Molecular Oncology

Precision immunotherapy: Giving the right drug to the right patient at the right time

James P. Allison, PhD, of the United States, and Tasuku Honjo, MD, PhD, of Japan, received the 2018 Nobel Prize in Physiology or Medicine for their work on immunotherapy of cancer.

The arrival of immune checkpoint inhibitors — specifically antibodies that target program death-1 (PD-1), program death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) — has transformed the landscape of cancer care.

Immune checkpoint inhibitors targeting PD-1, PD-L1 and CTLA-4 — including nivolumab (Opdivo, Bristol-Myers Squibb), pembrolizumab (Keytruda, Merck), avelumab (Bavencio; EMD Serono, Pfizer), atezolizumab (Tecentriq, Genentech), durvalumab (Imfinzi, AstraZeneca), cemiplimab (Libtayo, Regeneron) and ipilimumab (Yervoy, Bristol-Myers Squibb) — are FDA approved for the treatment of multiple cancers. These include melanoma, non-small cell lung cancer, Hodgkin lymphoma, renal cell carcinoma, gastric cancer, urothelial cancer, Merkel cell carcinoma, cutaneous squamous carcinoma and hepatocellular cancer, as well as microsatellite instability-high (MSI-H) tumors regardless of tumor type.

Vivek Subbiah, MD
Vivek Subbiah
Razelle Kurzrock, MD
Razelle Kurzrock

Despite high response rates in a few of the above tumors, the response rates in malignancies overall, as well as in some of the approved indications, have not been over 20%. Addition of novel checkpoint inhibitors targeting IDO, ICOS, TIM-3 and LAG-3 also has not yet been successful.

More recently, better results have been achieved with a combination of ipilimumab and nivolumab in metastatic melanoma, with response rates as high as 85% among patients with high PD-L1 expression, but at the cost of substantial immune-related toxicity.

Companion diagnostics in the form of PD-L1 staining have been of variable utility. We need better biomarkers to predict clinical response to these agents. This is of paramount importance not only for the drugs currently in clinical use, but also for new immunotherapies in development, both as single agents and in combination.

Immune checkpoint inhibitors

The immune system is regulated by a series of inhibitory and stimulatory receptors and ligands, including CTLA-4 and PD-1.

Tumor cells survive because they evade immune surveillance and destruction by suppressing the immune system, using molecules such as PD-L1 as checkpoints.

Anti-PD-1/PD-L1/CTLA-4 drugs can reverse this inhibition. Reactivating the immune system is critical, but that is not enough for a response to occur. The immune system must then differentiate the cancer cells from normal cells, which is enabled by immune recognition of neoantigens produced as a result of the mutanome.

Neoantigens vary in their immunogenicity. The higher the number of neoantigens, the greater the chances that some will elicit an immune response, ultimately resulting in eradication of the cells presenting those neoantigens.

Predicting response and resistance

Oncogenomics can augment immune profiling and help predict response and/or resistance to immunotherapy.

Mismatch repair gene defects leading to MSI-H, PD-L1 amplification and high tumor mutational burden (TMB) are the best-studied for response. Also, MDM2 amplification and EGFR alterations have been suggested as genomic markers for resistance and prediction of hyperprogression.

PD-L1 staining: PD-L1 staining using immunohistochemistry (IHC) is the first clinically approved biomarker for immunotherapy.

Across cancers, depending on the study, response rates range from 0% to 17% in PD-L1-negative cancers, and from 36% to 100% in PD-L1-positive cancers.

But, the PD-L1 IHC biomarker is far from perfect. For instance, patients with Kaposi sarcoma have high response rates to anti-PD-1 agents despite negative PD-L1 staining.

Standardization of PD-L1 positivity remains an issue, given discrepancies among the results attained with different staining antibodies. Hence, other markers for response and resistance are needed.

Microsatellite instability: Patients with mismatch repair deficiency lack the ability to detect and correct mistakes made by DNA polymerase in certain repetitive sequences of DNA called microsatellites. Genes usually aberrant include MLH1, PMS2, MSH2 and MSH6. The mismatch repair gene defects result in MSI-H, which is in turn associated with a high TMB. The numerous “frame-shifted” peptides (neoantigens) that emerge elicit an immune response.

The FDA approval of pembrolizumab for all tumors in children and adults with MSI-H cancer is a landmark event and epitomizes the marriage between precision oncology and immunotherapy.

Tumor mutational burden: TMB has emerged as a promising new predictive tool in patient selection for immunotherapy. The higher the TMB, the greater the chance of response to immune checkpoint blockade.

However, again, exceptions are seen. Kaposi sarcoma has a low TMB and responds well to checkpoint blockade. Most MSI-H tumors have a high TMB, but only a fraction of high TMB tumors are MSI-H. Even so, responses are seen in over 50% of high TMB tumors that are not MSI-H.

Thresholds for defining high TMB vary between assays and will need harmonization.

Further, the reason why some high TMB tumors do not respond and some low TMB tumors do respond remains unclear. The simplest explanation may be that, the more mutations, the higher the chance that one of those mutations will produce an immunogenic neopeptide, recognizable by the immune system that has been reactivated after checkpoint blockade.

PD-L1 gene amplification: PD-L1 amplification — due to amplification of locus 9p24.1, which contains PD-L1 and PD-L2 — is highly associated with Hodgkin disease, which demonstrates response rates to immune checkpoint blockade upward of 75% among heavily pretreated patients. PD-L1 amplification, as determined by next-generation sequencing, also is associated with high response rates in refractory solid tumors.

Hyperprogression: Reports have surfaced demonstrating that immunotherapy may not only be ineffective but, in some cases, may remarkably accelerate growth of the disease.

Genomic markers associated with elevated risk for hyperprogression include MDM2 amplification and EGFR alterations. More work is needed to validate these and other markers and to understand the underlying mechanisms.

Combination treatments

An important trend in clinical research has been the combination of anti-PD-1/PD-L1 agents with other available cancer treatments, including chemotherapy, gene-targeted agents and other immunotherapies.

Remarkably, although there are hundreds of trials using these combinations, very few have included biomarkers that might help determine which patients are more likely to respond.

Giving the right drug(s) to the right patient at the right time, however, demands that biomarkers be explored and validated to optimize combination treatment regimens.

References:

Galanina N, et al. Cancer Immunol Res. 2018;doi:10.1158/2326-6066.CIR-18-0121.

Goodman AM, et al. Mol Cancer Ther. 2017;doi:10.1158/1535-7163.MCT-17-0386.

Goodman AM, et al. JAMA Oncol. 2018;doi:10.1001/jamaoncol.2018.1701.

Kato S, et al. Clin Cancer Res. 2017;doi:10.1158/1078-0432.CCR-17-1990.

Patel SP, et al. Mol Cancer Ther. 2018;doi:10.1158/1535-7163.MCT-14-0983.

Subbiah V, et al. Oncologist. 2018;doi:10.1634/theoncologist.2017-0519.

For more information:

Razelle Kurzrock, MD, is chief of the division of hematology and oncology and director of Center for Personalized Cancer Therapy at Moores Cancer Center at University of California, San Diego. She can be reached at rkurzrock@ucsd.edu.

Vivek Subbiah, MD, is associate professor and center medical director of Clinical Center of Targeted Therapy in the department of investigational cancer therapeutics in the division of cancer medicine at The University of Texas MD Anderson Cancer Center. He can be reached at vsubbiah@mdanderson.org.

To contribute to this column or suggest topics, email Wafik S. El-Deiry, MD, PhD, FACP, at wafik.eldeiry@gmail.com.

Disclosures: Kurzrock reports research funding from Foundation Medicine Inc., Genentech, Grifols, Guardant Health, Incyte, Konica Minolta, Merck Serono, OmniSeq, Pfizer and Sequenom Laboratories, as well as consultant fees from Actuate Therapeutics, Genentech, Loxo, NeoMed and XBiotech. She also reports speaker fees from Roche, and has equity interest in CureMatch Inc. and IDbyDNA. Subbiah reports research funding for clinical trials from AbbVie, Amgen, Bayer, Berg Health, Blueprint Medicines, D3 Pharma, Fujifilm, GlaxoSmithKline, Incyte, Loxo Oncology, MultiVir, NanoCarrier, Northwest Biotherapeutics, Novartis, Pfizer, PharmaMar, Roche/Genentech and Vegenics.

James P. Allison, PhD, of the United States, and Tasuku Honjo, MD, PhD, of Japan, received the 2018 Nobel Prize in Physiology or Medicine for their work on immunotherapy of cancer.

The arrival of immune checkpoint inhibitors — specifically antibodies that target program death-1 (PD-1), program death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) — has transformed the landscape of cancer care.

Immune checkpoint inhibitors targeting PD-1, PD-L1 and CTLA-4 — including nivolumab (Opdivo, Bristol-Myers Squibb), pembrolizumab (Keytruda, Merck), avelumab (Bavencio; EMD Serono, Pfizer), atezolizumab (Tecentriq, Genentech), durvalumab (Imfinzi, AstraZeneca), cemiplimab (Libtayo, Regeneron) and ipilimumab (Yervoy, Bristol-Myers Squibb) — are FDA approved for the treatment of multiple cancers. These include melanoma, non-small cell lung cancer, Hodgkin lymphoma, renal cell carcinoma, gastric cancer, urothelial cancer, Merkel cell carcinoma, cutaneous squamous carcinoma and hepatocellular cancer, as well as microsatellite instability-high (MSI-H) tumors regardless of tumor type.

Vivek Subbiah, MD
Vivek Subbiah
Razelle Kurzrock, MD
Razelle Kurzrock

Despite high response rates in a few of the above tumors, the response rates in malignancies overall, as well as in some of the approved indications, have not been over 20%. Addition of novel checkpoint inhibitors targeting IDO, ICOS, TIM-3 and LAG-3 also has not yet been successful.

More recently, better results have been achieved with a combination of ipilimumab and nivolumab in metastatic melanoma, with response rates as high as 85% among patients with high PD-L1 expression, but at the cost of substantial immune-related toxicity.

Companion diagnostics in the form of PD-L1 staining have been of variable utility. We need better biomarkers to predict clinical response to these agents. This is of paramount importance not only for the drugs currently in clinical use, but also for new immunotherapies in development, both as single agents and in combination.

Immune checkpoint inhibitors

The immune system is regulated by a series of inhibitory and stimulatory receptors and ligands, including CTLA-4 and PD-1.

Tumor cells survive because they evade immune surveillance and destruction by suppressing the immune system, using molecules such as PD-L1 as checkpoints.

Anti-PD-1/PD-L1/CTLA-4 drugs can reverse this inhibition. Reactivating the immune system is critical, but that is not enough for a response to occur. The immune system must then differentiate the cancer cells from normal cells, which is enabled by immune recognition of neoantigens produced as a result of the mutanome.

Neoantigens vary in their immunogenicity. The higher the number of neoantigens, the greater the chances that some will elicit an immune response, ultimately resulting in eradication of the cells presenting those neoantigens.

PAGE BREAK

Predicting response and resistance

Oncogenomics can augment immune profiling and help predict response and/or resistance to immunotherapy.

Mismatch repair gene defects leading to MSI-H, PD-L1 amplification and high tumor mutational burden (TMB) are the best-studied for response. Also, MDM2 amplification and EGFR alterations have been suggested as genomic markers for resistance and prediction of hyperprogression.

PD-L1 staining: PD-L1 staining using immunohistochemistry (IHC) is the first clinically approved biomarker for immunotherapy.

Across cancers, depending on the study, response rates range from 0% to 17% in PD-L1-negative cancers, and from 36% to 100% in PD-L1-positive cancers.

But, the PD-L1 IHC biomarker is far from perfect. For instance, patients with Kaposi sarcoma have high response rates to anti-PD-1 agents despite negative PD-L1 staining.

Standardization of PD-L1 positivity remains an issue, given discrepancies among the results attained with different staining antibodies. Hence, other markers for response and resistance are needed.

Microsatellite instability: Patients with mismatch repair deficiency lack the ability to detect and correct mistakes made by DNA polymerase in certain repetitive sequences of DNA called microsatellites. Genes usually aberrant include MLH1, PMS2, MSH2 and MSH6. The mismatch repair gene defects result in MSI-H, which is in turn associated with a high TMB. The numerous “frame-shifted” peptides (neoantigens) that emerge elicit an immune response.

The FDA approval of pembrolizumab for all tumors in children and adults with MSI-H cancer is a landmark event and epitomizes the marriage between precision oncology and immunotherapy.

Tumor mutational burden: TMB has emerged as a promising new predictive tool in patient selection for immunotherapy. The higher the TMB, the greater the chance of response to immune checkpoint blockade.

However, again, exceptions are seen. Kaposi sarcoma has a low TMB and responds well to checkpoint blockade. Most MSI-H tumors have a high TMB, but only a fraction of high TMB tumors are MSI-H. Even so, responses are seen in over 50% of high TMB tumors that are not MSI-H.

Thresholds for defining high TMB vary between assays and will need harmonization.

Further, the reason why some high TMB tumors do not respond and some low TMB tumors do respond remains unclear. The simplest explanation may be that, the more mutations, the higher the chance that one of those mutations will produce an immunogenic neopeptide, recognizable by the immune system that has been reactivated after checkpoint blockade.

PD-L1 gene amplification: PD-L1 amplification — due to amplification of locus 9p24.1, which contains PD-L1 and PD-L2 — is highly associated with Hodgkin disease, which demonstrates response rates to immune checkpoint blockade upward of 75% among heavily pretreated patients. PD-L1 amplification, as determined by next-generation sequencing, also is associated with high response rates in refractory solid tumors.

PAGE BREAK

Hyperprogression: Reports have surfaced demonstrating that immunotherapy may not only be ineffective but, in some cases, may remarkably accelerate growth of the disease.

Genomic markers associated with elevated risk for hyperprogression include MDM2 amplification and EGFR alterations. More work is needed to validate these and other markers and to understand the underlying mechanisms.

Combination treatments

An important trend in clinical research has been the combination of anti-PD-1/PD-L1 agents with other available cancer treatments, including chemotherapy, gene-targeted agents and other immunotherapies.

Remarkably, although there are hundreds of trials using these combinations, very few have included biomarkers that might help determine which patients are more likely to respond.

Giving the right drug(s) to the right patient at the right time, however, demands that biomarkers be explored and validated to optimize combination treatment regimens.

References:

Galanina N, et al. Cancer Immunol Res. 2018;doi:10.1158/2326-6066.CIR-18-0121.

Goodman AM, et al. Mol Cancer Ther. 2017;doi:10.1158/1535-7163.MCT-17-0386.

Goodman AM, et al. JAMA Oncol. 2018;doi:10.1001/jamaoncol.2018.1701.

Kato S, et al. Clin Cancer Res. 2017;doi:10.1158/1078-0432.CCR-17-1990.

Patel SP, et al. Mol Cancer Ther. 2018;doi:10.1158/1535-7163.MCT-14-0983.

Subbiah V, et al. Oncologist. 2018;doi:10.1634/theoncologist.2017-0519.

For more information:

Razelle Kurzrock, MD, is chief of the division of hematology and oncology and director of Center for Personalized Cancer Therapy at Moores Cancer Center at University of California, San Diego. She can be reached at rkurzrock@ucsd.edu.

Vivek Subbiah, MD, is associate professor and center medical director of Clinical Center of Targeted Therapy in the department of investigational cancer therapeutics in the division of cancer medicine at The University of Texas MD Anderson Cancer Center. He can be reached at vsubbiah@mdanderson.org.

To contribute to this column or suggest topics, email Wafik S. El-Deiry, MD, PhD, FACP, at wafik.eldeiry@gmail.com.

Disclosures: Kurzrock reports research funding from Foundation Medicine Inc., Genentech, Grifols, Guardant Health, Incyte, Konica Minolta, Merck Serono, OmniSeq, Pfizer and Sequenom Laboratories, as well as consultant fees from Actuate Therapeutics, Genentech, Loxo, NeoMed and XBiotech. She also reports speaker fees from Roche, and has equity interest in CureMatch Inc. and IDbyDNA. Subbiah reports research funding for clinical trials from AbbVie, Amgen, Bayer, Berg Health, Blueprint Medicines, D3 Pharma, Fujifilm, GlaxoSmithKline, Incyte, Loxo Oncology, MultiVir, NanoCarrier, Northwest Biotherapeutics, Novartis, Pfizer, PharmaMar, Roche/Genentech and Vegenics.

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