Immunotherapy Branches Out | OncLive

Immunotherapy Branches Out

July 18, 2014

Immunotherapy agents are delivering impressive results in a broad range of tumor types, reinforcing the excitement in research and investment circles for anticancer strategies that actively harness the immune system

Jedd D. Wolchok, MD, PhD

Immunotherapy agents are delivering impressive results in a broad range of tumor types, reinforcing the excitement in research and investment circles for anticancer strategies that actively harness the immune system, according to experts analyzing an avalanche of data presented at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.

The modality once again emerged as a highlight of the annual meeting, even though many of the findings reported this year stemmed from early-stage clinical studies.

Several key trends are unfolding:

  • Checkpoint blockade agents are the leading form of immunotherapy under exploration, particularly antibodies targeting PD-1 or its ligand PD-L1, where results were reported in melanoma, non-small cell lung cancer (NSCLC), bladder cancer, and head and neck cancer (Table)
  • Adoptive T-cell therapy (ACT) is generating much interest, as evidenced by noteworthy results from a small cervical cancer study.1 Pharmaceutical investors have been channeling tens of millions of dollars into research involving various experimental ACT approaches in recent months
  • Combination studies that pair checkpoint agents with each other, with other forms of immunotherapy, and with targeted therapies are expected to become a main focus of immunotherapy research. ASCO highlights in this category included two melanoma studies: one that paired the anti-CTLA-4 antibody ipilimumab (Yervoy) with the anti-PD-1 agent nivolumab,2 and another that combined the oncolytic virus therapy T-VEC with ipilimumab.3

Leading immunotherapy researcher Jedd D. Wolchok, MD, PhD, summarized the broad trends emerging from the ASCO meeting in an interview with OncologyLive. Wolchok, chief of Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center in New York City, helped lead the clinical trial that led to the FDA’s approval of ipilimumab in metastatic melanoma three years ago. He also is among this year’s Giants of Cancer Care™ award winners.

“I see a lot of enthusiasm for immunotherapy in new diseases, bladder cancer being the example that I think was most recognized at ASCO this year in terms of new disease targets,” said Wolchok.“I see the checkpoint modulators having roles by themselves as well as in combination with each other. I also see the checkpoint blocking antibodies having a role when combined with other more conventional anticancer therapies—targeted therapies, radiation, chemotherapy—and seeing those trials mature, I think, is very important.”

Wolchok noted that researchers also are turning their attention toward checkpoints that activate the immune system, which includes his laboratory’s focus on OX40 and GITR.

“We also recognize that there is another part to immunotherapy— not just blocking the brakes, but also stepping on the gas by developing agonist agents for costimulatory pathways,” said Wolchok. “So we now have multiple tools available to try and modulate the immune response in the most potent way possible.”

Although Wolchok has concentrated on checkpoint agents, he feels there is room for many immunotherapy approaches in the anticancer armamentarium. “I don’t think we should say it is only going to be about checkpoint inhibitors, or only going to be about T cells, or only about those two things. There is a lot that we’ve learned about the need for additional immune-modulating agents, so we shouldn’t think exclusively about those two [approaches]. “We have to think more widely rather than more narrowly,” he said.

$9 Billion Market Forecast

The biopharmaceutical industry has been investing heavily in immunotherapy research, and those efforts are expected to bear fruit in the next decade.

The market for immunotherapy drugs will reach $9 billion in the United States, Western Europe, the United Kingdom, and Japan by 2022, according to the Decision Resources Group, a global healthcare analytical company.

Rachel Webster, MSc, DPhil

Checkpoint inhibitors, particularly agents that target PD-1 and its ligand PD-L1, are expected to account for most of that growth, with nearly $8 billion in sales in major markets, Decision Resources forecasts in its “Immunotherapies Pharmacor” report.4 “Clearly, immunotherapy was the highlight of the ASCO meeting. An enormous amount of data is coming out on the checkpoint inhibitors, particularly the PD1 agents and the anti-PDL-1 therapies,” said Rachel Webster, MSc, DPhil, an oncology analyst at Decision Resources. As a class, immune checkpoint agents “are demonstrating rapid, prolonged, very durable responses, and really unprecedented responses,” said Webster.

Moreover, immunotherapies are being evaluated more frequently in combination regimens, although cost considerations and cumulative adverse events (AEs) are emerging as issues, Webster said. “There is a lot of hyperthink around these agents,” she said.

Beyond the checkpoint agents, other novel forms of immunotherapy, particularly ACT strategies, have been attracting research funding from industry. For example, Juno Therapeutics, a partnership of three research centers launched last year to develop ACT approaches, attracted $120 million, one of the largest initial investments in biotech startup history. In June, Adaptimmune Limited announced a deal with GlaxoSmithKline potentially worth more than $350 million over seven years for access to its T-cell receptor engineering technology, another form of ACT.

In early results from a small study highlighted at ASCO, an ACT treatment targeting the human papillomavirus (HPV) delivered notable results in metastatic cervical cancer.1 Two of nine patients achieved durable complete responses that had lasted from 15 to 22 months at the time of the ASCO presentation.

A customized treatment was created for each patient by culturing T cells harvested from the patient’s tumor, testing the cells for reactivity against the HPV E6 and E7 antigens, and preferentially extracting and then expanding the reactive cultures.

The patient then received a single infusion of tumor- infiltrating lymphocytes, followed by aldesleukin dosed to tolerance.

Other novel immunotherapy approaches continue to advance in several tumor types, such as the PROSTVAC poxvirus-based vaccine in metastatic castration-resistant prostate cancer5 and the dendritic cell—based AGS-003 autologous therapy in metastatic renal cell carcinoma.6

Howard L. Kaufman, MD, a longtime melanoma researcher and vice president of the Society for Immunotherapy of Cancer, sees continuing enthusiasm for immunotherapy.

Howard L. Kaufman, MD

“Industry has really embraced immunotherapy as an important modality. I was amazed this year walking through the exhibit hall at ASCO and seeing just the sheer number of companies that are now interested in or starting some type of immunotherapy program,” said Kaufman, who is chief surgical officer and associate director for Clinical Science at the Rutgers Cancer Institute of New Jersey. “Increasingly, the mainstream oncology community is also recognizing this. We sometimes call it the fourth pillar of cancer treatment, joining surgery, chemotherapy, and radiation therapy as a critical modality.”

PD-1 Pathway Sweepstakes

Two years ago, the first findings from an early-phase clinical trial evaluating nivolumab, then known as BMS-936558, generated much excitement at the ASCO annual meeting with response rates as high as 28% among patients with different tumor types.7

Since then, Bristol-Myers Squibb has advanced the agent’s development across various tumor types in clinical trials that have enrolled more than 7000 patients. The FDA has granted nivolumab Fast Track status in NSCLC, melanoma, and renal cell carcinoma, and a Breakthrough Therapy designation in Hodgkin lymphoma.

In late June, Bristol-Myers announced that nivol- umab demonstrated a superior overall survival benefit compared with dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma; the results from the phase III Check- Mate-066 trial, based on an independent Data Monitoring Committee analysis, prompted the trial to be stopped early.8 In July, nivolumab was approved for patients with unresectable melanoma in Japan under the brand name Opdivo, making it the first PD-1 inhibitor to gain regulatory approval in any nation. Bristol- Myers then disclosed plans to submit an application to the FDA during the third quarter for nivolumab to be used in previously treated advanced melanoma.

Meanwhile, impressive results from Merck’s pembrolizumab (MK-3475) have had stock analysts handicapping which company will win the race to market in the United States. The FDA is scheduled to decide by October 28 on an application for pembrolizumab as a treatment for patients with advanced melanoma previously treated with ipilimumab. The agency also has granted Breakthrough Therapy status for pembrolizumab in advanced melanoma.

Featured abstracts at ASCO included a phase I study that showed an overall response rate (ORR) of 34% among patients with advanced melanoma, including a 40% ORR among participants who had not received prior ipilimumab therapy.9 Notably, 88% of patients had sustained responses at the time of analysis in October 2013 after a median follow-up of 12 months.

In NSCLC, pembrolizumab demonstrated significant antitumor activity in a phase 1B study that screened patients based upon PD-L1 expression. Among patients whose tumors were classified as PD-L1 positive (≥1% of tumor cells expressing PD-L1), the overall response rate was 26% by RECIST criteria and 47% by investigator-assessed immunerelated response criteria.10 Another agent is this category is MPDL3280A, which has received a Breakthrough Therapy designation in bladder cancer. The PD-L1 inhibitor will be evaluated in multiple tumor types, including pivotal studies in lung and bladder cancers that include a companion diagnostic, according to Genentech, which is developing the drug.

In research presented at ASCO, MPDL3280A reduced tumors in 43% of patients with previously treated metastatic urothelial bladder cancer whose tumors were considered positive for PD-L1 expression.11 “The bladder cancer data were particularly impressive in the context of this very difficult to treat indication,” said Webster, adding there are not many therapies for this indication.

Webster said it is too soon to determine which PD-1 or PD-L1 agent holds an edge clinically. “Trying to compare these therapies based on such early studies—I don’t think we can do that yet,” she said.

From a market point of view, however, getting a new drug to the clinic first is quite important. “The therapy that gets first to market is going to have an enormous advantage,” said Webster. “You can’t underestimate the importance of being first to market— physicians gaining experience and familiarity with a therapy, getting their patients on that therapy.”

Emphasis on Combinations

In the area of combination strategies, one study that attracted much attention at ASCO involved long-term results from a phase I study that evaluated concurrent nivolumab and ipilimumab in advanced melanoma.

Results were reported for 53 patients who were treated in three of four dosing cohorts.2

“The overall conclusion is that the concurrent therapy with nivolumab and ipilimumab produced . . . an unprecedented 1- and 2-year overall survival rate of 85% and 79%,” said Mario Sznol, MD, professor of Medical Oncology at Yale University School of Medicine, during a press briefing. “Of course, these are small cohorts of patients and this [these results] needs to be verified in phase III trials which haven’t been completed.”

He also noted that OS appeared higher in nivolumab dose cohorts ≥1 mg/kg and that substantial activity was observed in patients with PD-L1 low/negative disease.

Although the combination proved effective, there was a notable increase in toxicities. High-grade AEs increased from 53% of patients according to earlier 2013 data to 62% of patients (58/94) as reported at ASCO 2014. A significant portion of these highgrade AEs were lab abnormalities. One patient died after multiorgan failure that resulted from colitis.

“This [toxicity profile] raises some concerns,” said Sznol. “But many toxicities resemble those typically seen with ipilimumab monotherapy,” he said, adding that many of these are reversible with proactive management, education, and training. “It appears that the activity of the regimen would justify the increased rate of adverse events,” he said.

Similarly, Wolchok, who was one of the investigators on the study, said new AEs did not emerge from the combination. “I think we’re aware of what the toxicities are,” Wolchok said in an interview. “We are very wary and vigilant about detecting them early, and I think it is comforting that we have not heard of anything new.”

In another trial, the combination of T-VEC, the intratumoral injection talimogene laherparepvec, and ipilimumab demonstrated efficacy among 18 patients with previously untreated advanced melanoma.3 The phase IB study results indicated an overall response rate of 56%, with 33% of patients achieving a complete response.

Investigators found that there was no added toxicity with combining T-VEC and ipilimumab; most AEs were consistent with those observed with ipilimumab treatment. Grade 3/4 AEs occurred in 32% of patients.

Kaufman, who was among the investigators on the T-VEC trial, said combining immunotherapy agents may not necessarily result in greater toxicities (as it did with the ipilimumab/nivolumab study) but that side effect profiles would have to be considered carefully.

“It’s always weighing the potential for benefit, which I think with immunotherapy is significant— we’re talking about really durable responses with these agents—compared with putting up with what could be life-threatening toxicities,” said Kaufman.

Nevertheless, he believes combination regimens will be a major immunotherapy focus going forward. “When you start adding these things together you see really dramatic effects and I think that’s going to be the wave of the future,” said Kaufman.

Table. Society for Immunotherapy of Cancer’s Top ASCO Picks1

Agent

Description

Responses

Abstract (number)a

Bladder Cancer

MPDL3280A

Anti-PD-L1 antibody as monotherapy in phase I study in previously treated metastatic bladder cancer

  • 43% of 30 patients had ORR after 6 weeks’ follow-up
  • 52% of 25 patients with PD-L1—positive tumors had ORR

Powles et al (5011)

Cervical Cancer

Adoptive T-cell therapy

HPV-positive tumors treated with TILs selected for HPV E6 and E7 reactivity

  • CR in 2 of 9 patients
  • PR in 1 patient

Hinrichs et al (LBA3008)

Head and Neck Cancer

Pembrolizumab

(MK-3475)

PD-1 inhibitor given as single agent to patients prescreened for PD-L1 expression (KEYNOTE-012)

  • 51% patients (26/51) had decreased tumor burden
  • 19.6% patients (11/56) reached best overall response

Seiwert et al (6011)

Melanoma

Pembrolizumab

PD-1 inhibitor given as single agent; updated results of phase I study

  • 34% of 365 patients had ORR
  • 88% sustained response after median 12-month follow-up

Ribas et al (LBA9000)

Nivolumab plus ipilimumab (Yervoy)

Anti-PD-1 antibody nivolumab given concurrently with anti-CTLA-4 antibody ipilimumab in phase I study

  • 17% of 53 patients had CR
  • 42% of 53 patients ≥80% tumor reduction
  • Response ongoing in 18 of 22 patients

Sznol et al (LBA9003)

T-VEC plus ipilimumab

Oncovirus T-VEC combined with ipilimumab for patients with previously untreated, unresectable disease

  • 56% of 18 patients had ORR
  • 33% of 18 patients had CR
  • 72% disease control rate

Puzanov et al (9029)

Ipilimumab

Adjuvant ipilimumab vs placebo in patients with surgically treated stage III cutaneous melanoma in phase III trial (EORTC 18071)

  • 51.5% RFS rate at 2 years for ipilimumab (234 of 475 patients) vs 43.8% for placebo (294 of 476 patients)
  • 46.5% RFS rate at 3 years for ipilimumab vs 34.8% for placebo

Eggermont et al (LBA9008)

NSCLC

Pembrolizumab

Phase IB study in patients with no prior systemic therapy for metastatic disease with PD-L1—positive tumors (KEYNOTE-001)

  • 26% ORR by RECIST criteria among 42 evaluable patients
  • 47% ORR by irRC criteria among 45 evaluable patients

Rizvi et al (8007)

MEDI4736

PD-L1 inhibitor evaluated in ongoing phase I dose escalation trial; results reported for NSCLC

  • 16% ORR by RECIST criteria among 58 evaluable patients
  • 39% ORR by RECIST criteria among 13 patients with PD-L1—positive tumors at 10 mg/kg q2w dose

Brahmer et al (8021)

aAbstracts available at American Society of Clinical Oncology website, http://meetinglibrary.asco.org/

CR indicates complete response; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; HPV, human papillomavirus; irRC, immune-related response criteria; NSCLC, non—small cell lung cancer; ORR, objective response rate; PD-1, programmed death-1; PR, partial response; RECIST, Response Evaluation in Solid Tumors; RFS, recurrence-free survival; T-VEC, talimogene laherparepvec.

Reference

1. The promise of cancer immunotherapy continues to expand: highlights from the ASCO 2014 Annual Meeting. Society for Immunotherapy of Cancer website, http://www.sitcancer.org/ UserFiles/file/ASCO2014update.htm. Published June 11, 2014. Accessed July 6, 2014.

References

  1. tumorinfiltrating lymphocytes for cervical cancer. J Clin Oncol. 2014;32:5s(suppl; abstr LBA3008).
  2. Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). J Clin Oncol. 2014;32:5s(suppl; abstr LBA9003).
  3. Puzanov I, Milhem MM, Andtbacka RHI, et al. Primary analysis of a phase 1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma. J Clin Oncol. 2014;32:5s(suppl; abstr 9029).
  4. Nawaz K, Webster R. Immunotherapies Pharmacor—2014. Decision Resources Group website. http://www.decisionresources. com/Products-and-Services/Report?r=pcoron0614. Published June 2014.
  5. Mandl SJ, Rountree RB, Owen RB, et al. PROSTVAC, PSA-targeted immunotherapy: new edivence for mechanism of action. J Clin Oncol. 2014;32:5s(suppl; abstr 3080).
  6. Amin A, Dudek AZ, Logan TF, et al. Long-term survival in unfavorable-risk mRCC patients treated with a combination of autologous immunotherapy (AGS-003) plus sunitinib. J Clin Oncol. 2014;32:5s(suppl; abstr 4524).
  7. Topalian SL, Brahmer JR, Hodi FS, et al. Anti-PD1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: clinical activity, safety, and a potential biomarker of response. J Clin Oncol. 2012;30(suppl; abstr CRA2509).
  8. Phase 3 first-line melanoma study of nivolumab, an investigational PD-1 checkpoint inhibitor, demonstrates superior overall survival compared to dacarbazine; study stopped early [press release]. Princeton, NJ: Bristol-Myers Squibb; June 24, 2014.
  9. Ribas A, Hodi FS, Kefford R, et al. Efficacy and safety of the anti-PD-1 monocolonal antibody MK-3475 in 411 patients with melanoma. J Clin Oncol. 2014;32:5s(suppl; abstr LBA9000).
  10. Rizvi NA, Garon EB, Patnaik A, et al. Safety and clinical activity of MK-3475 as initial therapy in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2014;32:5s(suppl; abstr 8007).
  11. Powles T, Vogelzang NJ, Fine GD, et al. Inhibition of PD-L1 by MPDL3280A and clinical activity in patients with metastatic urothelial bladder cancer (UBC). J Clin Oncol. 2014;32:5s(suppl; abstr 5011).


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