UCSF Helen Diller Family Comprehensive Cancer Center

Lawrence D. Kaplan, MD, clinical professor of medicine, director, Adult Lymphoma Program, Division of Hematology-Oncology, University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, discusses research with bispecific monoclonal antibodies in follicular lymphoma.

Bispecific monoclonal antibodies were a big focus of research at the 2019 ASH Annual Meeting, says Kaplan, most of which target CD3 and CD20. Not only were these agents active in aggressive B-cell lymphomas, but they appear to have significant response rates in indolent B-cell lymphomas as well, including in patients who recur after CAR T-cell therapy.

Many of these studies have limited follow-up. However, these agents are expected to be a lot easier to administer in the outpatient setting with somewhat less toxicity than CAR T-cell therapy, says Kaplan. As a result, these agents may become more widely available to the patient populations who need them, Kaplan concludes.

Videos

Lawrence D. Kaplan, MD, discusses research with bispecific monoclonal antibodies in follicular lymphoma.

Dr. Kaplan on Research With Bispecific Monoclonal Antibodies in Follicular Lymphoma

Hope S. Rugo, MD, a professor in the Department of Medicine, Hematology/Oncology, and director, Breast Oncology and Clinical Trials Education, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, discusses the results of the phase 3 KEYNOTE-522 trial in triple-negative breast cancer (TNBC).

The field is going to be directed by the results of the MK-3475-522/KEYNOTE-522 trial, which was recently published in the 

. In that study, patients with early-stage TNBC received neoadjuvant pembrolizumab (Keytruda) plus paclitaxel and carboplatin followed by doxorubicin or epirubicin and cyclophosphamide. Patients who were randomized to pembrolizumab or placebo continued the chosen agent for 6 months of adjuvant therapy, says Rugo.

Investigators enrolled 1,174 patients to the trial, which was powered to detect event-free survival (EFS). Investigators reported pathologic complete response (pCR) rates in more than 13% of the first 602 patients who enrolled in the trial, says Rugo.

At the 2019 San Antonio Breast Cancer Symposium, the investigators showed more than a 20% improvement in the pCR rate in patients who had node-positive disease. Also, patients benefitted even if they could not complete the full course of treatment.

EFS data are pending, says Rugo. These data are anticipated later this year but are contingent on the number of events that occur.

Hope S. Rugo, MD, discusses the results of the phase 3 KEYNOTE-522 trial in triple-negative breast cancer (TNBC).

Dr. Rugo on the Results of the KEYNOTE-522 Trial in TNBC

Hope S. Rugo, MD, a professor in the Department of Medicine, Hematology/Oncology, and director, Breast Oncology and Clinical Trials Education, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, discusses recent updates with immunotherapy in triple negative breast cancer (TNBC).

It is a really exciting time in breast cancer, says Rugo. Many advances have been made in the immuno-oncology space in a disease where no good treatment options have been available. The breast cancer field is finally seeing some progress made. The combination of atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) was FDA approved for use as a first-line therapy for patients with metastatic PD-L1—positive TNBC who are at least 1 year out from their adjuvant or neoadjuvant taxane. The approval was based on data from the phase 3 IMpassion130 trial. Many patients in that trial had de novo metastatic disease.

Results showed a significant improvement in progression-free survival (PFS), although modest, around 2 months, but a marked 7-month difference in overall survival in the 41% of patients who had PD-L1—positive disease using an antibody called SP142. These are very exciting data, because it is the first and only checkpoint inhibitor approved in the treatment of patients with TNBC, Rugo adds.

This trial demonstrated that some criteria need to occur in order to see checkpoint inhibitor efficacy in those with metastatic disease and also brings to light the issue of which chemotherapy partner should be used. A lot has been learned about toxicity and managing adverse events, as well as increased awareness of immune-related toxicities because breast cancer was relatively late to the field, concludes Rugo.

Hope S. Rugo, MD, discusses recent updates with immunotherapy in triple negative breast cancer.

Dr. Rugo on Recent Updates With Immunotherapy in TNBC

It is a really exciting time in breast cancer, says Rugo. Many advances have been made in the immuno-oncology space in a disease where no good treatment options have been available. The breast cancer field is finally seeing some progress made. The combination of atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) was FDA approved for use as a first-line therapy for patients with metastatic PD-L1–positive TNBC who are at least 1 year out from their adjuvant or neoadjuvant taxane. The approval was based on data from the phase 3 IMpassion130 trial. Many patients in that trial had de novo metastatic disease.


Results showed a significant improvement in progression-free survival (PFS), although modest, around 2 months, but a marked 7-month difference in overall survival in the 41% of patients who had PD-L1–positive disease using an antibody called SP142. These are very exciting data, because it is the first and only checkpoint inhibitor approved in the treatment of patients with TNBC, Rugo adds.

The addition of immunotherapy to the triple-negative breast cancer (TNBC) armamentarium has led to a paradigm shift and sparked an abundance of research with immuno-oncology (IO) drugs in new combinations and settings, explained Hope S. Rugo, MD.

"It is a really exciting time in breast cancer," said Rugo. "We've seen so many advances in the IO [arena] in a disease where we haven't had good treatment options."

For example, in March 2019, the FDA granted 

an accelerated approval to the combination of atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane)

 for the frontline treatment of patients with unresectable locally advanced or metastatic PD-L1—positive TNBC.

The approval is based on findings from the phase 3 IMpassion130 trial, in which the combination led to a 40% reduction in the risk of disease progression or death compared with nab-paclitaxel alone in this patient population.

Results of the initial progression-free survival (PFS) analysis in the PD-L1—positive population showed a clinically meaningful median PFS of 7.4 months versus 4.8 months with atezolizumab/nab-paclitaxel versus nab-paclitaxel alone, respectively (HR, 0.60; 95% CI, 0.48-0.77; 

Additionally, an interim analysis of the PD-L1—positive population indicated a clinically meaningful improvement in overall survival (OS) with the combination at 25.0 months versus nab-paclitaxel alone at 15.5 months, respectively (HR, 0.62; 95% CI, 0.45-0.86). At 2 years, the OS rates in the intent-to-treat population were 42% and 39%, respectively.

Notably, the 2-year OS rates were higher in the PD-L1—expressing population at 51% in the atezolizumab arm versus 37% in the chemotherapy-alone arm.

Since the approval, AKT inhibitors and PARP inhibitors have entered the pipeline as potential combination partners with immunotherapy in the metastatic setting. Moreover, immunotherapy is being evaluated in the neoadjuvant setting as a potential way to accelerate a more robust immune response, explained Rugo.

, Rugo, professor in the Department of Medicine and director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, discussed the research that was born from the results of the IMpassion130 trial and the future of immunotherapy in TNBC.

: How did the results of the IMpassion130 trial impact the paradigm?

: The combination of atezolizumab plus nab-paclitaxel was approved as first-line therapy for patients with metastatic PD-L1—positive TNBC who are at least 1 year out from their adjuvant or neoadjuvant taxane. The approval was [based on the IMpassion130 trial results]. Many patients [in that trial] had de novo metastatic disease.

IMpassion130 showed a significant, though modest, improvement in PFS, but a marked difference in OS. For the 41% of patients who have PD-L1—positive disease, this is very exciting.

What are some remaining questions regarding the use of immunotherapy in TNBC?

We learned from IMpassion130 that checkpoint inhibitors, like what we have seen with trastuzumab (Herceptin) and pertuzumab (Perjeta), can have a greater impact on OS than on PFS, which suggests that we are changing the immune milieu microenvironment. It is a fascinating area of study and something that we have not seen before, except for with these antibodies.

From IMpassion130, we learned that there are clearly some criteria that need to be met in order for a patient with metastatic disease to respond to a checkpoint inhibitor. The issue of what chemotherapy partner to use is also an issue.

We also learned to be more alert in managing immune-based toxicities. Breast cancer was relatively late to the field [of immunotherapy. [Since the approval, we’ve learned that it’s important to] understand symptoms beyond mouth sores and diarrhea, such as adrenal insufficiency.

We are interested in whether or not checkpoint inhibitors combined with different chemotherapy partners will work for patients who relapse in a 6- to 12-month time period. A number of trials are looking at atezolizumab with paclitaxel partners, so you would not have to give nab-paclitaxel. There are also trials looking at atezolizumab and pembrolizumab (Keytruda) in patients who relapse earlier.

We saw a press release regarding the phase 3 MK-3475-355/KEYNOTE-355 trial, which evaluated pembrolizumab with gemcitabine and carboplatin, or paclitaxel and nab-paclitaxel. Many of those patients relapsed between 6 and 12 months. It was noted in the press release that investigators met their primary PFS endpoint, but in a subpopulation of patients who had a combined positive score of at least 10. That PD-L1 test is generally positive in about 80% of tumors. We are awaiting OS data from that trial.

What does the future of immunotherapy look like in breast cancer?

The field is going to be directed by the results of the phase 3 MK-3475-522/KEYNOTE-522 trial, which was recently published in the 

. In that study, pembrolizumab was given in the neoadjuvant setting, along with a chemotherapy backbone, that included paclitaxel and carboplatin followed by doxorubicin or epirubicin and cyclophosphamide. Patients randomized to pembrolizumab or placebo continued the chosen agent for 6 months after surgery.

The investigators enrolled almost 1200 patients in that trial, which was powered to detect event-free survival (EFS) as an end point. They reported pathologic complete response (pCR) rates in more than 13% of the first 602 patients who enrolled in the trial.

At the 2019 San Antonio Breast Cancer Symposium, the investigators showed that there was more than a 20% improvement in the pCR rate in patients who had node-positive disease. Also, patients benefitted even if they could not complete the [full course] of treatment. These are striking data.

We are waiting for EFS data. We hope to get that later this year, but it is hard to know as it is all event driven. The median follow-up was only 15.5 months at the first presentation at the 2019 ESMO Congress. They may need 2 to 3 years to get enough events.

Could you shed light on ongoing research with immunotherapy?

We are interested in trying to make "cold" tumors "hot". Essentially, that means getting tumors to be more immuno-reactive, so the body can react to them. You need several factors [to do this]. The tumor needs to look foreign. It cannot have many other features that it overcomes any attempt of the immune system [to activate itself]. Tumors should not be heavily pretreated because they would likely have multiple mechanisms of resistance. Then, you want to have an effective immune system. The host can't be so immunocompromised that they cannot respond. Of course, the cancer also needs to be responsive to chemotherapy.

There are trials currently looking at combining treatment with an AKT inhibitor that have shown interesting data. One single-arm study will randomize patients to ipatasertib and a taxane with or without atezolizumab.

There are other trials looking at the AKT inhibitors, ipatasertib and capivasertib, [in combination] with checkpoint inhibitors in patients with TNBC who have alterations in the PI3K pathway.

Combinations with PARP inhibitors are also of great interest. The phase 2/3 MK-7339-009/KEYLYNK-009 trial will [randomize patients to] gemcitabine/carboplatin and pembrolizumab induction, followed by continued chemotherapy and pembrolizumab or pembrolizumab and olaparib (Lynparza) maintenance. [The trial will enroll] patients with TNBC regardless of homologous recombination defects or 

 mutation status. We will see if we can stimulate the immune system in the maintenance phase to prolong disease control.

We also have vaccine trials and radiation trials looking at different ways to improve immune response. The space is evolving. We have a space for immunotherapy, but it is a small number of patients. We are looking to move these agents earlier in the course of therapy to cure more patients with this disease.

Schmid P, Adams S, Rugo HS, et al. IMpassion130: updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, phase III study of atezolizumab (atezo) + nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC). 

 2019;37(suppl 15; abstr 1003). doi:10.1200/JCO.2019.37.15_suppl.1003

Articles

Hope S. Rugo, MD, discusses the research that was born from the results of the IMpassion130 trial and the future of immunotherapy in triple-negative breast cancer.

Rugo Relays the State of Immunotherapy in TNBC

The addition of immunotherapy to the triple-negative breast cancer (TNBC) armamentarium has led to a paradigm shift and sparked an abundance of research with immuno-oncology (IO) drugs in new combinations and settings, explained Hope S. Rugo, MD.

"It is a really exciting time in breast cancer," said Rugo. "We've seen so many advances in the IO [arena] in a disease where we haven't had good treatment options."

For example, in March 2019, the FDA granted 

 for the frontline treatment of patients with unresectable locally advanced or metastatic PD-L1–positive TNBC.

The approval is based on findings from the phase 3 IMpassion130 trial, in which the combination led to a 40% reduction in the risk of disease progression or death compared with nab-paclitaxel alone in this patient population.

Results of the initial progression-free survival (PFS) analysis in the PD-L1–positive population showed a clinically meaningful median PFS of 7.4 months versus 4.8 months with atezolizumab/nab-paclitaxel versus nab-paclitaxel alone, respectively (HR, 0.60; 95% CI, 0.48-0.77; 

 <.0001).

Additionally, an interim analysis of the PD-L1–positive population indicated a clinically meaningful improvement in overall survival (OS) with the combination at 25.0 months versus nab-paclitaxel alone at 15.5 months, respectively (HR, 0.62; 95% CI, 0.45-0.86). At 2 years, the OS rates in the intent-to-treat population were 42% and 39%, respectively.

Notably, the 2-year OS rates were higher in the PD-L1–expressing population at 51% in the atezolizumab arm versus 37% in the chemotherapy-alone arm.

Since the approval, AKT inhibitors and PARP inhibitors have entered the pipeline as potential combination partners with immunotherapy in the metastatic setting. Moreover, immunotherapy is being evaluated in the neoadjuvant setting as a potential way to accelerate a more robust immune response, explained Rugo.

In an interview with 

, Rugo, professor in the Department of Medicine and director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, discussed the research that was born from the results of the IMpassion130 trial and the future of immunotherapy in TNBC.



: The combination of atezolizumab plus nab-paclitaxel was approved as first-line therapy for patients with metastatic PD-L1–positive TNBC who are at least 1 year out from their adjuvant or neoadjuvant taxane. The approval was [based on the IMpassion130 trial results]. Many patients [in that trial] had de novo metastatic disease.

IMpassion130 showed a significant, though modest, improvement in PFS, but a marked difference in OS. For the 41% of patients who have PD-L1–positive disease, this is very exciting.





We learned from IMpassion130 that checkpoint inhibitors, like what we have seen with trastuzumab (Herceptin) and pertuzumab (Perjeta), can have a greater impact on OS than on PFS, which suggests that we are changing the immune milieu microenvironment. It is a fascinating area of study and something that we have not seen before, except for with these antibodies.

From IMpassion130, we learned that there are clearly some criteria that need to be met in order for a patient with metastatic disease to respond to a checkpoint inhibitor. The issue of what chemotherapy partner to use is also an issue.

We also learned to be more alert in managing immune-based toxicities. Breast cancer was relatively late to the field [of immunotherapy. [Since the approval, we’ve learned that it’s important to] understand symptoms beyond mouth sores and diarrhea, such as adrenal insufficiency.

We are interested in whether or not checkpoint inhibitors combined with different chemotherapy partners will work for patients who relapse in a 6- to 12-month time period. A number of trials are looking at atezolizumab with paclitaxel partners, so you would not have to give nab-paclitaxel. There are also trials looking at atezolizumab and pembrolizumab (Keytruda) in patients who relapse earlier.

We saw a press release regarding the phase 3 MK-3475-355/KEYNOTE-355 trial, which evaluated pembrolizumab with gemcitabine and carboplatin, or paclitaxel and nab-paclitaxel. Many of those patients relapsed between 6 and 12 months. It was noted in the press release that investigators met their primary PFS endpoint, but in a subpopulation of patients who had a combined positive score of at least 10. That PD-L1 test is generally positive in about 80% of tumors. We are awaiting OS data from that trial.





The field is going to be directed by the results of the phase 3 MK-3475-522/KEYNOTE-522 trial, which was recently published in the 

. In that study, pembrolizumab was given in the neoadjuvant setting, along with a chemotherapy backbone, that included paclitaxel and carboplatin followed by doxorubicin or epirubicin and cyclophosphamide. Patients randomized to pembrolizumab or placebo continued the chosen agent for 6 months after surgery.

The investigators enrolled almost 1200 patients in that trial, which was powered to detect event-free survival (EFS) as an end point. They reported pathologic complete response (pCR) rates in more than 13% of the first 602 patients who enrolled in the trial.

At the 2019 San Antonio Breast Cancer Symposium, the investigators showed that there was more than a 20% improvement in the pCR rate in patients who had node-positive disease. Also, patients benefitted even if they could not complete the [full course] of treatment. These are striking data.

We are waiting for EFS data. We hope to get that later this year, but it is hard to know as it is all event driven. The median follow-up was only 15.5 months at the first presentation at the 2019 ESMO Congress. They may need 2 to 3 years to get enough events.





We are interested in trying to make "cold" tumors "hot". Essentially, that means getting tumors to be more immuno-reactive, so the body can react to them. You need several factors [to do this]. The tumor needs to look foreign. It cannot have many other features that it overcomes any attempt of the immune system [to activate itself]. Tumors should not be heavily pretreated because they would likely have multiple mechanisms of resistance. Then, you want to have an effective immune system. The host can't be so immunocompromised that they cannot respond. Of course, the cancer also needs to be responsive to chemotherapy.

There are trials currently looking at combining treatment with an AKT inhibitor that have shown interesting data. One single-arm study will randomize patients to ipatasertib and a taxane with or without atezolizumab.

There are other trials looking at the AKT inhibitors, ipatasertib and capivasertib, [in combination] with checkpoint inhibitors in patients with TNBC who have alterations in the PI3K pathway.

Combinations with PARP inhibitors are also of great interest. The phase 2/3 MK-7339-009/KEYLYNK-009 trial will [randomize patients to] gemcitabine/carboplatin and pembrolizumab induction, followed by continued chemotherapy and pembrolizumab or pembrolizumab and olaparib (Lynparza) maintenance. [The trial will enroll] patients with TNBC regardless of homologous recombination defects or 

 mutation status. We will see if we can stimulate the immune system in the maintenance phase to prolong disease control.

We also have vaccine trials and radiation trials looking at different ways to improve immune response. The space is evolving. We have a space for immunotherapy, but it is a small number of patients. We are looking to move these agents earlier in the course of therapy to cure more patients with this disease.

Hope S. Rugo, MD, a professor in the Department of Medicine, Hematology/Oncology, and director, Breast Oncology and Clinical Trials Education, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, discusses takeaways from the phase 3 IMpassion130 trial in metastatic triple-negative breast cancer (TNBC).

On March 8, 2019, the FDA granted an accelerated approval to the combination of atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) for the frontline treatment of patients with unresectable locally advanced or metastatic PD-L1—positive TNBC. The approval is based on findings from the phase 3 IMpassion130 trial, in which the combination led to a 40% reduction in the risk of disease progression or death compared with nab-paclitaxel alone in this patient population.

The trial revealed that not all patients with metastatic TNBC will respond to a checkpoint inhibitor, says Rugo. Additionally, determining the optimal chemotherapy partner to use with atezolizumab requires additional research.

IMpassion130 also highlighted that understanding how to best manage immune-related toxicities such as adrenal insufficiency is critical in TNBC, explains Rugo.

The role of checkpoint inhibitors in combination with other chemotherapy backbones is being investigated in patients with metastatic TNBC who relapse within a 6- to 12-month time period, says Rugo. Additional clinical trials are looking at atezolizumab and pembrolizumab (Keytruda) for patients who have an early relapse.

Hope S. Rugo, MD, discusses takeaways from the phase 3 IMpassion130 trial in metastatic triple-negative breast cancer.

Dr. Rugo on Takeaways From the IMpassion130 Trial in TNBC

On March 8, 2019, the FDA granted an accelerated approval to the combination of atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) for the frontline treatment of patients with unresectable locally advanced or metastatic PD-L1–positive TNBC. The approval is based on findings from the phase 3 IMpassion130 trial, in which the combination led to a 40% reduction in the risk of disease progression or death compared with nab-paclitaxel alone in this patient population.

Combining the PD-1 inhibitor pembrolizumab (Keytruda) with intratumoral plasmid interkeukin-12 (IL-12; tavokinogene telseplasmid; Tavo) electroporation elicited clinical responses in patients with immunologically quiescent advanced melanoma, according to results of a single-arm, phase 2 study (NCT02493361) published in 

Notably, the combination demonstrated a 41% objective response rate (n = 22; RECIST 1.1), which included a 36% complete response (CR) rate.

At a median follow-up of 20.1 months, the median progression-free survival was 5.6 months, and the median overall survival was not reached.

“Combining pembrolizumab with Tavo electroporation improved responses for these patients who were predicted to have very poor responses to single-agent immune checkpoint inhibition,” said corresponding study author Adil Daud, MD, director of Melanoma Clinical Research at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.

 “By using electroporation to deliver Tavo locally, we were able to avoid many of the toxicities associated with systemic IL-12 administration, while still attaining clinical responses and inducing immune-cell infiltration in treated and untreated melanoma lesions.”

Forty-one patients were screened for trial enrollment, all of whom were 18 years of age or older and had metastatic or unresectable melanoma with accessible lesions. Eligible patients had a CD8+ checkpoint positive cytotoxic lymphocytes percentage of less than 25%, according to baseline tumor biopsy results (n = 23). All but 1 of these patients had RECIST measurable disease at baseline.

Ten patients had prior exposure to PD-L1 inhibitors and 7 had prior exposure to CTLA-4 inhibitors. Patients on current immunosuppressive therapies, or those with uveal melanoma, active central nervous systemic metastases, carcinomatous meningitis, or active autoimmune disease requiring immunosuppressive agents were not included in the trial.

Tavo was given via injection at a dose of one-quarter of the patient’s tumor volume and a concentration of 0.5 mg/mL. The injection was followed by in vivo electroporation of 6 pulses at 1500 V/cm field strength and a pulse width of 100 µs at 300-millisecond intervals; moreover, at least 0.1 mL of Tavo was injected for every lesion less than 0.1 cm

. Pembrolizumab was given intravenously at a flat dose of 200 mg.

Notably, Tavo was delivered via electroporation directly into the melanoma lesions to avoid the toxicities of conventional systemic IL-12 administration.

Additionally, Tavo and pembrolizumab were given concurrently on day 1. Pembrolizumab was continued on day 1 of each 3-week cycle, and Tavo was continued on days 1, 5, and 8 of every other cycle.

The regimen was continued for up to 2 years if patients had stable disease or better. Patients were allowed to continue on treatment until disease progression was confirmed.

The tumor specimens that were evaluated had a low likelihood of response to PD-L1 inhibition based on predictive PD-L1 immunohistochemistry (IHC) biomarker assays that tested the 22C3 monoclonal antibody and IFNγ gene expression signatures.

“Immune checkpoint inhibition has become a common first-line treatment for melanoma in recent years,” said Daud. “However, approximately 40% of melanomas are considered to be ‘cold,’ meaning that they lack sufficient infiltration of immune cells within the tumor and therefore have poor responses to this therapy. The big question in the field is how to turn these ‘cold’ melanomas into ‘hot’ ones that will respond to immune checkpoint inhibition.”

A proportion of the patients who achieved an objective response had elevated lactate dehydrogenase at baseline, prior anti—PD-L1 exposure, or stage IIIb to IVc disease. Additionally, clinical responses were observed regardless of tumor-infiltrating lymphocyte (TIL) levels or IHC-measured PD-L1 protein levels at baseline.

One patient who had greater than 50 in-transit lesions at baseline and progressed on 3 prior checkpoint inhibitors achieved a partial response prior to developing progressive disease on the combination. A posttreatment biopsy revealed that the patient’s lesions showed a siderotic scar, with no evidence of residual melanoma by histopathology.

Further results revealed that 29.2% of untreated metastatic lesions, including those in the liver and lungs, decreased by more than 30% in width.

Additionally, natural killer T cells, T-cell trafficking and costimulation, cDC1-associated antigen presentation genes, antigen cross-presentation, T-cell activation and adaptive resistance-associated genes were increased with the combination.

A correlative analysis revealed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T-cell receptor clones, and systemic cellular immune responses.

Regarding safety, the combination was well tolerated. Grade 3 or higher treatment-related adverse events (AEs) were limited to pain (n = 1), cellulitis (n = 1), chills (n = 1), and sweats (n = 1).

“While our results are promising, a key limitation to this approach is that approximately 60% of patients still did not respond,” said Daud.

Despite this, studies are underway to further understand how to increase responses. A phase 2 study (NCT03132675) with pembrolizumab combined with Tavo is ongoing in patients who progressed on prior checkpoint inhibition.

Algazi AP, Twitty CG, Tsai KK, et al. Phase II trial of IL-12 plasmid transfection and PD-1 blockade in immunologically quiescent melanoma. [published online ahead of print May 6, 2020] 

. doi:10.1158/1078-0432.CCR-19-2217           

Interleukin-12 Electroporation May Sensitize Immunologically “Cold” Melanomas to Immune Checkpoint Inhibition [press release]. Philadelphia, PA: American Association for Cancer Research. May 6, 2020. Accessed May 11, 2020. bit.ly/2ztRepB.

Combining the PD-1 inhibitor pembrolizumab with intratumoral plasmid interkeukin-12 electroporation elicited clinical responses in patients with immunologically quiescent advanced melanoma.

Novel Combo Elicits Clinical Responses in Patients With "Cold" Melanomas



Notably, the combination demonstrated a 41% objective response rate (n = 22; RECIST 1.1), which included a 36% complete response (CR) rate.

At a median follow-up of 20.1 months, the median progression-free survival was 5.6 months, and the median overall survival was not reached.

“Combining pembrolizumab with Tavo electroporation improved responses for these patients who were predicted to have very poor responses to single-agent immune checkpoint inhibition,” said corresponding study author Adil Daud, MD, director of Melanoma Clinical Research at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.

 “By using electroporation to deliver Tavo locally, we were able to avoid many of the toxicities associated with systemic IL-12 administration, while still attaining clinical responses and inducing immune-cell infiltration in treated and untreated melanoma lesions.”

Forty-one patients were screened for trial enrollment, all of whom were 18 years of age or older and had metastatic or unresectable melanoma with accessible lesions. Eligible patients had a CD8+ checkpoint positive cytotoxic lymphocytes percentage of less than 25%, according to baseline tumor biopsy results (n = 23). All but 1 of these patients had RECIST measurable disease at baseline.

Ten patients had prior exposure to PD-L1 inhibitors and 7 had prior exposure to CTLA-4 inhibitors. Patients on current immunosuppressive therapies, or those with uveal melanoma, active central nervous systemic metastases, carcinomatous meningitis, or active autoimmune disease requiring immunosuppressive agents were not included in the trial.

Tavo was given via injection at a dose of one-quarter of the patient’s tumor volume and a concentration of 0.5 mg/mL. The injection was followed by in vivo electroporation of 6 pulses at 1500 V/cm field strength and a pulse width of 100 µs at 300-millisecond intervals; moreover, at least 0.1 mL of Tavo was injected for every lesion less than 0.1 cm

. Pembrolizumab was given intravenously at a flat dose of 200 mg.

Notably, Tavo was delivered via electroporation directly into the melanoma lesions to avoid the toxicities of conventional systemic IL-12 administration.

Additionally, Tavo and pembrolizumab were given concurrently on day 1. Pembrolizumab was continued on day 1 of each 3-week cycle, and Tavo was continued on days 1, 5, and 8 of every other cycle.

The regimen was continued for up to 2 years if patients had stable disease or better. Patients were allowed to continue on treatment until disease progression was confirmed.

The tumor specimens that were evaluated had a low likelihood of response to PD-L1 inhibition based on predictive PD-L1 immunohistochemistry (IHC) biomarker assays that tested the 22C3 monoclonal antibody and IFNγ gene expression signatures.

“Immune checkpoint inhibition has become a common first-line treatment for melanoma in recent years,” said Daud. “However, approximately 40% of melanomas are considered to be ‘cold,’ meaning that they lack sufficient infiltration of immune cells within the tumor and therefore have poor responses to this therapy. The big question in the field is how to turn these ‘cold’ melanomas into ‘hot’ ones that will respond to immune checkpoint inhibition.”

A proportion of the patients who achieved an objective response had elevated lactate dehydrogenase at baseline, prior anti–PD-L1 exposure, or stage IIIb to IVc disease. Additionally, clinical responses were observed regardless of tumor-infiltrating lymphocyte (TIL) levels or IHC-measured PD-L1 protein levels at baseline.

One patient who had greater than 50 in-transit lesions at baseline and progressed on 3 prior checkpoint inhibitors achieved a partial response prior to developing progressive disease on the combination. A posttreatment biopsy revealed that the patient’s lesions showed a siderotic scar, with no evidence of residual melanoma by histopathology.

Further results revealed that 29.2% of untreated metastatic lesions, including those in the liver and lungs, decreased by more than 30% in width.

Additionally, natural killer T cells, T-cell trafficking and costimulation, cDC1-associated antigen presentation genes, antigen cross-presentation, T-cell activation and adaptive resistance-associated genes were increased with the combination.

A correlative analysis revealed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T-cell receptor clones, and systemic cellular immune responses.

Regarding safety, the combination was well tolerated. Grade 3 or higher treatment-related adverse events (AEs) were limited to pain (n = 1), cellulitis (n = 1), chills (n = 1), and sweats (n = 1).

“While our results are promising, a key limitation to this approach is that approximately 60% of patients still did not respond,” said Daud.

Despite this, studies are underway to further understand how to increase responses. A phase 2 study (NCT03132675) with pembrolizumab combined with Tavo is ongoing in patients who progressed on prior checkpoint inhibition.