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In the Literature

TON - October 2019, Vol 12, No 5 - In the Literature

 

New Triple-Drug Regimen for Newly Diagnosed Patients with Multiple Myeloma

Until recently, patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation (ASCT), the multiagent regimen with lenalidomide (Revlimid) and dexamethasone was the standard of care. Results of the prespecified interim analysis of the MAIA trial demonstrated the benefit of adding daratumumab (Darzalex) to this combination therapy (Facon T, et al. N Engl J Med. 2019;380:2104-2115). Based on the results of this study, on July 1, 2019, the FDA approved this triple-drug regimen for use in this patient population.

MAIA was a randomized, open-label, international, phase 3 clinical trial of 737 adults with newly diagnosed multiple myeloma who were ineligible for ASCT. The patients were randomized in a 1:1 ratio to daratumumab, lenalidomide, and dexamethasone, or to standard of care with lenalidomide plus dexamethasone alone (control group). During the 28-day cycle, all patients received oral lenalidomide 25 mg on days 1 through 21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22. Patients in the 3-drug arm also received intravenous daratumumab 16 mg/kg once weekly for cycles 1 and 2, every 2 weeks for cycles 3 through 6, and then every 4 weeks thereafter. Treatment was continued until disease progression or unacceptable toxicities. The primary end point was progression-free survival (PFS). The secondary end points were time to disease progression, complete response (CR), and overall survival.

After a median follow-up of 28 months, disease progression or death had occurred in 26.4% of the patients in the daratumumab arm compared with 38.8% in the control group. The median PFS was not reached in the daratumumab arm and was 31.9 months in the control group. Overall, a 44% lower risk for disease progression or death was observed among the daratum­umab cohort than in the control group (hazard ratio, 0.56).

The benefit of adding daratumumab was also seen in CR and minimal residual disease (MRD). The percentage of patients with a CR or better was nearly 2 times higher in the daratumumab arm than in the control group (47.6% vs 24.9%, respectively); the percentage of patients who had negative MRD was more than 3 times higher in the daratum­umab group than in the control group (24.2% vs 7.3%, respectively).

As expected, certain adverse events were higher with the 3-drug regimen than the 2-drug regimen. Grade 3 or 4 neutropenia was 50% in the daratum­umab arm versus 35.3% in the control group; lymphopenia rates were 15.1% versus 10.7%, respectively; pneumonia, 13.7% versus 7.9%, respectively; and leukopenia, 11% versus 4.9%, respectively. Overall, the rates of serious adverse events, including those that resulted in death, were similar in the 2 groups.

“These findings can be added to those from a growing list of trials that support the use of daratumumab-based regimens across patient populations with multiple myeloma,” the researchers observed. With the recent FDA approval of this 3-drug regimen, adding dara­tumumab to lenalidomide and dexamethasone will likely become the new standard of care in newly diagnosed patients who are ineligible for ASCT.

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Alpelisib Prolongs Progression-Free Survival in Advanced Breast Cancer with PIK3CA Mutation

Approximately 40% of patients with hormone receptor (HR)-positive, HER2-negative breast cancer have mutations in the PIK3CA gene. Although endocrine-based therapy is the standard treatment, acquired resistance remains a challenge.

The recently approved alpelisib (Piqray), a PI3Kα-specific inhibitor, has demonstrated antitumor activity in early studies. Based on the phase 3 SOLAR-1 clinical trial, in May 2019, the FDA approved alpelisib in combination with fulvestrant (Faslodex) for the treatment of patients with HR-positive, HER2-negative advanced breast cancer and PIK3CA mutation. The results of the study were published just before the FDA approval of this new drug (André F, et al. N Engl J Med. 2019;380:1929-1940).

SOLAR-1 was an international, randomized, double-blind, placebo-controlled, phase 3 trial of 572 patients with HR-positive, HER2-negative advanced breast cancer who had undergone endocrine therapy. A total of 341 patients were randomized based on the presence or absence of a PIK3CA mutation. The patients were randomized in a 1:1 ratio to alpelisib 300 mg daily plus fulvestrant 500 mg every 28 days and once on day 15, or to placebo plus fulvestrant. The primary end point was progression-free survival (PFS). The secondary end points included overall response and safety.

At a median follow-up of 20 months, among patients with PIK3CA mutation–positive disease, the PFS was 11.0 months in the group that received alpelisib plus fulvestrant versus 5.7 months in the group that received placebo plus fulvestrant (hazard ratio for disease progression or death, 0.65; P <.001). In the cohort without a PIK3CA mutation, the hazard ratio was 0.85 (posterior probability of hazard ratio <1; 79.4%). The overall response rate in patients with PIK3CA mutation was greater in the alpelisib arm than in the placebo arm (26.6% vs 12.8%, respectively), as was the clinical benefit (61.5% vs 45.3%, respectively).

The proof-of-concept criteria, however, were not met in the cohort that did not have a PIK3CA mutation. The median PFS rate was 7.4 months in the alpelisib plus fulvestrant cohort and 5.6 months in the placebo plus fulvestrant cohort. At 12 months, the PFS rate was 28.4% in the alpelisib plus fulvestrant group compared with 22.2% in the placebo plus fulvestrant group.

The safety profile in this trial was similar to previous trials of alpelisib plus fulvestrant. A higher incidence of grade 3 or 4 adverse events was seen in the alpelisib cohort than in the placebo group, including hyperglycemia (36.6% vs 0.7%, respectively), rash (9.9% vs 0.3%, respectively), maculopapular rash (8.8% vs 0.3%, respectively), and diarrhea (6.7% vs 0.3%, respectively). Discontinuation rates of alpelisib and placebo because of adverse events were 25% versus 4.2%, respectively.

“These results show improvements in patients’ outcomes with the addition of an α-specific PI3K inhibitor to standard treatment for PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer, findings that validate PIK3CA as an important treatment target in this population,” the researchers observed.

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Long-Term Outcomes Affect Cost-Effectiveness of CAR T-Cell Therapy for DLBCL

The 2 chimeric antigen receptor (CAR) T-cell therapies available so far—axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah)—may be considered cost-effective treatments for adults with diffuse large B-cell lymphoma (DLBCL), depending on the long-term outcomes of these patients, according to a recent cost-effective analysis (Lin JK, et al. J Clin Oncol. 2019 Jun 3. Epub ahead of print).

DLBCL is the most common type of non-Hodgkin lymphoma, with approximately 61% of patients achieving long-term remission with first-line chemoimmunotherapy. However, patients who experience relapse or become refractory to multiple lines of therapy have a poor prognosis. Axicabtagene ciloleucel and tisagenlecleucel are FDA approved for the treatment of relapsed or refractory DLBCL in adults who have received ≥2 lines of systemic therapy or whose disease relapsed ≤12 months after stem-cell transplantation (SCT). Because the costs of the 2 CAR T-cell therapies are high at their list price of $373,000 each, clinicians need to factor in cost-effectiveness when determining the treatment options for this patient population.

“This work is important and timely, especially for health care payers and patients, because it provides evidence on the long-term value and affordability of resources spent on these innovative, yet extremely costly, CAR-T therapies,” wrote Campbell and Whittington in their editorial (Campbell JD, Whittington MD. J Clin Oncol. 2019 Jun 3. Epub ahead of print) accompanying the study publication.

The researchers evaluated the cost-effectiveness and budget impact for each of the 2 CAR T-cell therapies using a Markov model. The main outcomes were undiscounted life-years, discounted lifetime costs, discounted quality-­adjusted life-years (QALYs), and incremental cost-effectiveness.

In a scenario with a 40% rate for a 5-year progression-free survival (PFS), axicabtagene ciloleucel increased life expectancy by 8.2 years at $129,000 per QALY gained. At a 30% 5-year PFS rate, the analysis showed modest improvements in life expectancy by 6.4 years, with a $159,000 cost per QALY gained. For tisagenlecleucel, assuming a 35% rate for a 5-year PFS, life expectancy increased by 4.6 years, with a $168,000 cost per QALY gained. At a 25% rate for a 5-year PFS, improvements in life expectancy were smaller, at 3.4 years and more expensive at $223,000 per QALY gained.

In a budget analysis using 2018 prices, the cost of both CAR T-cell therapies was estimated to increase healthcare spending in the United States during the first 5 years by $12 billion for axicabtagene ciloleucel and by $9 billion for tisagenlecleucel. Price reductions to $250,000 for axicabtagene ciloleucel and $200,000 for tisagenlecleucel, or payment only for initial complete response, would result in a cost of less than $150,000 per QALY for each of the CAR T-cell therapies, even at 25% PFS.

“At 2018 prices, it is possible that both CAR-T therapies meet a less than $150,000 per QALY threshold. This depends on long-term outcomes compared with chemoimmunotherapy and SCT, which are uncertain,” concluded the authors. “Widespread adoption would increase non-Hodgkin lymphoma healthcare costs substantially. Price reductions or payment for initial response would improve cost-effectiveness, even with modest long-term outcomes.”

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Last modified: April 27, 2020