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Biologics and Their Interactions With Radiation
Introduction
Since the last edition of this seminal textbook, technological advances in “targeted” radiation therapy continue to improve our ability to deliver fractionated and at times ablative radiation doses even more accurately. Although these technical advancements have improved the radiation therapeutic ratio, resulting in reduced toxicities while increasing dose and decreasing overall treatment time, our ability to integrate radiation with therapies that target specific molecular aberrations in cancer remains a work in progress. In the interim, our understanding of the molecular mechanisms underlying malignant processes continues to develop, leading to the development of an ever-increasing pipeline of therapeutic agents that target dysregulated cancer-associated cellular pathways. The “yin and yang” interplay between radiation and these pathways is complex and dynamic with the dysregulation of certain pathways altering radiation sensitivity (DNA damage repair defects), while radiation exposure can, in turn, alter the activity of these same pathways. Adding to this complexity is the fact that radiation can affect the tumor microenvironment, impacting or improving the ability of the immune system to recognize and attack cancer cells. Therefore, we have broadly organized our discussion of biologically targeted agents into those that target cancer cell intrinsic pathways versus pathways that impact the tumor microenvironment ( Fig. 5.1 ).
The previous edition raised the important question of why so many combinations of radiation with targeted agents appear promising in preclinical and early clinical studies, but have failed to translate into successful Phase III clinical trials. This question is more relevant than ever before. Bioradiotherapy with the antiepidermal growth factor receptor (anti-EGFR) antibody, cetuximab, that initially seemed practice changing in an initial Phase III trial, now appears unlikely to supplant conventional chemotherapy in combination with radiation in patients with human papilloma virus (HPV)-positive cancers. Previously, the authors raised the possibility that perhaps this lack of success in confirmatory clinical trials could be due to a number of factors, including a dearth of preclinical studies evaluating the optimal sequencing of targeted agents with chemoradiation, need for dual targeting of specific pathways to achieve clinical efficacy, need for better biomarkers to select those patients most likely to benefit from the combination of targeted agents and radiotherapy, and different dosing strategies when combining targeted therapies with radiation or chemoradiation. We also raise the possibility that targeted therapies may benefit only a select subset of patients, and future clinical trials may need to be designed in ways to test the efficacy of biologics in the correct subset of patients. Next-generation sequencing is one such tool that may aid in personalizing cancer care and thereby optimize the design of future clinical trials. Finally, as radiation oncologists, we may need to change our mindset and look to radiation as a fire starter rather than the fire to enhance the efficacy and applicability of immune-enabling drugs. The recent results of the PACIFIC study may point us this way.
The previous edition of this chapter highlighted examples of the clinical translation of agents targeting the EGFR, angiogenesis, DNA repair, immune checkpoint, and PI3K/Akt/mTOR pathways. This edition will update the clinical evidence of some of these previously mentioned targeted agents and will also introduce some new agents in the pipeline. These include newer-generation tyrosine kinase inhibitors (TKIs), modulators of key dysregulated metabolic pathways, and inhibitors of transforming growth factor β (TGF-β). Perhaps the most significant development since the last edition is the rapid application of immunotherapy agents. The growing body of preclinical evidence for immunotherapeutics and their potential combination with radiation will be reviewed in depth in a separate chapter of this textbook. The current chapter will instead focus on the early clinical evidence supporting the combination of radiation with immunotherapy as well as some new strategies integrating potentially complementary molecularly targeted therapies on a radioimmunotherapy backbone. Of course, many additional agents are under investigation in the preclinical setting, and new targetable pathways will continue to be uncovered, especially as we move toward a molecular classification of cancer and with the improved integration of genomics into the process of care. In fact, the number of US Food and Drug Administration (FDA)–approved biologic targeted agents continues to expand ( Table 5.1 ). However, this chapter will focus on emerging targeted agents that are likely to play an increasing role in clinical radiation oncology in the near future. Our goal is to keep the practicing radiation oncologist up-to-date and cognizant of the clinical efficacy and potential toxicity of combining novel targeted agents with radiation.
TABLE 5.1
FDA-Approved Biologic Modifiers
| Agent | Class | Approved Indication | Key Toxicities |
|---|---|---|---|
| Afatinib a (Gilotrif) | mTKI: HER2, EGFR | Metastatic NSCLC | Skin effects |
| Aflibercept a (Zaltrap) | VEGFR fusion-protein antibody | Metastatic CRC | Hemorrhage GI perforation Poor wound healing |
| Alectinib b | ALK inhibitor | Crizotinib-refractory NSCLC | Fatigue, GI effects |
| Alemtuzumab a (Campath) | CD52 antibody | B-cell CLL | Cytopenias Infusion reactions |
| Axitinib a (Inlyta) | mTKI: VEGFR, PDGFR, CKIT | Metastatic RCC | HTN, GI effects, fatigue |
| Belinostat (Beleodaq) | HDAC inhibitor | Peripheral T-cell lymphoma | Fatigue, GI effects, anemia, fever |
| Bevacizumab a (Avastin) | Anti-VEGFR antibody | CRC Advanced NSCLC Metastatic RCC Recurrent glioblastoma multiforme Metastatic HER2-negative breast cancer |
Hemorrhage |
| Bortezomib a (Velcade) | Proteasome inhibitor | Multiple myeloma Mantle cell lymphoma |
Cytopenias GI effects Neuropathy |
| Bosutinib (Bosulif) | Src-Abl TKI | Ph(+) CML | GI effects |
| Brentuximab vedotin a (Adcetris) | CD30 antibody-drug conjugate | Refractory Hodgkin lymphoma Anaplastic large-cell lymphoma |
Cytopenias GI effects |
| Cabozantinib a (Cometriq) | mTKI: RET, VEGFR, TIE2, MET, TRKB | Metastatic medullary thyroid cancer | Hemorrhage GI perforation or fistula |
| Carfilzomib (Kyprolis) | Proteasome inhibitor | Refractory multiple myeloma | Cytopenias GI effects |
| Catumaxomab (Removab) | CD3, EpCAM antibody | Malignant ascites | Fever, GI effects |
| Ceritinib b (Zykadia) | ALK inhibitor | ALK(+) metastatic NSCLC after crizotinib | Fatigue, GI effects, hyperglycemia |
| Cetuximab a (Erbitux) | Anti-EGFR antibody | Irinotecan-refractory metastatic CRC with KRAS-wildtype HNSCC |
Anaphylaxis Skin rash |
| Crizotinib a (Xalkori) | ALK inhibitor | ALK(+) locally advanced or metastatic NSCLC | GI effects |
| Dabrafenib (Tafinlar) | BRAF inhibitor | Advanced melanoma with BRAF mutation | Skin effects |
| Daratumumab b | CD38 antibody | Refractory multiple myeloma | Cytopenias |
| Dasatinib a (Sprycel) | mTKI: Src, BCR-ABL, CKIT, PDGFR, TKI | Refractory CML or Ph(+) ALL | Myelosuppression |
| Denileukin diftitox (Ontak) | CD25-directed diptheria cytotoxin | CD25(+) cutaneous T-cell lymphoma | Infusion reaction Capillary leak syndrome Vision loss |
| Denosumab (Xgeva) | RANK ligand inhibitor | Bone metastases prevention Giant cell tumor of bone |
Musculoskeletal effects |
| Durvalumab a (Imfinzi) | PD-L1 antibody | Locally advanced unresectable NSCLC, advanced urothelial cancer | Autoimmune reactions |
| Erlotinib RT (Tarceva) | EGFR TKI | Chemotherapy-refractory NSCLC Advanced pancreatic cancer with gemcitabine |
Skin rash Diarrhea |
| Everolimus a (Afinitor) | mTOR inhibitor | Advanced RCC Progressive neuroendocrine tumors of pancreatic origin Subependymal giant-cell astrocytoma in tuberous sclerosis Advanced breast cancer with exemestane |
GI effects |
| Gefitinib a (Iressa) | EGFR TKI | Advanced and/or chemotherapy-refractory NSCLC | Skin rash Diarrhea |
| Ibrutinib b | Bruton TKI | Mantle cell lymphoma Waldenstrom macroglobulinemia CLL |
GI effects |
| Ibritumomab (Zevalin) | CD20 RIT | Relapsed or refractory low-grade or follicular B-cell NHL Follicular NHL with response to first-line chemotherapy |
Infusion reactions Cytopenias Mucocutaneous reactions |
| Idelalisib (Zydelig) | PI3K inhibitor | Recurrent CLL, follicular lymphoma | Hepatotoxicity Diarrhea Pulmonary Rash Mucositis GI perforation Infections |
| Imatinib a (Gleevec) | BCR-ABL TKI |
Philadelphia chromosome–positive CML or ALL GIST Dermatofibrosarcoma protuberans Myelodysplastic/myeloproliferative disorders Systemic mastocytosis |
Myelosuppression |
| Ipilimumab a (Yervoy) | CTLA-4 antibody | Advanced melanoma, advanced RCC, metastatic colorectal cancer | Autoimmune reactions |
| Lapatinib a (Tykerb) | mTKI: EGFR, HER2 | Refractory HER2 overexpressing advanced breast cancer with capecitabine | Rash Diarrhea |
| Atezolizumab a (Tecentriq) | PD-L1 | Metastatic bladder cancer | Autoimmune reactions |
| Nilotinib a (Tasigna) | BCR-ABL TKI | Ph(+) CML | QT prolongation |
| Nivolumab a (Opdivo) | PD-1 antibody | Advanced melanoma, advanced NSCLC, advanced small cell lung cancer, advanced RCC, recurrent/metastatic HNSCC, advanced urothelial, metastatic colorectal, HCC, refractory/relapsed lymphoma | Autoimmune reactions |
| Obinutuzumab b (Gazyva) | CD20 antibody | CLL | Infusion reactions Cytopenias PML |
| Ofatumumab b (Arzerra) | CD20 antibody | Refractory CLL | Cytopenias GI effects |
| Osimertinib a (Tagrisso) | TKI | EGFR mutated NSCLC | Diarrhea Rash Dry skin QT prolongation |
| Palbociclib b | CDK4, CDK6 | ER(+), HER2(−) advanced breast cancer | Cytopenias |
| Panitumumab a (Vectibix) | Anti-EGFR antibody | Irinotecan-refractory metastatic CRC without KRAS mutation | Anaphylaxis Skin rash |
| Pazopanib a (Votrient) | mTKI: VEGFR, PDGFR, CKIT | Metastatic RCC Advanced soft tissue sarcoma |
Hepatotoxicity |
| Pembrolizumab a (Keytruda) | PD-1 antibody | Advanced melanoma, metastatic NSCLC, metastatic/recurrent HNSCC, advanced urothelial, advanced colorectal, advanced gastric, advanced cervical, relapsed/refractory lymphoma | Auto-immune reactions |
| Pertuzumab a (Perjeta) | Anti-HER2 antibody | HER2 overexpressing breast cancer with trastuzumab and/or docetaxel | Cardiomyopathy Embryo-fetal toxicity |
| Radium-223 (Xofigo) | Calcium mimetic | Castration-resistant prostate cancer with bone metastases | GI effects |
| Ramucirumab (Cyramza) | VEGFR | Advanced or metastatic gastric or gastroesophageal adenocarcinoma | GI effects, HTN, headaches |
| Regorafenib (Stivarga) | mTKI: VEGFR, PDGFR, KIT, RET, TIE2, FGFR, RAF, MAPK | Unresectable or refractory GIST Previously treated CRC |
Hepatotoxicity |
| Rituximab a (Rituxan) | CD20 antibody | Non-Hodgkin lymphoma CLL |
Infusion reactions Tumor lysis syndrome Mucocutaneous effects PML |
| Romidepsin a (Istodax) | HDAC inhibitor | Cutaneous T-cell lymphoma | GI effects |
| Temsirolimus a (Torisel) | mTOR inhibitor | Advanced RCC | Rash Asthenia GI effects |
| Tositumomab I-131 (Bexxar) | CD20 RIT | Relapsed or refractory follicular NHL | Hypersensitivity Cytopenias |
| Trametinib a (Mekinist) | MEK inhibitor | Advanced melanoma | Cardiomyopathy Skin effects GI effects |
| Trastuzumab a (Herceptin) | Anti-HER2 antibody | HER2-neu overexpressing breast cancer | Cardiomyopathy |
| Sorafenib a (Nexavar) | mTKI: VEGFR, PDGFR, Raf, c-KIT | Unresectable hepatocellular carcinoma Advanced RCC |
Rash Diarrhea Hypertension |
| Sunitinib a (Sutent) | mTKI: VEGFR, PDGFR, c-KIT, Flt3 | Advanced RCC GIST Pancreatic neuroendocrine tumors |
Rash Diarrhea Hypertension |
| Vandetanib a (Caprelsa) | mTKI: RET, VEGFR, EGFR | Unresectable or metastatic medullary thyroid cancer | QT prolongation |
| Volasertib b | Polo-like kinase inhibitor | AML | Cytopenias |
| Vorinostat a (Zolinza) | HDAC inhibitor | Cutaneous T-cell lymphoma | GI effects |
| Vemurafenib a (Zelboraf) | BRAF kinase | Unresectable or metastatic melanoma with BRAF mutation | Photosensitivity and other skin effects |
ALL, Acute lymphocytic leukemia; ALK, anaplastic lymphoma kinase; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CRC, colorectal cancer; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; GI, gastrointestinal; GIST, gastrointestinal stromal tumor; HCC, hepatocellular carcinoma; HDAC, histone deacetylase; HNSCC, head and neck squamous cell carcinoma; HTN, hypertension; mTKI, multiple tyrosine kinase inhibitor; NHL, non-Hodgkin lymphoma; NSCLC, non–small cell lung cancer; PDGFR, platelet-derived growth factor receptor; Ph(+), Philadelphia chromosome positive mutation; PML, progressive multifocal leukoencephalopathy; RCC, renal cell carcinoma; RIT, radioimmunotherapy; SEGA, subependymal giant cell astrocytoma; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor.
a Concurrent trials with radiation are ongoing or have been completed.
b Initial approval by FDA Breakthrough Therapies program for expedited drug development under the FDA Safety and Innovation Act of 2012.
Cancer Cell Intrinsic Pathways
Epidermal Growth Factor Receptor
The EGFR family signaling process continues to be one of the most targeted pathways with many agents that could be used in conjunction with radiation. EGFR signaling regulates mesenchymal-epithelial interactions during growth and development, transmitting extracellular cues to intracellular signaling cascades. The family has four known members: EGFR, HER2 (erbB2), HER3 (erbB3), and HER4 (erbB4). These membrane-spanning tyrosine kinase receptors contain an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. Ligand binding induces a structural change that favors dimerization with the same member (homodimer) or a different member (heterodimer) of the family. Dimerization activates the intracellular tyrosine kinase domains, leading to receptor cross-phosphorylation and activation of many downstream signaling cascades through the recruitment of secondary effector proteins.
The end result of receptor activation, proliferation, differentiation, migration, or survival signaling depends on many factors, including which receptor pairs are formed and for how long they are activated. This, in turn, depends on which receptors are predominantly present in the cell and which ligand is involved in activation. There are two ligand families that activate the EGFR family receptors, the EGF-like and heregulin families. The EGF-like family includes EGF, TGF-α, amphiregulin, betacellulin, and HB-EGF. The heregulin (neuregulin) family includes many proteins resulting from splice variations of two different genes, all designated as heregulin with different subtypes. The ligands exhibit preference for particular receptors and induce different receptor combinations. HER2 has no known ligand. Instead, HER2 is the favored partner of the other receptors when a ligand binds to EGFR, HER3, or HER4. This complex interplay of receptors is important for understanding and interpreting the effect of an inhibitor of a single member of the EGF family.
The effect of receptor activation also depends on which downstream signals are activated involving DNA synthesis and repair, apoptosis evasion, growth factor signaling, and proliferation. EGFR family members signal via a diverse network of signal transduction pathways, including the protein kinase C (PKC), Ras-Raf-ERK, PI3K-Akt, and STAT pathways ( Fig. 5.2 ). Furthermore, various receptor pairs recruit different downstream effectors. For instance, HER3 contains multiple PI3K-binding motifs, resulting in strong signaling via PI3K, which plays a role in cell survival, invasion, and proliferation. Interestingly, HER3 alone among the receptors has an inefficient kinase domain, requiring heterodimerization with other family members to become phosphorylated. The need for heterodimerization juxtaposes the PI3K signal emanating from HER3 with the Ras-Raf-ERK or STAT signal emanating from EGFR, HER2, or HER4.
EGFR Family and Tumor Pathogenesis
In 1986, the Nobel Prize was awarded to Stanley Cohen for the discovery of growth factors resulting from his work in identifying EGF and its receptor. EGFR was first identified as a proto-oncogene because of its homology to the avian erythroblastosis (v-erb) oncogene. Aberrant function of EGFR or HER2 occurs frequently in human tumors; gene amplification results in massive overexpression in a proportion of gliomas and breast cancers. Alternatively, dysregulation occurs at more modest levels of expression when the receptor is activated as the result of autocrine stimulation, in which the tumor produces its own ligand to activate the receptor. This type of dysregulation occurs frequently in cancers of the head and neck, gastrointestinal system, and prostate gland. Another mechanism of dysregulation is the development of mutations in the kinase domain that render the kinase activity more potent, most clearly demonstrated in lung cancer. Likewise, mutations in the ligand-binding domain can cause the receptor to be constitutively active even in the absence of ligand, as occurs in a significant proportion of gliomas. Dysregulation via mechanisms other than amplification may not always result in overexpression as detected by standard immunohistochemical techniques, raising the issue of how best to identify all tumors in which EGFR dysregulation promotes tumor proliferation and resistance to therapy.
EGFR Family Inhibitors
The frequent dysregulation of the EGFR family in tumors makes the family an attractive target for exploitation. Remarkable progress has been made in the development of EGFR family inhibitors. Many antibodies directed against the extracellular domains of EGFR and HER2 and small-molecule tyrosine kinase inhibitors have been approved by the FDA for clinical application, with newer-generation antagonists in various stages of development.
The first EGFR family–targeted agent to be approved with radiation was cetuximab (Erbitux), an anti-EGFR monoclonal antibody that binds to the extracellular domain of EGFRs, interferes with ligand binding and, hence, dimerization and activation. Cetuximab has modest activity as a single agent but gives more encouraging results when it is combined with cytotoxic therapy. Cetuximab is typically given intravenously on a weekly schedule. When combined with radiation therapy, a loading dose is given the week before initiation of radiation treatment. Cetuximab gained FDA approval for use in treating metastatic colorectal cancer (mCRC) for patients with wild-type KRAS and in locally advanced head and neck cancers. After initial approval of cetuximab in mCRC, further molecular analysis demonstrated that patients with KRAS mutations in codons 12 or 13 were nonresponders, with survival benefits seen only in patients with wild-type KRAS ; this is presumably due to constitutive downstream activation of the EGFR signaling pathway with activating KRAS mutations. In head and neck cancers, we have yet to determine biomarkers that predict response to anti-EGFR therapy and are trying to elucidate where ADCC reactions come into play on determining response. This finding underscores the complexity of cancer biogenetics and marks an important turning point toward an era of personalized cancer therapy.
Further discussions regarding the use of EGFR inhibitors alone or with chemotherapy are beyond the scope of this chapter; however, we provide references related to these avenues. Our focus is a review of the use of these agents with radiation preclinically and the successes and failures in the clinical arena. One of the most frustrating aspects of this combination is the fact that we still struggle with a lack of predictive biomarkers related to response to EGFR inhibitors. Is it the ligand presence that predicts response? Does the presence of an EGFR mutation always predict response to EGFR inhibitors in diseases such as lung cancer or do we need to dig deeper? Is it based on gene amplification or high gene copy numbers in EGFR wild-type cancers?
Several small-molecule tyrosine kinase inhibitors targeting EGFR have gained FDA approval: gefitinib (Iressa), erlotinib (Tarceva), afatinib (Gilotrif), lapatinib (Tykerb), and osimertinib (Tagrisso). These compounds specifically inhibit the tyrosine kinase activity of an EGFR family receptor while relatively sparing the other EGFR family members and related tyrosine kinases. Gefitinib and erlotinib act on EGFR; lapatinib is active against HER2; and afatinib targets both EGFR and HER2. These small-molecule agents have shown modest benefits in patients with advanced malignancies (primarily in patients with EGFR mutations); however, they have yet to demonstrate any significant benefits in Phase II/III clinical trials with radiation. Past trials that combined agents such as erlotinib with temozolomide and radiation in patients with newly diagnosed glioblastoma multiforme (GBM) exhibited unacceptable toxicity with multiple treatment-related deaths and no evidence of increased efficacy. The primary toxicity of both gefitinib and erlotinib occurs in the skin, similar to cetuximab, and as diarrhea. However, infrequent cases of serious, life-threatening interstitial lung disease have also been reported for both agents as well as anaphylactic reactions in approximately 3% of patients treated with cetuximab. Caution is especially recommended combining anti-EGFR agents and anti-PDL1 checkpoint inhibitors due to reports of excessive pneumonitis. Because these reactions can be life threatening, careful monitoring is required with these agents.
Osimertinib, a third-generation EGFR TKI, has improved CNS penetration and significantly improves progression-free survival (PFS) and overall survival (OS) in patients with acquired EGFR mutations compared to the EGFR TKIs erlotinib and gefitinib. One Phase I trial in the United States (NCT03535363) and one Phase II TROG (NCT03497767) trial is testing the safety and efficacy of combining osimertinib with stereotactic radiosurgery (SRS) to control intracranial metastatic disease. With the mounting evidence that local radiation improves survival for patients with low-volume or oligometastatic disease, there will likely be more opportunities to combine radiation, especially stereotactic body radiation therapy (SBRT), with newer-generation EGFR TKIs. One currently recruiting trial at University of Texas MD Anderson Cancer Center in Houston, NORTHSTAR (NCT03410043), is actively testing the question of whether adding local consolidative therapy to osimertinib may benefit patients with advanced non–small cell lung carcinoma (NSCLC). This trial will enroll both treatment-naïve stage IIIB or stage IV NSCLC patients with EGFR exon 19 del/L858R mutation or patients with acquired EGFR T790M mutations refractory to earlier generation EGFR TKIs. All enrolled patients will receive induction osimertinib and patients with stable disease will be randomized to either osimertinib maintenance alone or osimertinib with investigator's choice of local therapy (radiation, surgery, or radiation and surgery) with a primary endpoint of PFS.
EGFR Family and Radiation Response
EGFR family members play an important role in radiation response. Preclinical studies showed that cells made to express v-erb were rendered radioresistant. Similarly, breast cancer cell lines become more radioresistant when made to overexpress HER2, and head and neck cancer cell radioresistance correlates with EGFR expression levels.
Clinical studies also suggest that EGFR family dysregulation influences radiation response. A study of 170 gliomas treated with primary radiotherapy demonstrated lower response rates in tumors that overexpressed EGFR; the response rate was 33% in EGFR-negative tumors, 18% in EGFR-intermediate tumors, and 9% in EGFR-positive tumors. In smaller series of patients with head and neck cancers, locoregional recurrence after radiotherapy was associated with EGFR overexpression. In breast cancer, a case-control series of patients with in-breast tumor recurrence after breast-conserving surgery and radiotherapy found that the proportion of patients with HER2 overexpression was higher in the recurrence group than in the controls.
Preclinical Studies of EGFR Family Inhibitors as Radiosensitizers
The role of EGFR family members in radiation response was further clarified by studies using newly developed EGFR family inhibitors. In virtually every study, EGFR or HER2 inhibitors demonstrated modest radiosensitization. Radiosensitization is more pronounced in vivo than in vitro and with fractionated-dose than with single-dose irradiation. Understanding of the mechanisms underlying enhanced radiosensitization is evolving. In every case, the combination of EGFR or HER2 inhibitors and radiation resulted in increased cell cycle arrest, predominantly in the G 1 phase, but with a substantial decrease in the S phase, which translates in vivo to decreased proliferation. Radiosensitization with EGFR family inhibitors also causes decreased angiogenesis. It is not yet clear whether this is an additive result of combined antiangiogenesis effects from both radiation and EGFR inhibitors or whether the EGFR inhibitors further increase the susceptibility of the vascular elements of the tumor to radiation. The combination of EGFR inhibitors and radiation increases apoptosis in some, but not all, models. Finally, EGFR inhibitors appear to directly interfere with EGFR-induced DNA-PK-dependent nonhomologous end-joining repair of radiation-induced DNA damage. What is lacking in past studies are designs that actually mimicked what we do in the clinic, including comparing chemoradiation to chemoradiation plus an EGFR inhibitor, for example, in the disease setting to be clinically studied rather than extrapolating from another tumor type. These types of studies, albeit performed in somewhat artificial systems, might have provided valuable information as to the best way to move forward in a clinical trial.
Clinical Studies of EGFR Family Inhibitors as Radiosensitizers
Promising preclinical studies with EGFR family inhibitors have translated into improved patient outcomes in randomized controlled trials when added to radiation alone primarily in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Well known and often cited is the Phase III trial that compared the efficacy of standard radiotherapy with standard radiotherapy plus the anti-EGFR antibody cetuximab. In this study, 424 patients with LA-HNSCC of the oropharynx, hypopharynx, or larynx were stratified by T stage, nodal status, and performance status and then were randomly assigned to receive radiotherapy alone or radiotherapy plus weekly concurrent cetuximab. Radiotherapy was delivered using one of three fractionation regimens (stratified): a once-daily regimen (2 Gy × 35 fractions over 7 weeks), a twice-daily regimen (1.2 Gy × 60–64 fractions over 6–6.5 weeks), or a concomitant-boost regimen (1.8 Gy × 30 fractions with a second daily fraction of 1.5 Gy for the last 12 treatment days over 6 weeks). Concurrent chemotherapy was not allowed. The primary endpoint was achieved with a 2-year local control of 56% in the radiotherapy-plus-cetuximab arm versus 48% in the radiotherapy-alone arm, with a median duration of local control of 36 months versus 19 months, respectively ( p = 0.02). OS was also significantly enhanced with combined therapy. Updated results at 5 years indicated a 45.6% 5-year OS in the radiotherapy-plus-cetuximab arm versus 36.4% in the radiotherapy-alone arm, with a median survival of 49 months versus 29 months, respectively ( p = 0.018).
Although concern for unwanted normal tissue effects when combining targeted drugs against EGFR and radiation therapy alone is justifiable, the additional morbidity of this approach appears minimal based on the experiences in the clinic to date. In the study by Bonner et al., the improvement in outcome was associated with an increase in acute skin, but not mucosal, toxicity. Furthermore, there were no differences between the groups on standardized quality-of-life assessment scores. In terms of potential predictors of outcome, a grade 2 or greater acneiform rash correlated with better survival rates (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.34–0.72; p = 0.002). This correlation, seen in other studies in multiple disease sites, has been hypothesized to be reflective of an anticancer immune response. In a separate trial, concurrent administration of adjuvant radiotherapy with trastuzumab in patients with early-stage breast cancer did not increase the incidence of acute radiation toxicity.
Results have been mixed in trials of EGFR inhibitors added to combination chemotherapy and radiation. RTOG 0234 (Radiation Therapy Oncology Group), a Phase II randomized trial comparing radiation plus cetuximab and either weekly cisplatin or weekly docetaxel in patients with LA-HNSCC, suggested that both regimens are feasible with outcomes superior to results from RTOG 9501, which used high-dose cisplatin on days 1, 22, and 43. Grade 3 to 4 myelosuppression was observed in 28% (cisplatin) and 14% (docetaxel) of patients. Dermatitis was seen in 39% of patients in each group. The rates of grade 3 or higher mucositis were 37% and 33% in the cisplatin and docetaxel arms, respectively. These rates seem low but are encouraging compared with historical controls. The 2-year distant metastasis rate was 13% in the group that received docetaxel and cetuximab versus 26% with cisplatin and cetuximab. One of the conclusions from this trial is that the perturbing growth factor signaling may allow us, under the right circumstances, to reduce administration of high doses of standard chemotherapy and reduce patient morbidity. A follow-up Phase II-III trial (RTOG 1216) is evaluating the use of cetuximab and docetaxel with postoperative radiation to radiation and cisplatin (weekly at 40 mg/m2) or radiation and weekly docetaxel. Readouts of this trial are expected in 2019. In the unresectable setting, the addition of cetuximab to the current standard of cisplatin and radiotherapy for LA-HNSCC was evaluated in the Phase III RTOG 0522, with results showing no improvement in PFS or OS, and worse grade 3 to 4 acute toxicities, including mucositis and skin reactions in patients receiving chemoradiation with cetuximab versus chemoradiation alone. Since cetuximab was thought to be better tolerated than cisplatin, several trials were launched (RTOG 1016, DeESCALaTe, TROG 12.01) to determine if bioradiotherapy with cetuximab is a viable alternative to cisplatin-based chemoradiation in HPV-positive patients. Recently published results from two of these studies indicate that cetuximab with radiation is inferior in terms of clinical outcomes to cisplatin with radiation while also having equivalent rates of toxicity.
In the Phase II trial ACOSOG Z4051, 70 patients with locally advanced esophageal adenocarcinoma received preoperative therapy with the EGFR monoclonal antibody panitumumab added to docetaxel, cisplatin, and radiation. Despite 54% of patients showing at least a near pathologic complete response, nearly half of all patients had grade 4 or higher toxicities, making this regimen unsuitable for further study. To our knowledge, this type of combination was not studied preclinically to assess its efficacy and safety before going forward into a clinical trial.
An alternative strategy is to evaluate the use of induction chemotherapy before using a combination EGFR inhibition and radiation. Exploring this approach was the TREMPLIN study, a Phase II randomized trial, which directly compared the addition of cisplatin versus cetuximab to radiation for 116 patients with LA-HNSCC of the larynx/hypopharynx with a greater than 50% response following three cycles of traditional induction chemotherapy. Larynx preservation at 3 months, larynx function at 18 months, and OS at 3 years demonstrated equivalent outcomes. Local failures were slightly higher in the cetuximab arm (8 vs. 5), but only the patients in the cetuximab arm eventually underwent salvage surgery (7 vs. 0). Grade 3 or higher rates of mucositis were similar between arms, and skin toxicity was roughly doubled in the cetuximab arm. However, acute renal toxicity was substantial in the cisplatin plus radiotherapy arm. This suggests that by using induction chemotherapy, we may be able to study combinations of biologically targeted agents without the added toxicity of conventional chemotherapy agents, assuming that the preclinical studies support this approach. An additional trial, the Gruppo di Studio Tumori della Testa e del Collo (GSTTC) trial, employed a 2 × 2 factorial design for 421 patients with LA-HNSCC randomized with and without induction chemotherapy and randomized to concurrent radiation with either cetuximab or cisplatin. Subgroup analyses showed a possible superior effect for induction chemotherapy followed by cetuximab and radiation; however, no significant interaction was found. The trial was not powered to directly compare survival outcomes between cisplatin with radiation and cetuximab with radiation. Toxicity rates were also similar between the two groups and patients receiving cetuximab actually required more treatment interruptions with a median radiation therapy (RT) duration of 8 weeks versus 7 weeks in the cisplatin arms. Additional trials examining cetuximab versus cisplatin show that cetuximab provides at best the same local control and OS outcomes with no improvement in toxicity.
The poor performance of EGFR inhibitors such as cetuximab in large confirmatory clinical trials illustrates the complexity of combining targeted agents with radiation and chemotherapy. Several issues may be at play. First, the sequencing of biologic agents, radiation, and chemotherapy needs to be more closely studied and tested in preclinical and model systems as certain sequencing approaches may, in fact, be antagonistic. Second, perhaps the clinical trials carried out thus far have not enrolled the optimal patient population, with a need to incorporate better biomarkers to direct clinical trial enrollment and therefore maximize recruitment of patients who have the highest chance to benefit from the experimental treatments. Despite the fact that EGFR is often overexpressed in HNSCC, EGFR expression levels are not predictive of a response. Also, in colorectal cancer, patients with KRAS mutations do not respond to cetuximab. At this stage of the game, it is unlikely that we will move forward with any further anti-EGFR trials with radiation or chemoradiation with the possible exception of highly selected patients who may have unique biology. One such group of patients was recently identified in a secondary analysis of RTOG 0522 that showed patients harboring a germline mutation in the 3′UTR of KRAS ( KRAS -variant) appeared to benefit disproportionately from the inclusion of cetuximab. Future trials may also benefit from evaluating radiation or chemoradiation followed by combinations of immunotherapy and targeted agents against EGFR.
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