Challenges of Managing FL: A Focus on PI3K Inhibitors and Next-Line Therapy

By Elizabeth Brem, MD, University of California, Irvine (Orange, CA)

Dr Brem sat down with the Journal of Clinical Pathways to discuss some of the challenges with managing FL, focusing on the incorporation of PIK3 kinase inhibitors in the treatment of these patients. 

Dr Brem reports that she is an investigator on NCT03488251 and has participated in speaker’s bureaus sponsored by Pharmacyclics and BeiGene as well as ad boards sponsored by Celgene and Bayer.

The original interview has been edited and converted to the below commentary piece with author review and approval.

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The good news about the current state of follicular lymphoma (FL) treatment is that, in the first-line setting, most patients experience long remission durations. The issues tend to arise in the second-, third-, and fourth-line settings.

The paradigm for quite some time has been rituximab plus a chemotherapy agent as initial therapy. In the United States, this upfront chemoimmunotherapy is typically bendamustine/rituximab based on the BRIGHT study1 and a similar study in Europe,2 showing perhaps better outcomes for BR with less toxicity compared to rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) / rituximab with cyclophosphamide, vincristine and prednisone. If the FL relapses several years later, options include either repeating chemoimmunotherapy or, now, giving lenalidomide plus rituximab (R2).3  R2 is now an approved option based on the AUGMENT study of R2 vs rituximab single agent. Overall survival (OS) was similar between arms, but the R2 group had an improved progression-free survival (PFS; the primary endpoint of the study); median PFS 39.4 months vs 14.1 months for single-agent rituximab. As expected, neutropenia was more common in the R2 group, but this was manageable. Febrile neutropenia was rare – 3% in the R2 group vs 1% with rituximab alone.3 It should be noted that there is also data for R2 therapy in the upfront setting. The RELEVANCE study randomized untreated patients to rituximab with chemotherapy or R2.4 A few things should be noted about this study: (1) most patients got R-CHOP in the chemoimmunotherapy arm, and (2) this study was designed as a superiority trial. The study did not meet its primary endpoint, but complete response/unconfirmed complete response (CR/uCR) rates (about 50%) and overall response rates (ORR, about 80%) were similar between arms.4 This is not an FDA-approved combination upfront, but anecdotally I know providers who use it off-label. Whether these patients who got R2 as their initial therapy would benefit from another course of R2 at relapse is another open question.

A difficult group of patients to treat are those who only get a short remission from their first therapy. Patients who are still in remission 24 months after chemoimmunotherapy have OS that is similar to their age-matched peers. This who relapse prior to 24 months (ie, fail to achieve event-free survival at 24 months [EFS24]) have a 50% to 80% 5-year OS, according to a large, retrospective analysis.5 Currently, we do not know how to prospectively identify these early relapse patients; some of these patients have low Follicular Lymphoma International Prognostic Index (FLIPI) scores, and most have grade 1-2 disease at diagnosis. If we could recognize those patients upfront, it is not clear what therapy should be given, but one could hypothesize that a nonchemotherapy approach like R2 may be preferable. Furthermore, it is unclear what the optimal therapy is for these patients who relapse soon after initial chemoimmunotherapy.

The intergroup study SWOG S1608 is attempting to provide answers to some of these questions by randomizing these early relapse patients to lenalidomide-based therapy, a PI3K inhibitor, or chemoimmunotherapy (patients receiving bendamustine upfront will receive CHOP in the second line or vice versa).6 Treatments from all three arms are combined with obinutuzumab with the thought that, for patients who relapse quickly after a rituximab-based therapy, an alternative anti-CD20 agent may have benefit. The hope is that this study will provide an idea of what therapy would most benefit patients who relapse very quickly after their first therapy. This study is also examining the m7-FLIPI, a prognostic score that incorporates molecular markers, to assess if this can be used to prospectively identify those at risk of early relapse.

In general, there are an increasing number of options for patients who have progressed after  anti-CD20 therapy or combination chemoimmunotherapy. As mentioned above, R2 is now an approved option based on the AUGMENT study of R2 vs rituximab single agent. For those who relapse after an anti-CD20 chemoimmunotherapy and R2, PI3K inhibitors have the potential to alter the treatment paradigm in this space. While these inhibitors have good activity, response rates are still less than 60%.7-9 Moreover, there are some patients who do not respond to them, and there are significant toxicity issues, namely autoimmune toxicities such as pneumonitis and colitis.7-9

Overview of PIK3 Inhibitors

The PI3kinase pathway does seem to be vulnerable to inhibition in FL and a couple of other lymphoid neoplasms. There are a few agents that have been approved, but these agents differ in a few ways, one of which pertains to that fact that PI3kinase has multiple isoforms. The approved agents target different isoforms, which leads to variance in side-effect profiles. The first PIK3 inhibitor on the market was idelalisib, which is administered orally. It targets the delta isoform of PI3k and showed a 54% ORR in patients with FL in a single-arm, phase 2 trial.7 When idelalisib was first approved, it was the first in its class and became an option for those who otherwise did not have available approved therapies. However, it has numerous adverse effects, the most problematic of which are pneumonitis, Pneumocystis jiroveci pneumonia (PJP), and diarrhea. The diarrhea and pneumonitis can persist or even begin after therapy discontinuation. Careful monitoring for autoimmune toxicities and PJP prophylaxis are recommended.10

The other oral inhibitor that has been approved is duvelisib, which targets the delta and gamma isoforms of PI3k. In a single-arm, phase 2 trial (DYNAMO), it showed a lower response rate than idelalisib, but these were slightly different patient populations.8 In general, we should not directly compare phase 2 studies, but this is the data available to us right now to help guide decisions between these PI3k drugs. Duvelisib appears to cause less anemia and thrombocytopenia than idelalisib with similar rates of pneumonitis and diarrhea. It should be noted that PJP prophylaxis was required on DYNAMO.8

The third available PIK3 inhibitor is copanlisib.11 It differs from the other 3 PI3k inhibitors in that it is administered intravenously and targets the alpha isoform of PI3K in addition to the delta isoform. The targeting of the alpha isoform changes the side-effect profile. This drug is unique in that it causes hypertension and hyperglycemia, although this is typically transient during the infusion. The autoimmune toxicities do appear less common with copanlisib compared to the oral options. For example, the rate of grade 3+ pneumonitis was only 1% in the CHRONOS-1 study of copanlisib.12

PFS and ORR across these three PI3k-targetted  agents appear to be exceedingly similar; the median PFS for all of them is approximately 10 to 11 months. Certainly, we would like to be able provide patients with more durable responses. Thus far, the studies leading to approval of these PI3k-targeted drugs have been single-arm, phase 2 trials, so there is still opportunity to better refine our understanding of how and when to best incorporate these agents. We need to explore questions like: Can (and should) we use these drugs earlier on? Would they have better responses if used in combination with other targeted agents?

I think it is worth mentioning a few agents that are commonly used in other lymphoma subtypes that unfortunately do not have much efficacy in FL, at least as single agents. Bruton tyrosine kinase inhibitors and BCL2 inhibition, while highly effective in chronic lymphocytic leukemia and mantle cell lymphoma, have not been terribly efficacious in FL to date. Despite a translocation involving BCL2 being present in FL, venetoclax has been shown to have response rates of < 40%, with or without rituximab, in relapsed or refractory FL.13,14 Ibrutinib has also been disappointing, with a response rate of only 20.9% in a phase 2 study.15

How PIK3 Inhibitors are Likely to be Used in Follicular Lymphoma

It will be interesting to see how PIK3 inhibitors fare when studied in a randomized fashion. Combination studies will also be very revealing. A phase 1/1b study of ublituximab (an anti-CD20) in combination with TGR-1202 (a PI3k data inhibitor) has completed accrual.16 TGR-1202 is also the PI3k drug being combined with obinutuzumab in SWOG S1608.6

Again, toxicity cannot be overlooked as an important consideration when deciding whether or not to use a PI3k inhibitor, particularly when considering a patient population that has been through two or three lines of prior therapy. The challenge is not only keeping the disease at bay but also maintaining patients’ quality of life. In most cases, I think patients should be engaged in a conversation about how these drugs vary in side-effect profile and route of administration. I personally tend to favor copanlisib, given that it appears to have lower rates of autoimmune side effects. Many patients have already been given rituximab or some form of chemotherapy, so I have not found the intravenous route of administration to be a huge barrier. However, I could imagine situations where one of the oral options might be preferred, such as for a patient who lives a distance from a cancer center and is unable to come for weekly visits.

Overview of Exciting New Agents

Bispecific antibodies have begun to make waves in lymphoma. Blinatumomab is an approved drug for acute lymphoblastic leukemia but a deterrent to using the drug in lymphomas is that it is administered continuously for a month.17 While patients may not mind intravenous drugs, they may prefer to avoid wearing a fanny pack with a continuous infusion drug for a month.

Newer bispecific antibodies, many of which engage CD20 on the lymphoma cells and CD3 on T cells, have much more convenient dosing schedules, such as either once-weekly intravenously or subcutaneously. As a result, utilizing this class of drugs is becoming much more plausible in the FL space. One of the agents, mosunetuzumab, was the topic of a plenary abstract at the 2019 American Society of Hematology (ASH) Annual Meeting.18 In patients with indolent lymphomas (n = 72), most of whom had FL (n = 69), the ORR was 63%; 43% of those were CRs. A similar drug, REGN1979, also had encouraging results that were presented at the 2019 European Hematology Association and ASH Annual Meetings. This agent has shown a 95% ORR with 77% being CRs, but so far numbers are smaller (n = 22).19,20

The other class of medicines that is starting to generate some buzz is conjugated antibodies. There are examples of these drugs having success in other lymphomas, namely brentuximab vedotin for Hodgkin lymphoma and polatuzumab vedotin for diffuse large B-cell lymphoma.

MT-3724 is a variable chain fragment targeting CD20 conjugated to a shiga-like toxin. One limitation to this approach is that is competes with rituximab or other anti-CD20 antibodies for CD20 binding, so this drug has only shown benefit in patients with undetectable rituximab levels. This drug is being studied mostly in diffuse large B-cell lymphoma, but one study right now in combination with gemcitabine and oxaliplatin (GemOx) is enrolling patients with a number of refractory B-NHL subtypes.21

Lastly, chimeric antigen receptor (CAR) T-cell therapy may find its place in the FL treatment landscape. There is data to suggest that, for some patients who have been through multiple rounds of therapy, CAR-T offers significant response rates. For example, in one series, the CR rate was 88%, and those who achieved a CR were still in remission at a median follow up of 24 months.22 The number of patients was small (n = 8), but such results are of course encouraging. These therapies may continue to have an expanding role in FL, though patients (and their providers) may be appropriately nervous about the risk of neurotoxicity and cytokine release syndrome. We still have much to learn about CAR-T cells, both in how to construct them and how to manage toxicities, but these agents or other cellular therapies may be able to offer a sustained remission and perhaps even a cure for at least a subset of patients.

 Access the original interview.

References

1. Flynn IW, van der Jagt R, Kahl BS, et al. Blood. 2014;123(19):2944-2952. doi:10.1182/blood-2013-11-531327

2. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203-10. doi:10.1016/S0140-6736(12)61763-2

3. Leonard JP, Trneny M, Izutsu K, et al. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol. 2019;37(14):1188-1199. doi:10.1200/JCO.19.00010

4.Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379(10):934-947. doi:10.1056/NEJMoa1805104

5. Maurer MJ, Bachy E, Ghesquières, et al. Early event status informs subsequent outcome in newly diagnosed follicular lymphoma. Am J Hematol. 2016;9[11]:1096-1101. doi:10.1002/ajh.24492

6. Obinutuzumab with or without umbralisib, lenalidomide, or combination chemotherapy in treating patients with relapsed or refractory grade I-IIIa follicular lymphoma. ClinicalTrials.gov identifier: NCT03269669. https://clinicaltrials.gov/ct2/show/NCT03269669. Updated January 31, 2020. Accessed February 3, 2020.

7. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;13;370(11):1008-1018. doi:10.1056/NEJMoa1314583

8. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-hodgkin lymphoma. J Clin Oncol. 2019;37(11):912-922. doi:10.1200/JCO.18.00915

9. Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol. 2017;35(35):3898-3905. doi:10.1200/JCO.2017.75.4648

10. Zydelig [package insert]. Foster City, CA: Gilead Sciences Inc; 2014.  https://www.gilead.com/~/media/Files/pdfs/medicines/oncology/zydelig/zydelig_pi.pdf. Revised October 2018. Accessed February 3, 2020.

11. Dreyling M, Morschhauser F, Bouabdallah K, et al. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol. 2017;28(9):2169-2178. doi:10.1093/annonc/mdx289

12. Dreyling M, Santoro A, Mollica L, et al. Updated safety and efficacy from the copanlisib CHRONOS-1 trial in patients with relapsed or refractory indolent B-cell lymphoma: low incidence of late-onset severe toxicities. Blood. 2017;130(suppl 1):2777. doi:10.1182/blood.V130.Suppl_1.2777.2777

13. Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35(8):826-833. doi:10.1200/JCO.2016.70.4320

14. Zinzani PL, Topp MS, Yuen SLS, et al. Phase 2 study of venetoclax plus rituximab or randomized ven plus bendamustine+rituximab (BR) versus BR in patients with relapsed/refractory follicular lymphoma: interim data. Blood. 2016;128(22):617. doi:10.1182/blood.V128.22.617.617

15. Gopal AJ, Schuster SJ, Fowler NH, et al. Ibrutinib as treatment for patients with relapsed/refractory follicular lymphoma: results from the open-label, multicenter, phase II DAWN study. J Clin Oncol. 2018; 36(23):2405-2412. doi:10.1200/JCO.2017.76.8853

16. Ublituximab in combination with TGR-1202 +/- ibrutinib or bendamustine in patients with B-cell malignancies. ClinicalTrials.gov identifier: NCT02006485. https://clinicaltrials.gov/ct2/show/NCT02006485. Updated November 5, 2019. Accessed February 3, 2020.

17. Blincyto [package insert]. Thousand Oaks, CA: Amgen Inc.; 2014. https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/blincyto/blincyto_pi_hcp_english.pdf. Revised March 2018. Accessed February 3, 2020.

18. Schuster SJ, Bartlett NL, Assouline S, et al. Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-cell (CAR-T) therapies, and is active in treatment through multiple lines. Blood. 2019;134(suppl 1):6. doi:10.1182/blood-2019-123742

19. Bannerji R, Allan JN, Arnason JE, et al. Clinical activity of REGN1979, a bispecific human, anti-CD20 x anti-CD3 antibody, in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). Blood. 2019;134(suppl 1):762. doi:10.1182/blood-2019-122451

20. Bannerji R, Arnason J, Advani R, et al. Emerging clinical activity of REGN1979, an anti-CD20 x anti-CD3 bispecific antibody (AB), in patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). Presented at: The European Hematology Association Annual Meeting; June 15, 2019; Amsterdam, The Netherlands. https://library.ehaweb.org/eha/2019/24th/267451/rajat.bannerji.emerging.clinical.activity.of.regn1979.an.anti-cd20.x.anti-cd3.html. Accessed February 3, 2020.

21. PK, PD, safety and tolerability of multiple dose regimens of MT-3724 with gemcitabine and oxaliplatin for the treatment of patients with relapsed/refractory diffuse large B cell non-Hodgkin’s lymphoma. ClinicalTrials.gov identifier: NCT03488251. https://clinicaltrials.gov/ct2/show/NCT03488251?term=MT-3724&draw=2&rank=2. Updated January 27, 2020. Accessed February 3, 2020.

22. Hirayama AV, Gauthier J, Hay KA, et al. High rate of durable complete remission in follicular lymphoma after CD19 CAR-T cell immunotherapy. Blood. 2019;134(7):636-640. doi:10.1182/blood.2019000905