The U.S. National Cancer Institute’s (NCI) PDQ Adult Treatment Editorial Board holds 6 in-person meetings a year in Rockville, Maryland. The Board has a new Editor-in-Chief, Eric Seifter, who was appointed after the sudden death of Franco Muggia. Dr. Seifter is an expert in hematologic oncology who sees patients with many types of cancer at his private practice and at Johns Hopkins Hospital.
Financial toxicity and cancer treatment is a controversial and timely topic in the United States. For Italian readers it might be of interest to know that Medicare is a federal health insurance for people who are 65 years or older, certain younger people with disabilities, and people with end-stage renal disease. Different parts of Medicare help cover specific services: Part A (Hospital Insurance) covers inpatient hospital stays, care in a skilled nursing facility, hospice care, and some home health care; Part B covers certain doctors’ services, outpatient care, medical supplies, and preventive services; Part D helps cover the cost of prescription drugs (including many recommended shots or vaccines). A source of particular concern is Part D since for high-price drugs, Medicare Part D beneficiaries who do not receive a low-income subsidy must pay a percentage of the drug’s price for each medication fill. Without that subsidy, which lowers out-of-pocket spending, beneficiaries typically pay hundreds or thousands of dollars for a single fill. [Dusetzina SB, Huskamp HA, Rothman RL, et al.: Many Medicare Beneficiaries Do Not Fill High-Price Specialty Drug Prescriptions. Health Aff (Millwood) 41 (4): 487-496, 2022]. The situation is particularly scary in case of orally administered cancer drugs. To give an example, the retail price of palbociclib is 13.919 USD per fill and the out of pocket spending per year per patient is 10.592 USD; similar results are seen for enzalutamide, apalutamide and osimertinib [Dusetzina SB: Your Money or Your Life – The High Cost of Cancer Drugs under Medicare Part D. N Engl J Med 386 (23): 2164-2167, 2022].
The following papers (Rectal cancer and Hematology/Oncology) were presented by the Editor in Chief.
The results of dostarlimab (a checkpoint inhibitor) in Mismatch Repair-Deficient rectal cancer are well-known, and therefore only the reference is listed here. [Cercek A, Lumish M, Sinopoli J, et al.: PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer. N Engl J Med, 2022. PMID: 35660797].
Adult Hodgkin Lymphoma Treatment
The ABVD regimen challenged the MOPP regimen back in 1975 [Bonadonna G, Zucali R, Monfardini S, et al. Combination chemotherapy of Hodgkin’s disease with Adriamycin, bleomycin, vinblastine and imidazole carboxamide versus MOPP. Cancer 1975; 36:252-59] and after almost 50 years is still considered a standard of care for the treatment of patients with Hodgkin’s Lymphoma. The substitution of bleomycin with brentuximab vedotin, an anti-CD30 antibody conjugated via a protease-cleavable linker to the potent anti-microtubule agent monomethyl auristatin E, was tested in ECHELON-1 in which patients with stage III/IV classical Hodgkin Lymphoma were randomized to first-line brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD; n=664) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; n = 670). At the recent ASCO meeting, investigators reported a pre-specified OS analysis after approximately 6 year’s follow-up. The estimated 6-year OS rates (95% CI) were 93.9% (91.6–95.5) vs 89.4% (86.6–91.7) with A+AVD vs ABVD, respectively. Overall, A+AVD had a comparable long-term safety profile to ABVD. Treatment-emergent peripheral neuropathy continued to resolve or improve in both arms, with 86% (379/443) and 87% (249/286) of cases in the A+AVD and ABVD arms either completely resolving (72% vs 79%) or improving (14% vs 8%) by last follow-up. Fewer second malignancies were reported in the A+AVD vs ABVD arm (23 vs 32). More female patients reported pregnancy (49 vs 28) or live births (42 vs 19 in females) in the A+AVD vs the ABVD arm; no stillbirths were reported. The cost of brentuximab vedotin for the classical 12 administrations is around 170.000 to 180,000 USD, almost 200 times more than bleomycin. [Ansell SM, Radford JA, Connors JM, et al.: Overall survival with brentuximab vedotin in stage III or IV Hodgkin’s lymphoma. NEJM 2022] A+AVD is now being compared to Nivolumab + AVD in a large intergroup prospective trial for patients with advanced stage Hodgkin’s lymphoma. There is no evidence to confirm the use of A+AVD in early stage patients.
Adult Non-Hodgkin Lymphoma Treatment
Mantle-cell lymphoma is a subtype of B-cell non-Hodgkin’s lymphoma and is considered to be incurable. Most patients with mantle-cell lymphoma are older and are unsuitable candidates for aggressive treatment or autologous stem-cell transplantation, a situation that results in unsatisfactory clinical outcomes. Combination therapy with bendamustine and rituximab has become one of the most-utilized first-line regimens for mantle-cell lymphoma, given evidence showing longer progression-free survival with this combination than with R-CHOP (35.4 vs. 22.1 months) and a better safety profile. In the trial discussed here, patients 65 years of age or older were randomized to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area on days 1 and 2) and rituximab (375 mg per square meter on day 1). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group. [Wang ML, Jurczak W, Jerkeman M, et al.: Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma. N Engl J Med 2022 DOI: 10.1056/NEJMoa2201817] It remains unclear if ibrutinib alone could achieve the same benefits, which would allow a chemotherapy-free approach which might avoid inducing mutations that confer subsequent resistant disease or the induction of myelodysplasia or other malignancies.
Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment
Autologous Stem-Cell Transplantation in newly diagnosed multiple myeloma. In patients with newly-diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown. In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma after one cycle of RVD were randomized (1:1) to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary endpoint was progression-free survival. Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, median progression-free survival was 46.2 months (95% CI, 38.1 to 53.7) in the RVD-alone group and 67.5 months (95% CI, 58.6 to not reached) in the transplantation group; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65). [Richardson PG, Jacobus SJ, Weller EA, et al.: Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma. N Engl J Med, 2022. DOI: 10.1056/NEJMoa2204925] The lack of an overall survival benefit calls into question whether the ASCT consolidation is mandated during induction therapy. The delay or abandonment of ASCT can be considered an option for some patients. This view would have been considered heresy prior to the publication of this study.
The role of bispecific antibodies in relapsed-refractory multiple myeloma.
Teclistamab is a T-cell–redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells.
This phase 1–2 study, enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. The primary end point was the overall response. Among 165 patients who received teclistamab, 77.8% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell–associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2). [Moreau P, Garfall AL, van de Donk NWCJ, et al.: Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med, 2022. DOI: 10.1056/NEJMoa2203478]
Breast Cancer Treatment
The papers in this session were presented by Joe Pater, Queen’s University Kingston, Ontario, Canada and Carol Tweed, Maryland Oncology Hematology Annapolis, MD
An anthracycline-free regimen in triple-negative breast cancer (TNBC). The value of platinum-based adjuvant chemotherapy in TNBC patients remains controversial, as does whether BRCA1 and BRCA2 (BRCA1/2) germline variants are associated with platinum treatment sensitivity. Participants were randomized to receive PCb (paclitaxel 80 mg/m2 and carboplatin [area under the curve = 2] on days 1, 8, and 15 every 28 days for 6 cycles) or CEF-T (cyclophosphamide 500 mg/m2 , epirubicin 100 mg/m2 , and fluorouracil 500 mg/m2 every 3 weeks for 3 cycles followed by docetaxel 100 mg/m2 every 3 weeks for 3 cycles). The primary end point was disease-free survival (DFS). Secondary end points included overall survival, distant DFS, relapse-free survival, DFS in patients with germline variants in BRCA1/2 or homologous recombination repair (HRR)–related genes, and toxicity. A total of 647 patients (mean [SD] age, 51 [44-57] years) with operable TNBC were randomized to receive CEF-T (n = 322) or PCb (n = 325). At a median follow-up of 62 months, DFS time was longer in those assigned to PCb compared with CEF-T (5-year DFS, 86.5% vs 80.3%, hazard ratio [HR] = 0.65; 95% CI, 0.44-0.96; P = .03). There was no statistically significant difference in overall survival between the groups (HR = 0.71; 95% CI, 0.42-1.22, P = .22). In the exploratory and hypothesis-generating subgroup analyses of PCb vs CEF-T, the HR for DFS was 0.44 (95% CI, 0.15-1.31; P = .14) in patients with the BRCA1/2 variant and 0.39 (95% CI, 0.15-0.99; P = .04) in those with the HRR variant. Safety data were consistent with the known safety profiles of relevant drugs. In conclusion, a paclitraxel-plus-carboplatin regimen may be an alternative adjuvant chemotherapy choice for patients with operable triple negative breast cancer. [Yu KD, Ye FG, He M, et al.: Effect of Adjuvant Paclitaxel and Carboplatin on Survival in Women With Triple-Negative Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol 6 (9): 1390-1396, 2020].
A longer follow-up for the Tolaney regimen (paclitaxel + carboplatin) with some clues on paclitaxel (Taxol) Induced Peripheral Neuropathy (TIPN). A total of 410 patients were enrolled from October 2007 to September 2010. After a median follow-up of 6.5 years, there were 23 DFS events. The 7-year DFS was 93% (95% CI, 90.4 to 96.2) with four (1.0%) distant recurrences, 7-year OS was 95% (95% CI, 92.4 to 97.7), and 7-year RFI was 97.5% (95% CI, 95.9 to 99.1). Genotyping (n = 230) identified one single-nucleotide polymorphism, rs3012437, associated with an increased risk of Taxol Induced Peripheral Neuropathy (TIPN) in patients with grade 2 or greater TIPN (10.4%). [Tolaney SM, Guo H, Pernas S, et al.: Seven-Year Follow-Up Analysis of Adjuvant Paclitaxel and Trastuzumab Trial for Node-Negative, Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer. J Clin Oncol 37 (22): 1868-1875, 2019].
T-DM1 has the same efficacy but is not less toxic compared to paclitaxel-trastuzumab in stage I, Her-2 positive, breast cancer patients. The ATEMPT trial was designed to determine if treatment with the antibody-drug conjugate trastuzumab emtansine (T-DM1) caused less clinically relevant toxicity (CRT) than paclitaxel plus trastuzumab (TH) and yielded clinically acceptable invasive disease-free survival (iDFS) among patients with stage I human epidermal growth factor receptor 2–positive (HER21) breast cancer (BC). The analysis population includes all 497 patients who initiated protocol therapy (383 T-DM1 and 114 TH). CRTs were experienced by 46% of patients on T-DM1 and 47% of patients on TH (P = .83). The 3-year iDFS for T-DM1 was 97.8% (95% CI, 96.3 to 99.3), which rejected the null hypothesis of an iDFS at 3 years >5% (P < .0001). [Tolaney SM, Tayob N, Dang C, et al.: Adjuvant Trastuzumab Emtansine Versus Paclitaxel in Combination With Trastuzumab for Stage I HER2-Positive Breast Cancer (ATEMPT): A Randomized Clinical Trial. J Clin Oncol 39 (21): 2375-2385, 2021].
How to determine when hormonal adjuvant treatment of breast cancer patients is long enough? In this Italian trial, conducted from 2005 to 2010, 2056 patients who had already received 2-3 years of tamoxifen were enrolled and randomly assigned to receive letrozole for 2–3 years (n=1030; control group) or for 5 years (n=1026; extended group). The 12-year disease-free survival rate was 62% (95% CI 57–66) in the control group and 67% (62–71) in the extended group (hazard ratio 0·78, 95% CI 0·65–0·93; p=0·0064). The 12-year overall survival was 84% (95% CI 82–87) in the control group and 88% (86–90) in the extended group (HR 0·77, 95% CI 0·60–0·98; p=0·036). The most common grade 3 and 4 adverse events were arthralgia (2·2% in the control group vs 3·0% in the extended group) and myalgia (seven [0·7%] vs nine [0·9%]). There were three (0·3%) serious treatment-related adverse events in the control group and eight (0·8%) in the extended group. Osteoporosis occurred in 47 (4·7%) patients in the control group and 81 (8·3%) in the extended group. No deaths related to toxic effects were observed. [Del Mastro L, Mansutti M, Bisagni G, et al.: Extended therapy with letrozole as adjuvant treatment of postmenopausal patients with early-stage breast cancer: a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 22 (10): 1458-1467, 2021].
A target therapy when the target is low can be a very good idea. The results of Trastuzumab Deruxtecan in previously-treated Her-2 low advanced breast cancer patients were presented at the plenary session of the ASCO annual meeting 2022 and were received with great enthusiasm by the attendees. The trial enrolled 557 patients with metastatic breast cancer who had previously received one or two lines of therapy and were randomized in a 2:1 ratio to trastuzumab deruxtecan or to the physician’s choice of chemotherapy. The majority of patients (494, 88.7%) had hormone receptor–positive disease and 63 (11.3%) had hormone receptor–negative disease. Among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice group (hazard ratio for disease progression or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P=0.001) Adverse events of grade 3 or higher occurred in 52.6% of the patients who received trastuzumab deruxtecan and 67.4% of those who received the physician’s choice of chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events. [Modi S, Jacot W, Yamashita T, et al.: Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. New Engl J Med 2022 DOI: 10.1056/NEJMoa2203690] Currently relapsing patients (hormone positive or negative) who were deemed her-2 “negative” by pathologists at diagnosis must now be re-evaluated since her2+ 1 and her2+ 2 without amplification may now be treated effectively using trastuzumab deruxtecan.
Stay tuned for more PDQ changes.