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POLARIX - Has Polatuzumab Vedotin Finally Given R-CHOP the Axe in Upfront DLBCL?

Brian Bazzell, PharmD
Clinical Pharmacy Specialist - Hematology/Oncology
Ann Arbor Veterans Affairs Healthcare System
Ann Arbor, MI

For nearly two decades, treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has been the standard approach for initial treatment of patients with diffuse large B-cell lymphoma (DLBCL). R-CHOP attains durable remissions in approximately 60% of patients, with those remaining in remission at 24 months attaining survival on par with the rest of the general population.1,2 However, 40% of those treated with R-CHOP will either have primary refractory disease or disease relapse within 24 months of initial treatment; many of these patients belong to high-risk subgroups known to confer a poor prognosis, including patients with genetic rearrangements in MYC and BCL2/BCL6 (often referred to as “double-hit” DLBCL).3

A number of clinical trials have attempted to improve survival outcomes in upfront treatment for high-risk patients, either via intensifying therapy (e.g. DA-R-EPOCH) or by adding novel drugs (e.g. lenalidomide, ibrutinib) in combination with R-CHOP.4–6 Unfortunately, all efforts to date have failed to improve survival outcomes compared to R-CHOP in first-line treatment of high-risk DLBCL, leading some to wonder if any novel treatment would succeed in this setting.

In December 2021, it appeared that the streak of negative trials in upfront DLBCL had finally come to an end. Results from the phase 3 POLARIX trial (polatuzumab + R-CHP vs R-CHOP) were first publicly presented at the American Society of Hematology (ASH) Annual Meeting and Exposition, with simultaneous online release of the manuscript in the New England Journal of Medicine.7 For the first time, a novel drug seemed to have improved outcomes compared to R-CHOP in upfront treatment of DLBCL, although controversy exists with regard to the impact these results may have on clinical practice. While some feel the results of POLARIX are practice-changing, others are less enthusiastic about the improvement, particularly given the high difference in cost between the regimens when vincristine is replaced with polatuzumab.

Given the controversy, POLARIX is a perfect trial to assess through the lens of oncology stewardship to determine whether polatuzumab-R-CHP should supplant R-CHOP as the treatment of choice in first-line treatment of DLBCL.

Polatuzumab vedotin in DLBCL
Polatuzumab vedotin is an antibody-drug conjugate that delivers the potent chemotherapeutic payload monomethyl auristatin E (MMAE) to DLBCL cells expressing CD79b, a component of the B-cell receptor, which is expressed on >90% of malignant B cells. Polatuzumab vedotin was initially granted accelerated FDA approval in June 2019 based on results of a single-arm, phase 2 trial in the relapsed/refractory DLBCL setting, in combination with bendamustine and rituximab in patients who had failed at least two prior lines of therapy.8 Rather than mandate a confirmatory phase 3 study in the relapsed/refractory DLBCL setting to attain full approval, the FDA opted to allow the drug’s manufacturer (Genentech/Roche) to use the POLARIX trial as its confirmatory phase 3 trial in the DLBCL space. This was allowed after publication of a promising phase 1/2b study of polatuzumab, rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) in the upfront setting demonstrated an impressive overall response rate (ORR) of 89%, with 77% of those who responded attaining a complete response (CR).9

While allowing a phase 3 confirmatory trial to be performed in a different treatment setting is unusual for a drug with accelerated approval, it ultimately is beyond the scope of this feature. Also of note, vincristine was removed from the CHOP portion of the pola-R-CHP regimen due to concern for overlapping neurotoxicity with polatuzumab’s MMAE payload, as it also is a potent microtubule inhibitor.

POLARIX
The POLARIX trial is a phase 3, double-blind, placebo-controlled trial in which 879 de novo DLBCL patients were randomized 1:1 to receive either pola-R-CHP (n = 440) or R-CHOP (n = 439).7 Eligible patients were adults aged 18-80 years (median = 65 vs 66, with ~70% >60 years in both arms), treatment naive, with CD20+ disease, with an ECOG performance status of 0-2 (~85% = 0-1 in both arms, 15% = 2), and an International Prognostic Index of 2-5 (i.e. intermediate/high risk disease; IPI = 2 in 38% if both arms, IPI = 3-5 in 62% of both arms). Patients with double-hit DLBCL were eligible for the trial (7.9% vs 5.7%). Exclusion criteria included patients with a history of indolent lymphoma (i.e. transformation to DLBCL), previous receipt of an anthracycline, or CNS disease on diagnosis. The primary outcome was progression-free survival (PFS), while event-free survival (EFS, event = progression/relapse, death, biopsy confirmed residual disease after treatment completion, or initiation of new anti-lymphoma therapy), CR rate assessed via PET-CT, and overall survival (OS) were secondary outcomes. Patients in both the pola-R-CHP and R-CHOP treatment arms received 8 cycles of treatment; the first six cycles received were pola-R-CHP or R-CHOP, with two additional cycles of rituximab mandated per protocol. These two extra cycles of rituximab are not standard practice outside of the clinical trial setting, slightly limiting the real-world applicability of the trial and possibly inflating survival outcomes of these trial patients compared to real-world patients. Additionally, all patients were required to receive G-CSF prophylaxis during the first six cycles of treatment, which is not always done for patients receiving R-CHOP in clinical practice and could have lowered neutropenia rates compared to real-world cohorts.

At a median follow-up of 28.2 months, two-year PFS was significantly higher in the pola-R-CHP arm compared to R-CHOP (76.7% vs 70.2%, HR = 0.73, p = 0.02), with an absolute difference at 2 years in PFS between the two arms of 6.5%. Two-year OS (88.7% vs 88.6%, HR = 0.94, p = 0.75), ORR (85.5% vs 83.8%), and CR rate (78.0% vs 74.0%) were not significantly different between pola-R-CHP and R-CHOP. No significant differences were noted between the treatment arms with regard to safety outcomes; the most common adverse events were peripheral neuropathy (52.9% [1.6% grade ≥3] vs 53.9% [1.1% grade ≥3]), nausea (41.6% [1.1% grade ≥3] vs 36.8% [0.5% grade ≥3 ]), neutropenia (30.8% [28.3% grade ≥3] vs 32.6% [30.8% grade ≥3]), and diarrhea (30.8% [3.9% grade ≥3 ] vs 20.1% [1.8% grade ≥3]). Febrile neutropenia (14.3% vs 8.0%) was higher in the pola-R-CHP arm compared to R-CHOP despite primary G-CSF prophylaxis, although the rate of grade ≥3 infection was similar between the arms (15.2% vs 12.6%).

Oncology Stewardship Assessment
To fully assess the capacity of polatuzumab vedotin (and the POLARIX trial) to change clinical practice, it is imperative to assess the drug using oncology stewardship principles that factor in efficacy, safety, and value before reaching a final decision. Based on the data from POLARIX, pola-R-CHP was found to improve PFS by an absolute difference of 6.5% compared to R-CHOP, with no differences in ORR, CR rate, or OS and a similar toxicity profile (albeit with the addition of growth factor prophylaxis, which is an additional costly intervention). To fully assess the impact of a PFS difference of 6.5%, determining the number needed to treat (NNT) and expected cost of therapy for each regimen is essential. Based on the absolute risk reduction of 6.5% for two-year PFS found in POLARIX, the NNT of pola-R-CHP is calculated to be 15.4; in other words, 16 patients would need to receive pola-R-CHP to prevent one relapse compared to R-CHOP. While at face value this doesn’t sound unreasonable, the financial impact must be assessed to determine if this return is worth the cost required to attain it.

Cost of therapy can be determined using the wholesale acquisition cost (WAC) obtained from the Micromedex RedBook, which is a conservative and generalizable drug pricing benchmark that does not factor in rebates or discounts negotiated by individual health systems or retailers. Using WAC pricing and average patient characteristics (BSA = 2.0 m2, weight = 75 kg), the cost of six cycles of pola-R-CHP is approximately $152,185; using the same parameters treatment with six cycles of R-CHOP costs approximately $58,650, for a total difference in cost of ~$100,000 per patient treated (without factoring in the cost of G-CSF prophylaxis mandated by the trial).10 Given that 16 patients would need to be treated with pola-R-CHP in order to prevent one relapse with R-CHOP, we find that the total cost to prevent one DLBCL patient from progressing is approximately $1.6 million. Although salvage therapy options for relapsed/refractory DLBCL (e.g. high dose chemotherapy + autologous transplant, chimeric antigen receptor T-cell therapy) are also very expensive, pola-R-CHP does not currently appear to be a cost effective way to prevent subsequent progression or relapse, given the small impact it has on PFS in the upfront treatment setting and the significant cost of substituting it for vincristine at current price points.

Conclusion
In conclusion, although POLARIX did find an improvement in PFS compared to R-CHOP, which some may argue infers a higher fraction of patients who attained cure, the lack of an OS difference, small absolute difference in PFS, and massive increase in cost of therapy when using pola-R-CHP make it hard to recommend this treatment regimen over R-CHOP in frontline treatment of DLBCL at this time.

REFERENCES

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  2. Maurer MJ, Ghesquières H, Jais JP, et al. Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol. 2014;32(10):1066-1073.
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  4. Bartlett NL, Wilson WH, Jung SH, et al. Dose-adjusted EPOCH-R compared with R-CHOP as frontline therapy for diffuse large B-cell lymphoma: Clinical outcomes of the phase III intergroup trial alliance/ CALGB 50303. J Clin Oncol. 2019;37(21):1790-1799.
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  6. Younes A, Sehn LH, Johnson P, et al. Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2019;37(15):1285-1295.
  7. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. N Engl J Med. 2022;386(4):351- 363.
  8. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2020;38(2):155-165.
  9. Tilly H, Morschhauser F, Bartlett NL, et al. Polatuzumab vedotin in combination with immunochemotherapy in patients with previously untreated diffuse large B-cell lymphoma: an open-label, non-randomised, phase 1b–2 study. The Lancet Oncology. 2019;20(7):998-1010. doi:10.1016/ s1470-2045(19)30091-9.
  10. IBM Micromedex RED BOOK - Overview. Accessed April 15, 2020. https://www.ibm.com/products/micromedex-red-book.
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