SITC Meeting Report: April 29 FDA ODAC Summary

The Society for Immunotherapy of Cancer (SITC) is pleased to present this report on the April 29, 2021, meeting of the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC).

Gastric and Gastroesophageal Junction Adenocarcinoma

In 2017, anti–PD-1 pembrolizumab was granted an accelerated approval for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (combined positive score [CPS] greater than or equal to 1) as determined by an FDA-approved test, and have failed two or more lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, human epidermal growth factor receptor 2 (HER2)/neu-targeted therapy. Approval was granted based on an observed 13.3% objective response rate (ORR) within Cohort 1 of KEYNOTE-059. However, both KEYNOTE-061 (second-line pembrolizumab vs. paclitaxel) and KEYNOTE-062 (first-line pembrolizumab in combination with 5-fluorouracil and cisplatin vs. chemotherapy alone) have failed to confirm an overall survival (OS) benefit of adding the PD-1 inhibitor to the treatment regimens for patients with PD-L1+ gastric or GEJ adenocarcinoma.

Pembrolizumab

On April 29, 2021, FDA ODAC met to discuss maintaining the indication for third-line pembrolizumab monotherapy for PD-L1+ patients with gastric or GEJ adenocarcinoma in light of currently available clinical trial data as well as the rapidly evolving treatment landscape for this patient population. The committee voted 6-2 to recommend rescinding the current indication.

Sponsor Position:

• Pembrolizumab monotherapy addresses a significant unmet medical need for treatment of heavily pre-treated patients who may not be able to tolerate chemotherapy
• Data provided by KEYNOTE-059 are consistent with data supporting alternative approvals in this patient population with a generally poor prognosis (ex. median OS is 6 months across clinical trials currently supporting treatment approvals)
• Pembrolizumab has an acceptable safety profile and is well tolerated in the third-line, PD-L1+ patient population
• By 2024, four ongoing clinical trials will provide data that may be able to confirm pembrolizumab clinical benefit in this patient population
• KEYNOTE-061 may not serve as appropriate comparisons for approval confirmation, as more recent data suggest earlier lines of gastric and GEJ treatment require chemotherapy addition
• KEYNOTE-590 data revealed an OS benefit of pembrolizumab addition to chemotherapy for the treatment of patients with esophageal or GEJ adenocarcinoma and supported FDA approval for first-line treatment

FDA Position:

• Recent approvals, including first-line PD-1 inhibitor nivolumab + FOLFOX or CAPEOX for patients with gastric and GEJ adenocarcinoma, may address the unmet medical need served by the discussed pembrolizumab indication
• ORR within the PD-L1+ patient population from Cohort 1 of KEYNOTE-059 may have been contaminated through the inclusion of patients with unknown tumor microsatellite instability/tumor mutational burden status
• Ongoing clinical trials by the sponsor evaluate pembrolizumab in combination with chemotherapy and are not assessing monotherapy as described within the current indication
• Given the low ORR demonstrated within KEYNOTE-059, the risk/benefit may not support approval given possibility of immune-related adverse events

Public Comment:

• This treatment addresses and unmet medical need for patients in third-line setting who have not received IO and those who cannot tolerate chemotherapy

Committee members cited currently available clinical trial data as not supporting the risk/benefit ratio of retaining the indication. They also noted that none of the currently ongoing clinical trials would serve to answer whether pembrolizumab monotherapy provides clinical benefit. Lastly, there was discussion on how recent first-line immunotherapy indications would likely become standard of care, and that future patients requiring third-line treatment may not be eligible for checkpoint inhibitor therapy. Given the recommendation to rescind the indication, committee members emphasized the importance of delaying any planned market removal to ensure that patients currently receiving the therapy could enter into an expanded access program or single patient IND to continue treatment. The FDA was in support of these measures and emphasized that they were cognizant of the impact upon patients if the indication were to be ultimately rescinded.

Hepatocellular Carcinoma

Anti PD-1 nivolumab, the first checkpoint inhibitor to be marketed for treatment of patients with hepatocellular carcinoma (HCC) whose disease progresses after treatment with the first-line vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) sorafenib, gained accelerated approval in September 2017. Approval was based on the results of one of the treatment arms of the multicenter, open-label, phase I/II trial CheckMate 040, which showed a confirmed ORR in this patient population of 14.3% (95% CI: 9.2, 20.8), with 91% of responders having responses lasting 6 months or longer and 55% having responses lasting 12 months or longer. A second anti-PD-1 agent, pembrolizumab, received accelerated approval for the same indication based on an independent central review-assessed ORR of 17% (95% CI: 11, 26) with 89% of responders having durations of 6 months or longer and 56% having response durations of 12 months or longer in the single-arm, multicenter, phase I/II study KEYNOTE-244.

Advanced HCC is associated with a very poor prognosis and the disease almost always develops against a background of cirrhosis, complicating therapy selection in patients with poor liver function and high burden of comorbidities. Since the initial accelerated approvals of pembrolizumab and nivolumab, the treatment landscape for HCC has changed, with the combination of the anti-PD-L1 atezolizumab plus the anti-VEGF bevacizumab attaining full approval for first-line treatment of HCC based on significant OS and PFS improvements in the multi-center, open-label IMbrave150 trial. However, up to 15% to 20% of patients with HCC cannot be treated with bevacizumab due to bleeding risk. Nivolumab in combination with anti-CTLA-4 ipilimumab also received accelerated approval for patients with HCC who have been previously treated with sorafenib in March 2020. This indication was not under consideration at this meeting.

Review of the HCC indications for nivolumab and pembrolizumab monotherapies was motivated by the low response rates in their respective registration studies as well as failure to verify clinical benefit in the designated confirmatory studies CheckMate 459, which did not meet efficacy thresholds for OS benefit in the first-line setting, and KEYNOTE-240, which did not achieve pre-specified statistically significant OS improvement in the identical to the registration trial post-sorafenib setting.

Pembrolizumab

On April 29, 2021, FDA ODAC voted 8 to 0 in favor of maintaining the accelerated approval of pembrolizumab for patients with HCC who have previously been treated with sorafenib. The unanimous decision was based on the substantial unmet need for second-line immunotherapy options in the population ineligible for bevacizumab treatment as well as the panel’s opinion that KEYNOTE-240 demonstrated clinically meaningful benefit despite not meeting pre-specified significance thresholds in OS.

Sponsor Position:

• Pembrolizumab monotherapy represents an important option for the significant proportion of patients with HCC who cannot receive first-line bevacizumab and whose disease progresses after sorafenib
• The incremental benefit of second-line pembrolizumab is analogous to the approved second-line TKIs, and the toxicities associated with pembrolizumab monotherapy are largely manageable
• Durable responses seen with pembrolizumab monotherapy are clinically meaningful

FDA Position:

• ORR with pembrolizumab monotherapy was low in the registration trial KEYNOTE-244 and the confirmatory trial KEYNOTE-240
• Recognizing that the bevacizumab-ineligible population represents a significant unmet need, patients at high risk for bleeding with bevacizumab were not included in KEYNOTE-244 and KEYNOTE-240

Public Comment:

• HCC is associated with very poor prognosis and significant unmet need, especially for the patients with poor underlying liver function or who cannot receive first-line atezolizumab + bevacizumab due to bleeding risk
• Removing options for second-line therapies is not in the best interest of patients with HCC

Alternative confirmatory trials for pembrolizumab have completed accrual and results are anticipated soon. Specifically, the final analysis of KEYNOTE-394, which is evaluating benefit in the post-sorafenib setting in an East Asian population is expected as early as June or July of 2021, and the results of the LEAP-002 trial comparing first-line pembrolizumab in combination with the VEGF-TKI lenvatinib to lenvatinib monotherapy will be available in 2023.

Nivolumab

In a 4 to 5 vote, ODAC recommended rescinding the indication for nivolumab for the treatment of patients with HCC and prior sorafenib therapy. There was unanimous agreement from committee members that voting was difficult due to the many factors, including the earlier vote to maintain the indication for pembrolizumab monotherapy. Those in favor of continued accelerated approval for nivolumab in this patient population highlighted the unmet need for second-line options. Rationale against continuing the indication centered on the lack of OS benefit in CheckMate 459 and the inadequacy of the proposed alternative studies to generate satisfactory evidence for efficacy in the second-line setting. Discussion also narrowed in on whether data exist to recommend nivolumab monotherapy over an ipilimumab + nivolumab combination regimen, including debate over whether the group of patients deemed unfit for the dual checkpoint inhibitor combination represent a new indication that was not formally defined nor evaluated in trials to date.

Sponsor Position:

• Nivolumab fills an unmet medical need for the patients who cannot receive bevacizumab in the first-line and whose disease progresses after TKI therapy
• Nivolumab monotherapy is well-tolerated in patients with HCC and associated with fewer toxicities than the ipilimumab-containing combination regimen
• Exploratory analyses in CheckMate 459 favor benefit for healthcare-related quality of life with nivolumab
• Delayed benefit was seen at longer follow-up in CheckMate 459, possibly due to subsequent systemic therapy use in sorafenib arm, including immunotherapy

FDA Position:

• Availability of first-line atezolizumab + bevacizumab (in addition to other second-line options, including combination ipilimumab + nivolumab) has changed the HCC treatment landscape
• Statistically significant OS benefit with nivolumab monotherapy was not shown in the designated confirmatory trial, CheckMate 459
• Alternative confirmatory trials CheckMate 9DX (adjuvant nivolumab) and CheckMate 9DW (first-line ipilimumab + nivolumab) will not provide evidence for benefit with second-line monotherapy
• Data are lacking on efficacy of the monotherapy in the population of patients who cannot tolerate first-line bevacizumab as well as those deemed ineligible for other second-line therapies, such as ipilimumab + nivolumab

Public Comment:

• Nivolumab monotherapy is an important option for many HCC patients, especially given the increased potential for toxicity with ipilimumab-containing combinations
• The safety and adverse event profile of nivolumab is favorable compared to other available second-line therapies for HCC

The FDA is not required to implement the recommendations of ODAC. Committee members also noted that nivolumab is widely available for other FDA-approved indications and that off-label use remains a possibility for the patients with second-line HCC. If the indication were to be ultimately rescinded, expanded access programs and single patient INDs also remain possibilities to allow for continued access.

JITC Letter from the Editor - February 2019

Dear JITC Readers,

In the February edition of the JITC Digest, there are four articles of note of which I would like to highlight. First, the article “EnanDIM - a novel family of L-nucleotide-protected TLR9 agonists for cancer immunotherapy,” by Kerstin Kapp et al. reports the development of EnanDIM® molecules, a novel family of chemically defined TLR9 agonists with the ability to activate the innate and adaptive immune systems and elicit potent anti-tumor responses without generating off-target effects. The described immunological features of EnanDIM® molecules in this study suggest the potential for combination with other immunotherapeutic approaches and prompts the need for further preclinical and clinical development.

Next, the research article, “Tumor microenvironment modulation enhances immunologic benefit of chemoradiotherapy,” by Aurelie Hanoteau et al. investigated clinically relevant in vivo models combining chemoradiotherapy (CRT) with two immunomodulatory drugs: cyclophosphamide (CTX) and L-n6-(1-iminoethyl)-lysine (L-NIL). Results demonstrated that alteration of the tumor immune microenvironment can render refractory tumors susceptible to CRT and suggests the potential for clinical translation of this approach.

Furthermore, the article, “Avelumab in patients with previously treated metastatic melanoma: phase 1b results from the JAVELIN Solid Tumor trial,” by Ulrich Keilholz et al. presents safety and efficacy data from previously treated patients with locally advanced or metastatic melanoma enrolled in the phase 1b, dose-expansion part of the JAVELIN Solid Tumor trial. Avelumab demonstrated durable responses and an acceptable safety profile, as well as encouraging efficacy for patients with PD-L1–positive tumors and those who had progressed after ipilimumab therapy.

Finally, Jana de Sostoa et al.’s article, “Targeting the tumor stroma with an oncolytic adenovirus secreting a fibroblast activation protein-targeted bispecific T-cell engager,” details a novel strategy to minimize the antiviral immune response needed to target cancer calls and fibroblast activation protein-alpha (FAP). By inserting a bispecific T-cell Engager (FBiTE) targeting FAP into the oncolytic adenovirus, ICOVIR15K, Sostoa’s group developed an FBiTE-armed adenovirus (ICO15K-FBiTE) shown to enhance viral spread and overall anti-tumor efficacy without increasing clinical toxicity. Similar results with a similar FAP-BiTE were reported by an Oxford-based group using the oncolytic group B adenovirus enadenotucirev (Freedman JD et al. Cancer Res Dec 15, 2018).

Additionally, I welcome you all to enjoy a new feature through SITC Connect where JITC editors share a monthly reading list of publications of interest elsewhere in the field that add value to what readers can find in JITC. Check out the first edition of “JITC’s Reading List” and stay tuned for new content from each month’s featured editor.

With best regards,

Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer

To view the entire February 2019 JITC Digest, please click here. 

Focused Radiation May Help Turn on the Immune System

Focused Radiation May Help Turn on the Immune System

by Christian Hyde, MD

Radiation given in combination with immunotherapy can potentially kick-start an exhausted immune system. This has been most famously observed in a melanoma patient on Ipilimumab, published by Dr. Michael Postow and others in the New England Journal of Medicine. At first, the ipilimumab worked, and her tumors shrank. Then the tumors developed resistance and regrew. By radiating one of her tumors near the spine, with 3 large doses of radiation, her immunity was restored, and all her tumors shrank, not just the irradiated tumor. The combination increased tumor specific T-cells and antibodies.

The result has a scientific nickname: the abscopal effect, derived from a combination (aptly enough) of two words—ab, for “away,” and scopus, for “target.” The effect, first reported about 50 years ago, is currently rare, seen in a small number of patients who undergo radiation therapy for metastatic disease.

Radiation doses of 8 to 10 Gray appear to be ideal to wake up the immune system and cause the tumor to become inflamed such that it is fertile ground for immune activity. Recent work by Dr. Silvia Formenti and others has shown that these high doses of radiation makes cancer cells look and act like virus-infected cells. The radiated cancer cells produce interferon and display more surface antigens, helping to target themselves for immune destruction, using many of the same pathways as a virus-infected cell. 

The abscopal effect is rare because radiation also simultaneously increases the production of inhibitory blomolecules and regulatory T-cells, which stop killer T-cells from overdoing their job. The same processes that activate the immune system thus control how far it can spread, shutting down the immune response before it causes too much collateral damage in the body, keeping radiation responses local.

At least three key pathways have been shown to limit the spread of anti-tumor immunity after radiation:

1. Regulatory T-cells increase in response to radiation. These “Tregs” can be recruited by tumors to help protect tumor cells from immune destruction.
2. Programmed Death-Ligand 1, or PD-L1. Tumor cells increase this protein on their cell membrane in response to radiation, a change that can be detected on circulating tumor cells during a course of radiation therapy. This makes them resistant to CD-8 T-cell killing.
3. IDO-1 is an enzyme that is upregulated in tumor surroundings in response to radiation, which paralyzes killer T-cells crossing into the area, like soldiers getting stuck in a moat.

All three of these mechanisms were shown to be at work by Dr. Elena Muraro and others following 3 daily doses of 10 Gray each in breast cancer patients with up to 6 metastases irradiated. In theory, if a patient takes immunotherapy drugs like ipilimumab, nivolumab, and epacadostat during radiation, it may help deplete the Tregs, overcome PD-L1, and block IDO, respectively, allowing a local immune response to broaden to other metastases. 

Chemotherapy has taught us that multiple drugs, usually 4 or more with independent mechanisms, are needed before cure rates exceed 90%, such as ABVD for Hodgkin’s lymphoma. Blocking one resistance pathway is seldom enough, just like blocking one road into a city won’t stop all traffic; traffic simply increases on all the other roads. There are many available routes of immunity to regulate, including checkpoints, cytokines, antibodies, and cells. It’s probably not until we get multi-drug combinations, added to radiation, that the distant abscopal effect becomes a regular thing. In the meantime, the “adscopal”, or local synergist effects of radiation plus PD-1 inhibitors, are also showing promise.

Why combine immunotherapy with targeted radiation therapy?

by Christian Hyde, MD

In the World War 2 movie, "Saving Private Ryan," a small town held by Allied foot soldiers is being over-run by Nazi tanks. At the crucial moment in the battle, when all hope seems lost, a friendly Allied airplane turns the tide by bombing an armored tank and rallying the exhausted defenders.

Dorsal Fins and Immune-Mediated Adverse Reactions

by Dr. Terence Rhodes

It is no small secret that I have galeophobia. It is a moderate case. It doesn’t keep me from the beach.  My top choice for vacation is the beach. Sun, slumber, sand, and the sound of the crashing waves is a recipe for relaxation. Venturing into the ocean water, however, is a concoction for anxiety. What lurks beneath the waves? 

The phobia of sharks likely comes from my over-consumption of news and media. From “Jaws” to the latest “Sharknado (Sharknado 5: Global Swarming),” sharks have terrorized movie characters and moviegoers alike for decades. 

SITC 2017 Scientific Highlights - Nov. 11

The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights from the Saturday programs (Nov. 11, 2017) of the 32nd Annual Meeting in National Harbor, Md. (Scroll to the bottom of this blog post to view the Glossary).

Dendritic cell acquisition of MHC I controls CD8+ T cell priming

Brandon MacNabb, BS (University of Chicago) presented data supporting the concept of MHC I antigen presentation by Batf3-lineage DCs as a critical component of CD8+-mediated anti-tumor response. Researchers initially generated H2-KbAB (MHC I+) and Kb-/-(MHC I-) C1498.SIY acute myeloid leukemia cell lines and subsequently engrafted C57BL/6 mice to determine the contribution of tumor cell MHC I presentation in CD8+ T cell priming. Initial assessment revealed reduced tumor growth in C1498.SIY KbAB mice compared to C1498.SIY Kb-/- mice. CD8+ T cell proliferation was also increased in KbAB mice compared to Kb-/- mice (p < 0.05). The observed C1498.SIY KbAB-dependent CD8+ proliferation was abolished in Batf3-/- C57BL/6 mice (p < 0.01). IFN-ϒ secretion was also decreased in Batf3-/- KbAB mice, suggesting that Batf3 initiates CD8+ priming. Transfer of autologous T cells from KbAB tumor-bearing mice offered complete protection from tumor growth in tumor-free mice. Conversely, autologous T cells from Kb-/- mice offered no such protection. Interestingly, DCs isolated from the TME and the tumor-draining lymph node in tumor-positive mice had increased KbAB MHC I expression (p < 0.001), suggesting DC acquisition of tumor-derived MHC I. Ex vivo experiments confirmed that migratory KbAB DCs are capable of CD8+ priming. These data reveal the importance of Batf3-lineage DCs and tumor-derived MHC I presentation in CD8+ T cell activation of anti-tumor response, providing insight into potential development of DC-oriented therapies. 

SITC 2017 Scientific Highlights - Nov. 10

The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights from the first day of the 32nd Annual Meeting in National Harbor, Md. (Scroll to the bottom of this blog post to view the Glossary)

Co-administration of novel anti-sMIC antibody increases anti-CTLA-4 therapeutic response in TRAMP/MIC mice (O22)

Jennifer Wu, PhD (Northwestern University, Chicago, IL) presented recently-published data investigating the efficacy of a novel antibody targeting the highly immunosuppressive human activation immune receptor natural killer group 2D (NKG2D) ligand, sMIC, with the goal of increasing anti-CTLA-4 therapeutic response. Using a TRAMP (transgenic adenocarcinoma of the mouse prostate)/MIC mouse model, Wu’s group found that mice with increased circulation of tumor-derived sMIC receiving anti-CTLA-4 had ~25% decrease in survival over 8 weeks compared to mice receiving placebo (p < 0.05), as well as an increased risk of immune-related colitis. TRAMP/MIC mice receiving anti-CTLA-4 in combination with anti-sMIC had reduced prostate tumor burden (~0.25g vs ~6g, respectively; p < 0.001), increased DC activation, enhanced TCR/CD3 signaling, and increased T cell clonality in tumor infiltrates compared to mice receiving anti-CTLA-4 alone (P < 0.05). CR was observed in 4/5 combination-treated mice for at least 120 days post-therapy, with no cases of immune-related colitis. These pre-clinical anti-sMIC/anti-CTLA-4 data align with clinical observations in patients with mCRPC, melanoma and multiple myeloma who have demonstrated improved responses to anti-CTLA-4 therapy if they develop sMIC autoantibodies during the course of treatment. These results suggest that sMIC may act as a predictive biomarker for anti-CTLA-4 response. Furthermore, including anti-sMIC antibodies in CTLA-4-targeted therapies may reduce irAES and increase treatment efficacy.