cancer have the potential to derive benefit from adjuvant chemotherapy. 

ctDNA Assays May Indicate the Best Resectable CRC Recipients for Adjuvant Chemotherapy

Adjuvant oral fluoropyrimidine derivative S-1 is now a recommended standard of care for patients with biliary tract cancer after the agent prolonged overall survival compared with surgery in a phase 3 study (UMIN000011688).

Results presented at the 2022 Gastrointestinal Cancers Symposium showed that the 3-year overall survival (OS) rate was 77.1% (95% CI, 70.9%-82.1%) with S-1 and 67.6% (95% CI, 61.0%-73.3%) with surgery alone (HR, 0.694; 95% CI, 0.514-0.935; one-sided 

 = .008). Patients also had better 3-year relapse-free survival with S1 at 62.4% (95% CI, 55.6%-68.4%) and 50.9% (95% CI, 44.1%-57.2%), respectively (HR, 0.797; 95% CI, 0.613-1.035).

“Adjuvant S-1 therapy led to significantly longer survival than surgery alone on patients with resected BTC,” Masafumi Ikeda, MD, PhD, of National Cancer Center Hospital East, said during the presentation.

A total of 440 patients were enrolled onto the study, with 222 in surgery-alone arm and 218 in the S-1 arm. Those receiving S-1 were given 40 mg/m2 twice per day for 4 weeks on and 2 weeks off for a total of 4 cycles. Patients were eligible for this study if they had curatively resected biliary tract cancer, were between the ages of 20 and 80, and had a performance score of 0 or 1.

Patients receiving S-1 had a median age of 68 years compared with 70 years for surgery alone, and most patients in either group were male (74% vs 68%) and had an ECOG performance score of 0 (88% vs 87%). The primary tumor site was most likely extrahepatic (57% vs 55%), followed by ampulla of vater (17% vs 16%), gallbladder (14% vs 15%), and intrahepatic (12% vs 14%) in the S-1 and surgery-alone arms, respectively.

Most patients in the S-1 and surgery groups had a resection status of R0 (86% vs 85%, respectively) and stage II disease (58% vs 59%), followed by stage III (17% vs 17%), stage I (16% vs 16%), and stage IV (9% vs 8%). Most patients had no lymph node involvement (N0; 61% vs 59%).

OS by subgroup analysis mostly favored S-1 compared with surgery alone, including those with ECOG performance scores of 0 (0.70; 95% CI, 0.51-0.97;

 = .0632) and 1 (0.85; 95% CI, 0.39-1.85) as well as those with extrahepatic (0.80; 95% CI, 0.54-1.17; 

 = .5344), ampulla of vater (0.49; 95% CI, 0.22-1.12; 

 = .3041), gallbladder (0.64; 95% CI, 0.30-1.35), and intrahepatic (0.75; 95% CI, 0.30-1.89; 

The most common grade 3 adverse effects (AEs) in the S-1 arm was neutrophil decrease (14%) which occurred in only 1% of the surgery-alone arm. Other common grade 3 AEs were anemia (4% vs 1%), white blood cell decrease (3% vs less than 1%), aspartate aminotransferase increase (3% vs <1%), and diarrhea (3% vs 0%).

Ikeda M, Nakachi K, Konishi M, et al. Adjuvant S-1 versus observation in curatively resected biliary tract cancer: A phase III trial (JCOG1202: ASCOT). 

. 2022;40(suppl 4):382. doi:10.1200/JCO.2022.40.4_suppl.382

In a phase 3 study, patients with biliary tract cancer who received adjuvant oral fluoropyrimidine derivative S-1 lived longer than patients who underwent surgery. 

Oral Fluoropyrimidine Prolongs Survival as Adjuvant Treatment for Biliary Tract Cancer

In older patients with previously untreated chronic lymphocytic leukemia, continued progression-free survival (PFS) improvement was demonstrated with ibrutinib (Imbruvica)–containing regimens compared with bendamustine plus rituximab (Rituxan; BR), according to updated results from the phase 3 AO41202 trial (NCT01886872) that were presented at the 63rd American Society of Hematology Annual Meeting.

At the median follow-up of 55 months, the ibrutinib-containing regimens showed superior PFS compared with the BR group. At 48 months, 47% of patients in the BR arm were progression free (95% CI, 0.39-0.55) vs 76% in both the ibrutinib-alone arm and the ibrutinib plus rituximab arm (95% CI, 0.69-0.82).

“While all patients do appear to benefit from ibrutinib-based regimens compared with BR, high-risk patients appear to derive the greatest benefit at this time period,” Jennifer A. Woyach, MD, lead author on the study, said during the presentation.

A total of 547 patients were randomized 1:1:1, with 183 in the BR group, 182 in the ibrutinib-alone group, and 182 in the ibrutinib plus rituximab group. In the 2 latter groups, 94 and 91 patients are still on treatment, respectively. There were 37 patients in the BR group who crossed over to the ibrutinib groups.

Patients were given 90 mg/m2 of bendamustine on days 1 and 2 of each cycle, and 375 mg/m2 of rituximab on day 0 of cycle 1 then 500 mg/m2 on day 1 of cycles 2 to 6. In the ibrutinib groups, patients were given 420 mg of ibrutinib daily until disease progression and 375 mg/m2 of rituximab each week for 4 weeks beginning at cycle 2 day 1, then day 1 for cycles 3 to 6.

Overall patient characteristics included a median age of 71 years, with 67% being male. A total of 10% had a 

 mutation; 53% were Zap-70 unmethylated, defined as less than 20% methylation; and 61% were 

unmutated. ECOG scores between 0 to 1 were found in 97% of patients and 6% had deletion 17p.

When comparing the regimens in terms of PFS, both ibrutinib alone (HR, 0.36; 95% CI, 0.26-0.52; 

 <.0001) and ibrutinib plus rituximab were superior to BR (HR, 0.36; 95% CI, 0.25-0.51; 

 <.0001). Between regimens, ibrutinib plus rituximab and ibrutinib alone were similar (HR, 0.99; 95% CI, 0.66-1.48; 

All subgroup analyses favored ibrutinib-containing regimens vs BR. Patients with 

-mutated disease were the only group for which the confidence interval crossed 1.00, with Woyach pointing out that this marker was only able to be analyzed in 66% of the cohort.

In the multivariate analysis for PFS, investigators combined the 2 ibrutinib arms as previous analyses did not show a significant difference between them. Besides comparing treatment groups of ibrutinib with or without rituximab (I/IR) vs BR (HR, 0.32; 95% CI, 0.23-0.45; 

 <.0001), factors of increasing age at 5-year intervals (HR, 1.26; 95% CI, 1.08-1.47; 

 = .004), b2 macroglobulin of 5 or more (HR, 1.84; 95% CI, 1.33-2.55; 

 abnormality (HR, 1.65; 95% CI, 1.01-2.69; 

 = .04), and karyotype abnormalities with a 1 unit increase (HR, 1.07; 95% CI, 1.02-1.14; 

 = .01) were associated with less favorable outcomes overall. Conversely, Zap-70 methylation of 20% or more was associated with more favorable outcomes (HR, 0.69; 95% CI, 0.50-0.94; 

When investigators tested for interactions between treatment groups (I/IR vs BR) and prognostic factors, they found no significant difference in treatment affect were noted based on karyotype abnormalities or b2 macroglobulin. However, age played a role in treatment efficacy with the highest interaction being in those who were 80 years old (HR, 0.55; 95% CI, 0.31-0.98). Additionally, no 

 abnormality (HR, 0.39; 95% Ci, 0.27-0.55) to those that did (HR, 0.07; 95% CI, 0.03-0.18) and those with a Zap-70 methylation greater than 20% (HR, 0.61; 95% CI, 0.37-1.01) saw an interaction. 

“Although the protective effect of ibrutinib is apparent across subgroups of patients, we found some evidence that ibrutinib-based regimens were even more protective for younger patients and for those with the most high-risk genomic abnormalities, including 

 abnormalities as well as Zap-70 methylation less than 20%,” Woyach said.

Additionally, the overall survival rate at 48 months in the BR group was 84% (95% CI, 0.77-0.89), vs 85% in the ibrutinib-alone group (95% CI, 0.79-0.90) and 86% (95% CI, 0.79-0.90) in the ibrutinib plus rituximab group.

Adverse effects of atrial fibrillation or flutter were seen in both groups, but was more common for those in the ibrutinib groups. At 36 months, atrial fibrillation or flutter was seen in 3.8% of patients treated with BR and 15.7% treated with ibrutinib. Hypertension was also seen more in the ibrutinib regimen groups than the BR, occurring in 52.6% and 26.7%, respectively.. 

“Atrial fibrillation and hypertension increase with time on therapy, but these toxicities don’t appear to outweigh the superior efficacy of the drug,” Woyach concluded.

Woyach J, Ruppert A, Heerema N, et al. Long-term results of Alliance A041202 show continued advantage of ibrutinib-based regimens compared with bendamustine plus rituximab (BR) chemoimmunotherapy. Presented at the 63rd American Society of Hematology Annual Meeting. December 11-14, 2021. Atlanta, Georgia. Abstract 639. https://bit.ly/3EWod2w

Compared to those who received rituximab and bendamustine, elderly patients treated with ibrutinib-containing regimens for chronic lymphocytic leukemia saw a progression-free survival benefit.

In Older Patients With Chronic Lymphocytic Leukemia Ibrutinib Regimens Yield Superior Efficacy

According to a study presented during the ASH Annual Meeting 2021, time and costs associated with managing adverse effects (AEs) for patients with chronic lymphocytic leukemia (CLL) treated with acalabrutinib (Calquence), ibrutinib (Imbruvica), or venetoclax (Venclexta) could aim in better decision making regarding which therapy to select.

During the 2-month study period, time spent managing AEs totaled to 13,008 minutes for all 3 treatments (229 for acalabrutinib, 500 for ibrutinib, and 377 for venetoclax). The overall personnel cost per AE management amounted to $22.8 (standard deviation, $16.5), after applying labor costs to mean time spent on each. The lowest costs were noted in the acalabrutinib group ($19.9; SD, $15.8), potentially due to a smaller proportion of oncologists performing management for AEs associated with this therapy.

“Findings from this study underscore the importance of taking into account the time and personal costs related to AE management when deciding among novel agents,” Hetalkumari Patel, PharmD, BCOP, lead author of the study, said during the presentation.

A total of 49 health care practitioners were evaluated for this study, of whom 36 reported managing 1 or more AEs over the study period with 13 (36.1%) being oncologists, 13 (36.1%) registered nurses, 5 (13.9%) pharmacists, 3 (8.3%) nurse practitioners, and 2 (5.6%) physician assistants. Out of 421 patients, 108 (26%) had received acalabrutinib, 186 (44%) were treated with ibrutinib, and 129 (31%) had venetoclax in any line of therapy. Within the last month, treatment with each corresponding agent occurred in a mean of 8.9 (SD, 9.6), 11.5 (SD, 10.1), and 7.9 patients (SD, 6.9), respectively. Practices were most frequently in urbanized areas (n = 18), followed by urban clusters (n = 17) and rural areas (n = 15).

A mean of 55.5 (SD, 41.7) healthcare clinicians (median, 31.0) were found across the different practices analyzed. Additionally, a mean of 12.4 days (SD, 13.8) were spent managing AEs (median, 6.0).

Patient characteristics overall included a median of 1.6 days (SD, 1.0) of AE management and 2.6 AE activities (SD, 2.4). Patients had a median age of 67.3 years and a majority (58.9%) were male. A total of 30 patients (7.1%) experienced grade 3 or higher AEs.

Overall, oncologists managed AEs most frequently compared with registered nurses, pharmacists, and nurse practitioners/physician assistants (NPs/PAs). In the acalabrutinib group, 46.7% of AEs were managed by oncologists, 41.9% were managed by registered nurses, 8.3% were managed by pharmacists, and 3.1% were managed by NPs/PAs. In the ibrutinib group, 67.8% of AEs were managed by oncologists, 16.4% by registered nurses, 12.2% by pharmacists, and 3.6% by NPs/PAs. In the venetoclax group, corresponding rates were 70.3%, 21.0%, 7.7%, and 1.1%.

“The smaller proportion of oncologists managing AEs for patients treated with acalabrutinib compared to ibrutinib or venetoclax suggests differences in the type and complexity of AEs experienced by patients on acalabrutinib,” wrote the study authors. “This is further evidenced by the fact that the most common AE among patients with acalabrutinib was headache vs thrombocytopenia and anemia for ibrutinib and venetoclax, respectively.”

The mean time spent per AE in minutes in the acalabrutinib group was 12.2 minutes for oncologists, 12.0 for registered nurses, 12.3 minutes for pharmacists, and 10.7 minutes for NPs/PAs. In the ibrutinib group, corresponding time spent amounted to 10.4 minutes, 8.4 minutes, 17.9 minutes, and 25.8 minutes. In the venetoclax group, those times were 11.0 minutes, 12.2 minutes, 18.2 minutes, and 12.5 minutes, respectively.

In the acalabrutinib group, mean costs for AE management by an oncologist was $33.10 vs $7.30 for registered nurses, $12.70 for pharmacists, and $9.60 for NPs/PAs. In the ibrutinib group, costs were $28.40 for oncologists, $5.10 for registered nurses, $18.40 for pharmacists, and $23.60 for NPs/PAs. In the venetoclax group, corresponding costs were $29.90, $7.40, $18.79, and $11.20.

“Additional research is needed to confirm the differences observed in this study regarding the types of AEs and health care practitioners managing AEs, stratified by treatment, for patients with CLL,” concluded Patel.

Patel H, Wahlstrom S, DerSarkissian M, et al. Time and personnel costs associated with adverse event (AE) management among patients with chronic lymphocytic leukemia (CLL) treated with acalabrutinib, ibrutinib, or venetoclax. Presented at the 63rd 2021 American Society of Hematology Annual Meeting. December 11-14, 2021. Atlanta, Georgia. Abstract 2999. https://bit.ly/3s0xu60

The costs of treatment and time spent managing adverse effects varied significantly in patients with chronic lymphocytic leukemia treated with acalabrutinib, ibrutinib, and venetoclax. 

Oncologists Could Make Better CLL Treatment Decision Based on Cost and Time Spent of Managing Adverse Events

For transplant ineligible multiple myeloma, daratumumab (DARA; Darzalex), lenalidomide (Revlimid), and dexamethasone (D-Rd) given to patients as first-line (1L) treatment resulted in an overall survival (OS) benefit vs waiting for second-line (2L) treatment, according to a presentation from the 2021 American Society of Hematology Conference.

Data from this study showed that patients had a 2.5-year OS benefit when given D-Rd followed by regimens that contained pomalidomide (Pomalyst) and carfilzomib (Kyprolis) compared with those receiving bortezomib (Velcade), lenalidomide, and dexamethasone (VRd) first and then a DARA-containing regimen.

“Given the totality of these data, D-Rd should be the standard of treatment for patients with transplant-ineligible newly diagnosed multiple myeloma,” Rafael Fonesca, MD, director for Innovation and Transformational Relationships at the Mayo Clinic in Phoenix, Arizona, stated during the presentation.

Investigators looked at data from 3 previously reported trials to formulate a clinical question regarding optimal treatment sequences. The phase 3 SWOG S0777 trial (NCT00644228)2 helped establish VRd as standard of care for newly diagnosed multiple myeloma without intent for immediate transplants, with statistically significant OS benefit noted vs Rd (

 = .0114). Patients in this group younger than 65 had a better OS benefit. In the phase 3 MAIA trial (NCT02252172),3 previously untreated patients who were given D-Rd had a statistically significant PFS (HR, 0.53; 95% CI, 0.43-0.66; 

 <.0001) and OS benefit (HR, 0.68; 95% CI, 0.53-0.86; 

Fonseca then turned to the POLLUX trial (NCT02076009), which looked at D-Rd vs Rd in this patient population with relapsed disease. The data indicated that D-Rd resulted in a 66% reduction in the risk of disease progression or death vs Rd in the overall population (HR, 0.44; 95% CI, 0.35-0.54; 

 <.0001).4 He noted that the patient population was much younger than those from MAIA and about 60% had been given transplant prior to enrollment.

Additionally, a study that was published in 2020 involving a real-world data set of almost 22,000 patients showed an attrition loss of almost 50% with each line of therapy.

“We wanted to integrate data regarding attrition rates,” Fonseca said. “There is significant attrition between lines of therapy [with] up to 50% loss of patients per line of therapy. [Therefore, we wanted to know if] it makes sense to save treatments for later.”

Three clinical scenarios were explored. In one, patients were treated with 1L D-Rd and then at relapse, received a pomalidomide- or carfilzomib-containing regimen. The other 2 scenarios included those who were treated with VRd or Rd in the 1L who then received DARA regimens at relapse. A conservative attrition rate of 27.2% derived from the MAIA trial that excluded censored patients was utilized for this study.

The OS in the 27.2% attrition rate group showed that D-Rd in the 1L had estimated 5-, 10-, and 15-year OS rates of 69.9%, 46.7%, and 30.1%, respectively. Corresponding rates in the 1L VRd and Rd arms at the 5- (60.7% and 54.9%, respectively), 10- (35.4% and 28.6%), and 15-year (21.2% and 15.8%) timepoints were lower than those seen with 1L D-Rd. Results were similar assuming a higher attrition rate of 58.8%.

The median OS for D-Rd in the 1L was 9.1 years compared with VRd in the 1L at 6.7 years and 5.7 years for Rd in 1L, with results consistent regardless of attrition rates.

Fonesca also detailed some strengths such as attrition rates accounting for patients who do not receive therapy beyond the 1L and use of real-world data in the 2L. The limitations included that no variation in attrition rates were considered for individual treatments and mixed data sources from clinical trials and real-world data were used in the analysis.

1.Fonesca R, Facon T, Hashim M, et al. First-Line Use of Daratumumab, Lenalidomide, and Dexamethasone Confers Survival Benefit Compared with Second-Line Use of Daratumumab-Based Regimens in Transplant-Ineligible Patients with Multiple Myeloma: Analysis of Different Clinical Scenarios. Presented at the 2021 American Society of Hematology Annual Congress. December 11-14, 2021. Virtual. Abstract 118. https://bit.ly/3pLLttF

2.Durie BGM, Hoering A, Sexton R, et al. Longer term follow-up of the randomized phase III trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (Pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT). 

. 2020;10(5):53. doi:10.1038/s41408-020-0311-8

3.Facon T, Kumar SK, Plesner T, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. 

. 2021;22(11):1582-1596. doi:10.1016/S1470-2045(21)00466-6

4.Bahlis NJ, Dimopoulos MA, White DJ, et al. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. 

. 2020;34(7):1875-1884. doi:10.1038/s41375-020-0711-6

Compared to those who waited and received second line daratumumab-based regimens for transplant-ineligible newly diagnosed multiple myeloma, patients receiving daratumumab, lenalidomide, and dexamethasone in the first line saw better overall survival.

Survival Benefit in Transplant-Ineligible Multiple Myeloma Seen With Frontline Vs Second Line Use of Daratumumab Combos

Regardless of estrogen or progesterone receptor (PR) status, adjuvant metformin (Fortamet) did not improve invasive disease-free survival (IDFS) or overall survival (OS) in patients with early breast cancer, according to results from the phase 3 CCTG MA.32 trial (NCT01101438) presented at the 2021 San Antonio Breast Cancer Symposium. 

The primary analysis showed that outcomes in patients with estrogen receptor (ER)–positive and PR-positive disease was similar between the metformin and placebo arms (HR, 1.01; 95% CI, 0.84-1.21; 

“Metformin does not improve IDFS, OS, or other breast cancer [BC] outcomes in moderate/high risk estrogen receptor (ER)/PR-positive or ER/PR-negative breast cancer patients and should not be used as breast cancer treatment in those groups,” Pamela J. Goodwin, MD, MSc, FRCPC, lead investigator and Professor of Medicine at the University of Toronto, said during the presentation.

The research team attempted to determine if metformin was capable of inducing better tumor responses based on the association of obesity with poor breast cancer outcomes and the agent’s ability to promote weight loss and lower insulin levels.

Metformin was given at 850 mg twice per day for 5 years versus placebo, with a 4-week ramp up of once daily. Patients were eligible for this study if they had a diagnosis of invasive breast cancer within 1 year and negative margins following surgery. Tumors had to be staged as T1c to T3 and N0 to N3, with T1cN0 requiring additional adverse features. All patients must have received standard breast cancer therapy and be not diabetic.

The primary analysis was in patients with ER/PR–positive breast cancer, with 1268 patients in the metformin group and 1265 in the placebo group. They had median ages of 52 (range, 25-74) and 53 (range, 25-74) years, respectively, and 62.1% and 60.2% were postmenopausal. A total of 52.5% and 54.2%, respectively, had T2 tumor stage, and most disease was grade 2 or grade 3. Additionally, 16.5% and 17.4% had HER2-positive disease, with 97% receiving trastuzumab (Herceptin).

IDFS events were noted in 18.5% and 18.3% of patients receiving metformin and placebo, respectively. Rates of distant, local/regional, and contralateral invasive recurrence as well as new primary cancer were similar between groups.

In total, 131 patients (10.3%) in the metformin arm died compared with 119 (9.9%) in the placebo arm (HR, 1.10; 95% CI, 0.86-1.41; 

 = .47). Cause of death in the metformin arm included breast cancer (n = 99; 7.8%), other primary malignancies (n = 15; 1.2%), and cardiovascular disease (n = 4; 0.3%) among other factors (n= 13; 1.0%) with rates being similar to those in the placebo group.

A total of 21.7% of patients in the metformin arm experienced grade 3 or higher adverse effects compared with 18.7% in the placebo arm. Symptoms include nausea, vomiting, bloating, and diarrhea.

Results involving patients with ER/PR-negative breast cancer showed that futulity was established at 29.5 months of follow-up with 172 IDFS events. At the 96-month follow-up, there were 245 IDFS events in 1116 patients, with no benefit noted for the use of metformin on IDFS (HR, 1.01; 95% CI, 0.79-1.30; 

 = .92) or OS (HR, 0.89; 95% CI, 0.64-1.23; 

The exploratory analysis looked at patients who had HER2-positve breast cancer. Interestingly, patient who had at least 1 C allele of a prespecified ATM associated rs11212617 snp had a higher pathologic complete response rate with metformin than those who had no allele. Goodwin said any C allele is associated with a metformin benefit on glucose control in diabetes.

A total of 620 HER2-poistive cases were analyzed, with 99.4% receiving chemotherapy and 96.5% receiving trastuzumab. There were 99 IDFS events, and 47 OS events. When looking at the entire HER2-positive population, patients had fewer IDFS events when taking metformin (HR, 0.64; 0.43-0.95; 

 = .026) compared with the placebo arm. There were also fewer patient deaths with metformin (HR for OS, 0.53; 95% CI, 0.30-0.98; 

There was a significant interaction between snp and IDFS with metformin (HR, 0.51; 95% CI, 0.31-0.83; 

 = .007), whereas those with the AA genotype had no benefit of metformin (HR, 1.32; 95% CI, 0.58-2.96; 

 = .51). This association extended to OS with the snp being statistically significant for metformin benefit (HR, 0.35; 95% CI, 0.17-0.73; 

 = .003) vs the AA genotype (HR, 2.15; 95% CI, 0.56-8.36; 

“Exploratory analyses in HER2-positive breast cancer suggested a beneficial effect of metformin on IDFS and OS, notably in patients with at least one C allele of the rs11212617 snp. These observations should be replicated in future research,” concluded Goodwin.

Goodwin PJ, Chen BE, Gelmon KA, et al. CCTGMA.32, a phase III randomized double-blind placebo controlled adjuvant trial of metformin (MET) vs placebo (PLAC) in early breast cancer (BC): Results of the primary efficacy analysis. Presented at: San Antonio Breast Cancer Symposium; December 7-10, 2021; Virtual. Abstract GS1-08

Improved invasive disease-free survival or overall survival rates for patients, regardless of hormone receptor status, was not improved with metformin, according to results of a phase 3 trial.