Daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone (D-Rd) demonstrated an overall survival (OS) advantage in the first-line setting compared with the same agents in the second-line setting in patients with transplant-ineligible multiple myeloma, according findings from a study presented during the 

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.

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

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

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

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

Articles

Daratumumab, lenalidomide, and dexamethasone demonstrated an overall survival advantage in the first-line setting compared with the same agents in the second-line setting in patients with transplant-ineligible multiple myeloma.

Daratumumab Combos Showcase Superior Survival in First- Vs Second-Line Settings in Transplant-Ineligible Multiple Myeloma

Metformin (Fortamet) failed to improve invasive disease-free survival (IDFS) or overall survival (OS) when used as adjuvant treatment in patients with early breast cancer, irrespective of estrogen or progesterone receptor (PR) status, according to data from the phase 3 CCTG MA.32 trial (NCT01101438) presented during the 

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 effectscompared 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

Metformin failed to improve invasive disease-free survival or overall survival when used as adjuvant treatment in patients with early breast cancer, irrespective of estrogen or progesterone receptor status. 

Adjuvant Metformin Does Not Improve Survival Outcomes in Early Breast Cancer

Mobocertinib (previously TAK-788) was found to provide a meaningful clinical benefit with acceptable tolerability in patients with 

 exon 20 insertion–positive metastatic non–small cell lung cancer (NSCLC) who had previously achieved disease control of 6 months or longer with EGFR TKIs, according to data from a phase 1/2 trial presented during the International Association for the Study of Lung Cancer (IASLC) 

The overall response rate (ORR) per independent review committee (IRC) assessment was 40% (95% CI, 19.1%-63.9%) with a duration of response (DOR) of 13.0 months (95% CI, 5.6-13.5). In this phase 1/2 trial (NCT02716116), the safety profile was consistent with the known effects of mobocertinib and with the broader class of EGFR TKIs.

“The overall response rate in previously treated patients receiving first-, second-, or third-generation EGFR TKIs is less than 10%, with a median PFS [progression-free survival] of less than 4 months,” Alexander Spira, MD, PhD from Virginia Cancer Specialists and US Oncology Research, said during a presentation.

There were 20 patients enrolled to this cohort of the phase 2 expansion portion of the trial, with a median age of 61 years (range, 38-78) and the majority (55%) being women. About half (55%; n = 11) were never smokers and had brain metastases at baseline (50%; n = 10). Prior therapies included platinum-based chemotherapy in 80% and immunotherapy in 65%, and all patients received at least 1 prior EGFR TKI.

All patients had prior TKI therapy, with the median time on therapy being 7.8 months (range, 4.0-37.6). Of note, 11 patients (55%) had received EGFR TKI therapy as their most recent prior treatment, with 7 patients receiving poziotinib (NOV120101), 3 receiving osimertinib (Tagrisso), and 1 on an investigation TKI.

At the median follow-up of 14.2 months (range, 5.2-21.1), the investigator-assessed ORR per RECIST 1.1 was 20% (95% CI, 5.7%-43.7%).

The disease control rate (DCR) by IRC was 90% (95% CI, 68.3%-98.8%) and the confirmed DCR per investigator analysis was 90% (95% CI, 68.3%-98.8%).

The median progression-free survival was 7.3 months (95% CI, 3.6-13.0) and the median overall survival was not reached (14.7-not reached). The rate of OS at 6 months was 94.7% and 78.6% at 12 months.

From baseline, all but 1 patient (95%) had a reduction in target lesion diameter. This was specifically seen in patients with the 

There were 10 patients (50%) who experienced treatment-emergent adverse effects (AEs) greater than grade 3, while 4 (20%) experienced any-grade treatment-related AEs (TRAEs). There were 7 patients (35%) who had serious AEs, 4 (20%) with AEs leading to dose reductions, and 2 (10%) leading to discontinued treatment.

Overall, 90% of patients had any-grade diarrhea that was treatment related, but only 1 was grade 3 or higher. Additional TRAEs included nausea (35%), pruritis (30%), and rash (20%).

“Mobocertinib treatment provided a clinically meaningful benefit for patients with 

 exon 20 insertions and metastatic NSCLC who had greater than 6-month disease control or response to prior 

Spira A, Ramalingam SS, Neal J, et al. Mobocertiniv in EGFR exon 20 insertion-positive metastatic NSCLC patients with disease control on prior EGFR TKI therapy. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 2021. Virtual. Abstract OA15.01.

Mobocertinib was found to provide a meaningful clinical benefit with acceptable tolerability in patients with EGFR exon 20 insertion–positive metastatic non–small cell lung cancer who had previously achieved disease control of 6 months or longer with EGFR TKIs.

Mobocertinib Elicits Antitumor Activity in EGFR Exon 20 Insertion+ NSCLC After Disease Control With EGFR TKIs

Mobocertinib (TAK-788) plus ado-trastuzumab emtansine (T-DM1; Kadcyla) demonstrated inhibitory effects in 

 exon 20 insertion–mutated lung cancer cell lines, according to preclinical findings presented during the International Association for the Study of Lung Cancer (IASLC) 2021 World Conference on Lung Cancer.

Investigators found that adding T-DM1 to mobocertinib resulted in shrinkage of tumors with acquired resistance against mobocertinib monotherapy at around 6 weeks.

“Mobocertinib in combination with T-DM1 exhibits potent efficacy in HER2 exon 20 YVMA mutant lung cancer,” Han Han, MD, from New York University Medical Center, said during a presentation of the data.

Using a patient-derived xenograft model, mobocertinib has shown inhibition against HER2 exon 20 insertion–mutant cell lines. This was confirmed in a phase 2 clinical trial (NCT02716116) in patients with non–small cell lung cancer and mutations in 

The off-target effects on Y-type EGFR from tyrosine kinase inhibitors (TKIs) is a major contributor to adverse effects. When compared with other TKIs, mobocertinib was found to have better selectivity for HER2 exon 20 insertions, which investigators believe may result in a better safety profile on patients.

 exon 20 YVMA mutations, which cover more than 90% of all 

 exon 20 insertion mutations in human lung cancer, mobocertinib’s inhibitory activity against these tumors was demonstrated. However, exon 20 YVMA–mutant cell lines would become resistant after 4 to 6 weeks of treatment.

Investigators noted elevated HER2 expression by flow cytometry on H1781 and Ba/F3 YVMA cell lines with mobocertinib treatment. Additionally, upregulation of HER2 by mRNA level was recorded.

These findings led to the use of 3 candidate agents plus mobocertinib, with T-DM1 showing the best efficacy. Progression-free survival was extended with its use and was able to overcome acquired resistance with mobocertinib monotherapy.

Han H, Li S, Chen T, et al. Targeting HER2 exon 20 insertion-mutant lung adenocarcinoma with a novel tyrosine kinase inhibitor-mobocertinib. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 2021. Virtual. Abstract MA11.02.

Mobocertinib plus ado-trastuzumab emtansine demonstrated inhibitory effects in HER2 exon 20 insertion–mutated lung cancer cell lines. 

Ariana Pelosci

Articles

Daratumumab Combos Showcase Superior Survival in First- Vs Second-Line Settings in Transplant-Ineligible Multiple Myeloma

Adjuvant Metformin Does Not Improve Survival Outcomes in Early Breast Cancer

Mobocertinib Elicits Antitumor Activity in EGFR Exon 20 Insertion+ NSCLC After Disease Control With EGFR TKIs

Mobocertinib Plus T-DM1 Elicits Preclinical Activity in HER2 Exon 20 Insertion+ Lung Cancer Models