September 2020 Edition Vol.11, Issue 9

Immunotherapy: Giant Leap for Oncology, Small Step for Certain Cancers

By Chase Doyle

The impact of immunotherapy on the cancer treatment landscape is undeniable, but within certain tumor types, the approach is still struggling to gain a foothold.

During the 2020 ASCO Virtual Education Program, Kunle Odunsi, MD, PhD, Cancer Center Deputy Director at Roswell Park Comprehensive Cancer Center, in Buffalo, NY; Toni K. Choueiri, MD, Director of the Lank Center for Genitourinary (GU) Oncology at Dana-Farber Cancer Institute/Brigham and Women’s Hospital and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School, in Boston; and Jeremy S. Abramson, MD, Associate Professor of Medicine at Harvard Medical School and Director of the Lymphoma Program at Massachusetts General Hospital, in Boston, discussed the current immunotherapy paradigms in ovarian cancer, renal cell carcinoma (RCC), and lymphoma, respectively.

Immunotherapy in Ovarian Cancer: Barriers to Effective Response

Although being an immunogenic disease, ovarian cancer has not seen blockbuster results with immunotherapy like in other solid tumors.1 Vaccines, immune checkpoint inhibitors, adoptive T-cell therapies, oncolytic viruses and cytokines, and other treatment approaches have all yielded disappointing rates of response.

In his discussion, “Overview of Immunotherapeutic Approaches in Ovarian Cancer” Dr. Odunsi outlined some of the barriers to effective immunotherapy in ovarian cancer and proposed several potential solutions.

Although there are a number of inhibitory mechanisms that actively impede antitumor immunity, including cellular networks, soluble factors, and metabolic mechanisms, Dr. Odunsi focused on molecular mechanisms—specifically co-inhibitory receptors/ligands such as PD-1 that play a major role in immunotherapies in other solid tumors.

According to Dr. Odunsi, data from the KEYNOTE-100 trial, which tested the anti-PD-1 inhibitor pembrolizumab in two cohorts of patients with advanced recurrent ovarian cancer (cohort A enrolled 285 patients; cohort B 91), the objective response rate between the two groups was only 8%.2 Still, 29% of patients had some form of disease stabilization, “which suggests there may be opportunities for combination therapies,” said Dr. Odusni.

Published phase II trial results in recurrent or persistent ovarian cancer showed a response rate of 12.2% with single-agent nivolumab (n=49) versus 31.4% of patients who received nivolumab plus ipilimumab (n=51).3

Median progression-free survival (PFS) nearly doubled in patients receiving dual checkpoint inhibition (3.9 months vs. 2.0 months), and approximately 40% of patients had disease stabilization in the combination arm.

Although median overall survival (OS) was seven months higher in patients receiving nivolumab plus ipilimumab versus single-agent nivolumab, it was not statistically significant, said Dr. Odunsi.

Additional studies have unsuccessfully explored immunotherapy plus standard chemotherapy combinations. The phase III JAVELIN trial, which tested avelumab in combination with and/or following chemotherapy versus chemotherapy alone in treatment-naïve patients with epithelial ovarian cancer, was stopped after PFS with the combination therapy showed no improvement versus control.4

According to Dr. Odunsi, adding a VEGF inhibitor to immunotherapy has led to greater efficacy. A phase II trial of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide in recurrent ovarian cancer showed a complete or partial response in 19 of 40 patients.5

Importantly, 25% of patients had a PFS greater than 12 months, “which was really quite remarkable,” said Dr. Odunsi.

Finally, several ongoing trials have combined immune checkpoint inhibitors with PARP inhibition. (See OBR green’s August 2020 article: https://obroncology.com/article/making-sense-of-maintenance-in-ovarian-cancer/.) The sensitivity of tumors with homologous recombination deficiency to PARP inhibition and the inherent immunogenicity of these tumors suggests potential synergy with single or dual checkpoint blockade, said Dr. Odunsi.

In a study of niraparib in combination with pembrolizumab (n=62), an overall response rate of 18.3% and a median PFS of 3.4 months in patients with platinum-resistant ovarian cancer was reported.6

Median duration of response has not been reached. Of note, the overall response rate was 47% and the PFS was 8.3 months in patients with BRCA-mutated tumors.

Ultimately, said Dr. Odunsi, although immune checkpoint inhibitors have shown promise in ovarian cancer, their effectiveness may be limited by multiple immune suppressive networks in the tumor microenvironment. He further stated that effective immunotherapy will require reprogramming the tumor microenvironment to overcome immune resistance via combination strategies.

“It will also be important to personalize combination immunotherapy strategies based on an individual’s tumor immune landscape, and this will require identifying appropriate biomarkers,” he concluded.

RCC: Treatment Options after Immunotherapy Fails

Immunotherapy may be struggling to make progress in ovarian cancer, but it has already changed the treatment landscape of renal cell carcinoma (RCC). Currently, six FDA-approved immunotherapy options are available for kidney cancer either as a single agent or in combination with another immunotherapy or targeted therapy. These agents have significantly improved PFS and OS versus standard of care in advanced RCC, but relapse still occurs.

In his presentation, “After Immune Oncology (IO) Therapy Fails, What’s Next?”, Dr. Choueiri summarized the evidence for treatment options following progression on immunotherapy.

Single-Agent VEGF TKIs

According to Dr. Choueiri, the vast majority of data supporting single-agent VEGF tyrosine kinase inhibitors (TKIs) following immune checkpoint inhibition are retrospective, and no study has enrolled more than 90 patients. Nevertheless, activity has been demonstrated without “concerning signals of amplified or unusual toxicities,” said Dr. Choueiri.

In addition, a phase III study of tivozanib, an oral VEGF TKI, showed significant benefit in PFS versus sorafenib following progression on EGFR TKIs.7 Many of these patients had also progressed on a checkpoint inhibitor, said Dr. Choueiri, who noted that tivozanib has not yet been FDA approved.

Additional Immunotherapy

Evidence supporting a single-agent checkpoint inhibitor following progression on a different checkpoint inhibitor is limited to a small retrospective cohort of 23 patients.8 Although seven of these patients had responses, “the evidence for this approach is almost non-existent,” said Dr. Choueiri.

There is better evidence supporting dual checkpoint inhibition in this setting. Retrospective analysis of nivolumab plus ipilimumab following progression on pembrolizumab and axitinib demonstrated an overall response rate of 20%.9 Responses were durable and the regimen was tolerated, said Dr. Choueiri.

A sequential approach — nivolumab treatment followed by ipilimumab — to alleviate the toxicity of combination immunotherapy is not recommended based on limited activity overall (<15%) and no complete responses.10

Immunotherapy Plus VEGF Inhibition

In patients who have progressed on checkpoint inhibition, there is also the option of adding a VEGF inhibitor to immunotherapy. One non-randomized, prospective study combining lenvatinib with pembrolizumab showed “very compelling activity,” said Dr. Choueiri, with an overall response rate of 52%.11 However, the same level of response might be accomplished without the checkpoint inhibitor, he suggested.

A randomized phase III study of cabozantinib plus atezolizumab versus cabozantinib alone in patients who have progressed on prior immune checkpoint inhibition is looking to answer that question.

Novel Targets

Finally, there is a vast landscape of novel agents being explored in RCC. Dr. Choueiri highlighted MK-6482, a small molecule inhibitor of HIF-2α, which demonstrated a response rate of 24% (n=55) and a PFS of 11 months as a single agent in a heavily pre-treated population with clear cell RCC.12

A phase III trial randomizing patients who have progressed on VEGF-targeted therapy and immune checkpoint inhibition to MK-6482 versus everolimus is now enrolling.

“New targets are always very welcome in RCC,” Dr. Choueiri concluded.

CAR T-Cell Therapy in Aggressive B-Cell Lymphomas

Another form of immunotherapy, chimeric antigen receptor (CAR) T-cell therapy, has changed the treatment paradigm for multiply relapsed/refractory B-cell lymphomas, producing durable remissions, and possibly cures, in patients who were previously considered incurable. In fact, this approach has been so successful that investigators are now comparing anti-CD19 CAR T cells with standard salvage chemotherapy regimens.

In his presentation, “Are CARs Going to Replace Standard Salvage and First-line Therapies in Aggressive Lymphomas?”, Dr. Abramson discussed the evidence supporting CAR T-cell therapy in the second-line and even first-line settings of aggressive B-cell lymphomas.

According to Dr. Abramson, modern autologous stem cell transplant (ASCT) trials show poor outcomes in the salvage setting. In the ORCHARD trial, which compared the efficacy of ofatumumab (O) versus rituximab (R) in combination with cisplatin, cytarabine, and dexamethasone (DHAP) salvage treatment, followed by ASCT in 447 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), only one third of patients had a sufficient response to proceed to transplant.13 Furthermore, less than 25% of patients achieved a durable PFS.

“The modern approach to high-dose chemotherapy in the second-line setting is a flawed therapy that has low success rates in the modern era,” said Dr. Abramson.

This issue is currently being addressed in at least three randomized controlled trials comparing CAR T-cell therapy with traditional second-line salvage therapy and transplant in aggressive B-cell lymphomas:

  • Zuma-7: Axicabtagene ciloleucel versus ASCT in second-line DLBCL
  • Belinda: Tisagenlecleucel versus ASCT in second-line DLBCL
  • Transform: Lisocabtagene maraleucel versus ASCT in second-line DLBCL

CAR T-cell therapy is also being tested in patients with relapsed DLBCL in the second-line setting who are considered ineligible for high-dose chemotherapy transplant. Results from the PILOT study of lisocabtagene maraleucel in this population (n=29) demonstrated an overall response rate of 89%, and 56% of patients achieved a complete response.14

“These data are promising,” said Dr. Abramson. “Ongoing trials will establish the role for CAR T-cell therapy as second-line management for both transplant-eligible and non-transplant-eligible patients with DLBCL failing front-line therapy.”

With respect to front-line therapy, however, Dr. Abramson noted that none of the high-risk subsets perform poorly enough with modern upfront chemoimmunotherapy to warrant the use of CAR T cells as induction therapy, especially given that CAR T cells are available with curative intent in the setting of relapsed/refractory disease. Patients, particularly those with chemotherapy-sensitive disease in the front-line setting, said Dr. Abramson, can do quite well with chemoimmunotherapy.

According to Dr. Abramson, however, early identification of likely treatment failure, such as with interim PET scan or potentially other novel biomarkers, may be a way to target early CAR T cells in high-risk patients destined to fail upfront chemoimmunotherapy.15


References

  1. Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348(3):203-213.
  2. Matulonis UA, Shapira-Frommer R, Santin AD, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol. 2019;30(7):1080-1087.
  3. Zamarin D, Burger RA, Sill MW, et al. Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: An NRG Oncology Study. J Clin Oncol. 2020;38(16):1814-1823.
  4. Pfizer, 2019. Merck KGaA, Darmstadt, Germany, and Pfizer Announce Discontinuation of Phase III JAVELIN Ovarian PARP 100 Trial in Previously Untreated Advanced Ovarian Cancer. Merck KGaA And Pfizer. [online] Available at: https://www.pfizer.com/news/press-release/press-release-detail/merck_kgaa_darmstadt_germany_and_pfizer_announce_discontinuation_of_phase_iii_javelin_ovarian_parp_100_trial_in_previously_untreated_advanced_ovarian_cancer [Accessed 25 August 2020].
  5. Zsiros E, Frederick PJ, Akers SN, et al. A phase II trial of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide for recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. Gynecologic Oncology. 2019;154(Supplement 1, 23).
  6. Konstantinopoulos PA, Waggoner S, Vidal GA, et al. Single-arm phases 1 and 2 trial of niraparib in combination with pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma. JAMA Oncol. 2019;5(8):1141-1149.
  7. Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020;21(1):95-104.
  8. Ravi P, Mantia C, Su C, et al. Evaluation of the safety and efficacy of immunotherapy rechallenge in patients with renal cell carcinoma . JAMA Oncol. 2020;e202169.
  9. Gul A, Stewart TF, Mantia CM, et al. Salvage ipilimumab and nivolumab in patients with metastatic renal cell carcinoma after prior immune checkpoint inhibitors. J Clin Oncol. DOI: 10.1200/JCO.19.03315. Published online June 03, 2020.
  10. Atkins MB, Jegede O, Haas NB, et al. Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced renal cell carcinoma (RCC) (HCRN GU16-260). J Clin Oncol 38, no. 15_suppl (May 20, 2020) 5006-5006.
  11. Lee CH, Shah AY, Hsieh JJ, et al. Phase II trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) for disease progression after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell renal cell carcinoma (mccRCC). J Clin Oncol 38, no. 15_suppl (May 20, 2020) 5008-5008.
  12. Choueiri TK, Plimack ER, Bauer TM, et al. Phase I/II study of the oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC). J Clin Oncol. 38, no. 6_suppl (February 20, 2020) 611-611.
  13. van Imhoff GW, McMillan A, Matasar MJ, et al. Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large b-cell lymphoma: The ORCHARRD Study. J Clin Oncol. 2017;35(5):544-551.
  14. Sehgel AR, Godwin J, Pribble J, et al. Lisocabtagene maraleucel (liso-cel) for treatment of second-line transplant noneligible relapsed/refractory aggressive non-hodgkin lymphoma: initial results from the PILOT study. Blood (2019) 134 (Supplement_1): 2882.
  15. Dührsen U, Müller S, Hertenstein B, et al. Positron emission tomography-guided therapy of aggressive non-hodgkin lymphomas (PETAL): a multicenter, randomized phase III trial. J Clin Oncol. 2018;36(20):2024-2034.

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