Relapsed refractory DLBCL

 

1. Tafasitamab - CD 19 Ab: approved with lenalidomide for patients with R/R DLBCL ineligible for ASCT. median OS 3 yr. 2L, ineligible for ASCT. CR 43%, ORR 60%, 1 yr  OS 74%. L-MIND study.

2. Loncasituximab- ADC against CD19: with revlimid or ibritunib with 50% ORR. 3L. LOTIS -2 trial. PFS 10 months. Neutropenia, tpenia, and increased GGT.

3. Polatuzumab- ADC against CD79b- 3rd line for R/R. in combo with BR. Can be 2nd line if not ASCT candidate or CAR-T candidate.

4. Selinexor- XPO1 inhibitor- approved 3L. SADAL study. Cytopenias, fever, fatigue. ORR 28%. median PFS 9 m.

Other agents:

1. Pembrolizumab - approved for R/R primary mediastinal B-cell lymphoma (PMBL) based on the results of KEYNOTE-170 which demonstrated an ORR of 41.5% (CR 20.8%), with median PFS and OS of 4.3 and 22.3 months

2 Brentuximab +/- Rituxan in CD 30+ DLBCL . Works even without CD 30 positivity. 

2025 update: BV 1.2 mg/kg q 3 weeks+ rituxan q 3 weeks+ Lenalidomide 20 mg daily- 3rd line versus R2 as the comparator. Median OS 13.8  m versus 8.5 months. ( JCO March 2025) ECHELON-3. The PFS was low. Therefore may be a bridging therapy to ASCT or CAR-T. This regimen worked even in those who relapsed after CAR-T and high IPI.

3. Revlimid and other CELMods: single agents with < 30% ORR.

Reference

Myeloma

 1. Frontline transplant eligible: VRD dara for younger patients stringent CR, depth of response and MRD all higher with quadruplet. Translates to better PFS. Trend toward better OS.

CASSIOPEIA ( VTD-dara) and GRIFFIN ( VRD-Dara).

2. Relapsed MM:  First relapse: ( second line)

Bortezomib is suboptimal at the time of the first relapse for len-refractory patients based on CASTOR study results

Len refractory ( progression on len or within 60 days of last dose): Dara or Isatuximab ( anti CD 38 antibody) with second gen PI ( Karfilzomib) with low dose dex

a. Dara- Kd--> CANDOR --> PFS 29 months ( for all comers, 1/3 len refractory)

b. Isa-Kd--> IKEMA--> PFS 36 months ( all comers, 1/3 len refractory). Kd arm PFS 15 m

Lenalidomide sensitive patients at the time of first relapse: POLLUX study-- Dara - len-dex-- median PFS 4 yr.

3. Relapsed myeloma: second relapse: ( third line)

 Pom/dex backbone with CD 38 antibody: ICARIA and APOLLO

a.  Istatuximab + Len/dex: ICARIA:  PFS, 11.5 months, versus 6.5, with a hazard ratio of 0.6. So that’s a 40% reduction in the risk of death of progression with isatuximab/pom/dex versus pom/dex alone

b. Dara-Pom dex- APOLLO: Median PFS 12 months for triplet versus 7 for Pd alone. Of note Dara was used subcut not IV.

4.  What is Iberdomide? It is a CELMoD. Cerebron ligase modulators have more affinity in binding and degrading substrates needed by the myeloma cell. 10-20 times more potent than Lenalidomide.

5. If you progress on an anti CD 38, how long should the patient be off the antibody before you retreat? Ans: at least 6 months for the CD 38 to get expressed again on the myeloma cells.

6. MAIA study elderly non transplant eligible: the median progression-free survival was 44.5 months in the daratumumab group, as compared with 17.5 months in the control group.

Metastatic breast cancer- CCO

 

1. Based on current indications and clinical guideline recommendations, patients with hormone receptor (HR)–positive/HER2-negative MBC can receive a CDK4/6 inhibitor with either an AI or fulvestrant as first-line treatment for MBC. PARP inhibitors, immunotherapy, and antibody–drug conjugates (ADCs) can be use din subsequent lines of treatment, including after chemotherapy.

2. Current guidelines and expert recommendations suggest testing peripheral blood and metastatic TNBC biopsy samples for PD-L1, BRCA1/2 mutation, and HER2 status to assess patient eligibility for available treatment options. Patients with a PD-L1 CPS score of ≥10 are eligible for chemotherapy plus pembrolizumab, whereas patients with germline BRCA1/2 mutations should receive a PARP inhibitor (olaparib or talazoparib) or platinum-based chemotherapy. HER2 expression testing may be recommended in patients with previously diagnosed TNBC who have progressed on chemotherapy with or without pembrolizumab to determine optimal ADC-based therapy: Patients with HER2-low disease should receive T-DXd, and those with HER2-zero disease could consider sacituzumab govitecan.

Discussion regarding frontline choice of CDK4/6 inhibitors in MBC:

In MONALEESA-2 and MONALEESA-7, ribociclib in combination with ET yielded a statistically significant improvement in OS compared with ET alone (hazard ratios in both trials: 0.76).^7,8 MONALEESA-3 included a first-line cohort evaluating ribociclib plus fulvestrant and showed significantly improved OS with ribociclib plus fulvestrant compared with fulvestrant alone (median OS: 67.6 vs 51.8 months; hazard ratio: 0.67).⁹

MONARCH-3, the trial evaluating abemaciclib as part of first-line therapy, has not yet shown a statistically significant improvement in OS. An interim analysis of survival has been reported for abemaciclib plus AI compared with AI alone (median OS: 67.1 vs 54.5 months; hazard ratio: 0.754), which looks very promising based on what we have seen in MONALEESA-2.¹⁰ However, we are awaiting the final statistical analysis from MONARCH-3, which is anticipated by the end of 2023. 

Unfortunately, the PALOMA-2 trial with first-line palbociclib plus letrozole did not yield a survival advantage compared with letrozole alone (median OS: 53.9 vs 51.2 months; hazard ratio: 0.956).¹¹ Nonetheless, certain subsets of patients do very well with palbociclib-based treatment, including older women, patients with bone-only disease, and patients with more ET-sensitive disease. As such, palbociclib is not an unreasonable choice for patients when ribociclib and abemaciclib are not ideal options.

RIGHT Choice trial- use Ribo with ET front line for aggressive MBC. PFS 24 m compared to 12 m with chemo even in the first 3 months.

Impending liver failure would be the only reason to use traditional chemo

Gem carbo ( Gem D1,8 dose reduced 800), carbo ( AUC 4 or5) or 50% dose reduced vinorelbine if bili > 2.

Taxol dose reduced unless Bili > 7.5 and AST/ALT> 10 ULN

Monitoring for CDK4/6 inhibitors

Monitoring plan for antineoplastic therapy

Monitor labs for neutropenia and LFT abnormalities for all 3. CBC, CMP q 2 weeks for first 2 month, then monthly for next 2 months. Then q 3 m . LFT issues less likely with palbo.

Clinical monitoring for PE/DVT ( abema) and ILD with all 3.

Diarrhea with abema:

 For either grade ≥3 diarrhea or persistent grade 2 diarrhea that does not resolve within 24 hours, we want to suspend abemaciclib treatment until the toxicity improves to grade ≤1, and then restart abemaciclib at a reduced dose.¹For grade 2 diarrhea that does not resolve within 24 hours with antidiarrheal agents, suspend abemaciclib treatment until the toxicity improves to grade ≤1, and then restart abemaciclib at the same dose level. For grade 1 diarrhea, no dose modifications are required, and I often tell patients they can take one half to a full dose of loperamide once per day and continue therapy without suspending treatment.

LFT abnormality with abema:

with abemaciclib, no dose modification is required for grade 1 or 2 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation without increase in bilirubin above 2 times the upper limit of normal (ULN). Patients who experience persistent or recurrent grade 2 ALT/AST elevation or grade 3 ALT/AST elevation without an increase in bilirubin should hold abemaciclib until the toxicity resolves to grade 1 or baseline levels and then resume with a dose reduction. Patients with ALT/AST elevation >3 times the ULN with an increase in bilirubin or those with a grade 4 ALT/AST increase should discontinue the CDK4/6 inhibitor

Neutropenia with ribo

In patients receiving ribociclib, the prescribing information recommends monitoring complete blood counts every 2 weeks for the first 2 cycles, after the subsequent 4 cycles, and as clinically indicated.¹⁵ No dose adjustments are required for grade 1 or 2 neutropenia. If grade 3 neutropenia develops, suspend treatment until neutropenia resolves to grade ≤2, and then resume at the same dose. If there is recurrent grade 3 neutropenia or febrile neutropenia (with single episode of fever of >38°C or above 38°C for more than 1 hour and/or concurrent infection), stop treatment until neutropenia resolves to grade ≤2, and then resume at the next lower dose level. If grade 4 neutropenia develops, stop treatment until neutropenia resolves to grade ≤2, and then resume treatment at the next lower dose level.

Metastatic TNBC

1. Keynote 355: 

The final efficacy data from KEYNOTE-355 are summarized on this slide.²⁰ Although the trial enrolled all-comers, approximately 40% of patients were PD-L1 positive based on a CPS score ≥10. If we look at median OS on the left, we can see approximately 7-month improvement with the addition of pembrolizumab to chemotherapy in patients with a CPS score of ≥10, with median OS of 16.1 months without pembrolizumab vs 23.0 months with pembrolizumab (1-sided P = .0093). In addition, 14% more patients were alive at 2 years in the pembrolizumab-containing arm.

In the first-line metastatic setting in KEYNOTE-355, we saw that those patients receiving pembrolizumab experienced modestly higher levels of colitis (1.8% vs 1.4%) and pneumonitis (2.5% vs 0%), and the most common events were hypothyroidism (15.8% vs 3.2%) and hyperthyroidism (4.3% vs 1.1%).²⁰ These just occur at lower incidences than in the neoadjuvant and adjuvant curative setting.

2. However, if a patient is PD-L1 positive with CPS of ≥10, then I would hold the PARP inhibitor until after progression on first-line chemotherapy plus pembrolizumab. PARP inhibitors show PFS but no OS benefit in gBRCA. So even in such patients, if CPS>10, use Keynote 355 regimen.

Subsequent lines