Improving Outcomes with Chemoradiotherapy in the Mucosal Squamous Cell Carcinomas - Immune Checkpoint Inhibition and Broken Promises.

Cancers arising at mucosal surfaces include cancers of worldwide significance: cancer of the cervix and head and neck squamous cell carcinomas (HNSCC), which comprise 20% of cancers in India [[1]India State-Level Disease Burden Initiative Cancer CollaboratorsThe burden of cancers and their variations across the states of India: the Global Burden of Disease Study 1990–2016.Lancet Oncol. 2018; 19: 1289-1306Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar], anal squamous cell cancer (ASCC; rising in incidence in high-income countries) and rare tumours where evidence-based approaches to treatment are limited (vulval, vaginal and penile cancers). They share biology and epidemiology, associated with high-risk subtypes of human papillomaviruses (HPV) [[2]de Sanjosé S. Serrano B. Tous S. Alejo M. Lloveras B. Quirós B. et al.Burden of human papillomavirus (HPV)-related cancers attributable to HPVs 6/11/16/18/31/33/45/52 and 58.JNCI Cancer Spectr. 2018; 2: pky045Crossref PubMed Google Scholar] or chronic inflammation and tobacco exposure. They typically present with locally advanced disease and are treated with radical chemoradiotherapy (CRT) as they are relatively radio-sensitive and surgery brings significant morbidity and mortality (e.g. colostomy or tracheostomy). Relapses are not infrequent in patients presenting with locally advanced disease, typically at the primary site, although metastatic disease is increasingly seen. Although comprehensive prophylactic HPV vaccination and tobacco control programmes would be expected to significantly reduce their incidence (and vaccines are in development to help patients already affected with HPV [[3]Harper D.M. Nieminen P. Donders G. Einstein M.H. Garcia F. Huh W.K. et al.The efficacy and safety of Tipapkinogen Sovacivec therapeutic HPV vaccine in cervical intraepithelial neoplasia grades 2 and 3: randomized controlled phase II trial with 2.5 years of follow-up.Gynecol Oncol. 2019; 153: 521-529Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]), incidence is likely to increase over the next 20 years before a reduction is seen. Improving outcomes for the locally advanced mucosal SCCs then presents a major challenge of global importance. CRT continues to undergo technical refinement – advances in radiotherapy planning increase doses to the tumour while sparing normal tissues. However, CRT is close to the ceiling of toxicity and previous attempts to add further drugs resulted in increased toxicity without improving outcomes [[4]Garg M.K. Zhao F. Sparano J.A. Palefsky J. Whittington R. Mitchell E.P. et al.Cetuximab plus chemoradiotherapy in immunocompetent patients with anal carcinoma: a phase II Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group Trial (E3205).J Clin Oncol. 2017; 35: 718-726Crossref PubMed Scopus (60) Google Scholar]. Importantly, after CRT the tumour remains in situ, cleared over a number of months by the immune system. Immune checkpoints (PD-1/PD-L1) that inhibit tumour immune recognition are thought to play an important role in facilitating tumorigenesis [[5]Howitt B.E. Sun H.H. Roemer M.G. Kelley A. Chapuy B. Aviki E. et al.Genetic basis for PD-L1 expression in squamous cell carcinomas of the cervix and vulva.JAMA Oncol. 2016; 2: 518-522Crossref PubMed Scopus (108) Google Scholar] and resistance to CRT [[6]Yoneda K. Kuwata T. Kanayama M. Mori M. Kawanami T. Yatera K. et al.Alteration in tumoural PD-L1 expression and stromal CD8-positive tumour-infiltrating lymphocytes after concurrent chemo-radiotherapy for non-small cell lung cancer.Br J Cancer. 2019; 121: 490-496Crossref PubMed Scopus (83) Google Scholar]. Immune checkpoint inhibitors (ICI) have revolutionised the treatment of cancer during the last decade [[7]Larkin J. Chiarion-Sileni V. Gonzalez R. Grob J.J. Rutkowski P. Lao C.D. et al.Five-year survival with combined nivolumab and ipilimumab in advanced melanoma.N Engl J Med. 2019; 381: 1535-1546Crossref PubMed Scopus (2097) Google Scholar]. ICIs appear to be particularly effective in cancers with frequent mutations and those of viral aetiology [[8]Yarchoan M. Hopkins A. Jaffee E.M. Tumor mutational burden and response rate to PD-1 inhibition.N Engl J Med. 2017; 377: 2500-2501Crossref PubMed Scopus (2033) Google Scholar]. They have efficacy across the mucosal SCCs in the metastatic setting, with studies reporting efficacy in HNSCC [[9]Seiwert T.Y. Burtness B. Mehra R. Weiss J. Berger R. Eder J.P. et al.Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial.Lancet Oncol. 2016; 17: 956-965Abstract Full Text Full Text PDF PubMed Scopus (1214) Google Scholar], anal [[10]Morris V.K. Salem M.E. Nimeiri H. Iqbal S. Singh P. Ciombor K. et al.Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study.Lancet Oncol. 2017; 18: 446-453Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar,[11]Rao S. Anandappa G. Capdevila J. Dahan L. Evesque L. Kim S. et al.A phase II study of retifanlimab (INCMGA00012) in patients with squamous carcinoma of the anal canal who have progressed following platinum-based chemotherapy (POD1UM-202).ESMO Open. 2022; 7100529Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar] and cervical, vulval and vaginal cancers [[12]Naumann R.W. Hollebecque A. Meyer T. Devlin M.J. Oaknin A. Kerger J. et al.Safety and efficacy of nivolumab monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma: results from the phase I/II CheckMate 358 trial.J Clin Oncol. 2019; 37: 2825-2834Crossref PubMed Scopus (234) Google Scholar]. There has, therefore, been significant interest in the addition of ICIs to CRT across these cancers, supported by results of the PACIFIC trial in non-small cell lung cancer, where durvalumab improved overall survival following CRT [[13]Antonia S.J. Villegas A. Daniel D. Vicente D. Murakami S. Hui R. et al.PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.N Engl J Med. 2018; 379: 2342-2350Crossref PubMed Scopus (1900) Google Scholar] and Checkmate 577 testing nivolumab after CRT for oesophageal cancer [[14]Kelly R.J. Ajani J.A. Kuzdzal J. Zander T. Van Cutsem E. Piessen G. et al.CheckMate 577 Investigators. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer.N Engl J Med. 2021; 384: 1191-1203Crossref PubMed Scopus (674) Google Scholar], where both have become standard of care. A number of trials then embarked on combining ICIs with CRT across the mucosal tumours, typically testing a block of adjuvant treatment ± a concurrent component. However, the first tranche of these are now reporting and to date, somewhat unexpectedly, results are disappointing. Two large phase III trials tested the addition of ICIs to CRT in patients with HNSCC and have reported primary outcomes. Javelin head and neck 100 [[15]Lee N.Y. Ferris R.L. Psyrri A. Haddad R.I. Tahara M. Bourhis J. et al.Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.Lancet Oncol. 2021; 22: 450-462Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar] randomised 697 patients undergoing radical CRT for locally advanced HNSCC to ± avelumab (anti PD-L1) with patients in the experimental arm receiving a single infusion pre-CRT, then concurrent avelumab during CRT and continuing for 12 months. There was no improvement in progression-free survival, the primary outcome measure (hazard ratio 1.21; 95% confidence interval 0.93–1.57, favouring the placebo group). Keynote 412 (NCT03040999) tested the same approach (neoadjuvant, concurrent and then adjuvant), this time with the PD-1 inhibitor pembrolizumab [[16]ESMO CongressPresidential Symposium II. LBA5 - Primary results of the phase III KEYNOTE-412 study: pembrolizumab (pembro) with chemoradiation therapy (CRT) vs placebo plus CRT for locally advanced (LA) head and neck squamous cell carcinoma (HNSCC).https://oncologypro.esmo.org/meeting-resources/esmo-congress/primary-results-of-the-phase-iii-keynote-412-study-pembrolizumab-pembro-with-chemoradiation-therapy-crt-vs-placebo-plus-crt-for-locally-advancGoogle Scholar], again in patients with locally advanced HNSCC. In total, 804 patients were randomised between the two arms; with a median follow-up of 47.7 months (range 37.0–61.4) the primary outcome measure of event-free survival was not statistically different between arms (hazard ratio 0.83; 0.68–1.03, P = 0.0429) although the trend did favour the pembrolizumab arm. In the cohort of patients with high levels of PD-L1 expression in the pre-treatment biopsy specimen (n = 685), event-free survival just met significance (hazard ratio 0.80; 0.64–1.00). Information on overall survival is awaited. Moving to cervical cancer, the phase III CALLA trial (NCT03830866) randomised 770 patients undergoing CRT (+brachytherapy) for locally advanced disease to ± concurrent durvalumab, with patients in the experimental arm continuing adjuvant treatment for up to 2 years. With a median follow-up of 18.5 months [[17]Monk B. Toita T. Wu X. Limón J.C. Zhou Q. Tarnawski R. et al.O001/#504 Durvalumab, in combination with and following chemoradiotherapy, in locally advanced cervical cancer: results from the phase 3 international, randomized, double-blind, placebo-controlled Calla trial.Int J Gynecol Cancer. 2022; 32: A2-A3Google Scholar], the addition of durvalumab did not improve the primary outcome measure of progression-free survival (hazard ratio 0.84; 95% confidence interval 0.65–1.08; P = 0.174. Again, overall survival data are awaited. Although there are no randomised trial results published in ASCC, there are multiple ongoing studies. RADIANCE (Germany), CORINTH (UK), NCI-EA2165 (USA) and NCT05374252 (China) are all combining PD-1 inhibitors with standard CRT, with neoadjuvant, concurrent and adjuvant immunotherapy schedules all being investigated. Chemoimmunotherapy followed by CRT is being used in the INTER-ION trial (France) for locally advanced disease. There are no current immunotherapy studies for the other rare HPV-driven tumours (vulval, vaginal and penile). Although the results from trials in anal cancer and further trials in HNSCC and cervical cancer might yet buck the trend (Table 1), it is pertinent to consider these unexpected results. Radiotherapy technique, the choice and schedules of immunotherapeutic drug(s) and patient selection are potential reasons why these first CRT-ICI combination trials may have failed to improve outcomes in mucosal SCCs.Table 1Phase III trials in human papillomavirus (HPV)-associated squamous cell carcinomas investigating radiotherapy–immunotherapy combinationsTrial identifierTitleInclusion criteriaImmunotherapyImmunotherapy regimen in relation to CRTnEstimated completionAnalNCT05374252Chemoradiotherapy Combined With or Without PD-1 Blockade in Anal Canal Squamous Carcinoma PatientsStage III anal cancerAnti-PD-1 SintilimabAdjuvant10231/12/2025NCT03233711Nivolumab After Combined Modality Therapy in Treating Patients With High Risk Stage II-IIIB Anal CancerStage IIB-III anal cancerAnti-PD-1 NivolumabAdjuvant34431/4/2024CervicalNCT05173272Induction Chemotherapy Combined With Immunotherapy Followed by Concurrent Chemoradiation in Advanced Cervical CancerCervical cancer FIGO 2018 stage Ib3-IIIc2Anti-PD-1 SlulimumabNeoadjuvant with chemotherapy28628/12/2028NCT05235516A Study of AK104/Placebo Combined With Chemoradiotherapy For The Treatment of Locally Advanced Cervical Cancer (AK104-305)Cervical cancer FIGO 2018 stage IIIA-IVAAnti-PD-1/CTLA-4 bi-specific antibody CadonilimabConcurrent63601/05/2029NCT04221945Study of Chemoradiotherapy With or Without Pembrolizumab (MK-3475) For The Treatment of Locally Advanced Cervical Cancer (Keynote A-18)Cervical cancer FIGO 2014 stages IB2–IIB with N+ or III–IVAAnti-PD-1 PembrolizumabConcurrent and adjuvant98007/12/2024Head and neck squamous cell carcinomaNCT03765918Study of Pembrolizumab Given Prior to Surgery and in Combination With Radiotherapy Given Post-surgery for Advanced Head and Neck Squamous Cell Carcinoma (MK-3475-689)Stage III OP HPV-positive cancer, stage III/IVA OP HPV-negative cancer, stage III/IVA larynx/HP/oral cavity cancerAnti-PD-1 PembrolizumabNeoadjuvant and concurrent70430/07/2026NCT03576417A Trial Evaluating the Addition of Nivolumab to Cisplatin-RT for Treatment of Cancers of the Head and Neck (NIVOPOSTOP)Oral cavity, OP, HP or larynx cancer with high risk of relapseAnti-PD-1 NivolumabNeoadjuvant, concurrent and adjuvant68001/09/2027NCT03952585De-intensified Radiation Therapy With Chemotherapy (Cisplatin) or Immunotherapy (Nivolumab) in Treating Patients With Early-Stage, HPV-Positive, Non-Smoking Associated Oropharyngeal Cancerp16-positive T1-2N1M0 or T3N0M0 OP cancerAnti-PD-1 NivolumabNeoadjuvant, concurrent and adjuvant71128/02/2025NCT03700476Sintilimab (PD-1 Antibody) and Chemoradiotherapy in Locoregionally-advanced Nasopharyngeal Carcinoma (CONTINUUM)Stage III/IVA nasopharyngeal cancerAnti-PD-1 SintilimabNeoadjuvant, concurrent and adjuvant42501/01/2025NCT01810913Testing Docetaxel-Cetuximab or the Addition of an Immunotherapy Drug, Atezolizumab, to the Usual Chemotherapy and Radiation Therapy in High-Risk Head and Neck CancerStage III/IV p16 negative oral cavity, OP, larynx, HP cancerAnti-PD-L1 AtezolizumabNeoadjuvant, concurrent and adjuvant61301/01/2027NCT03258554Radiation Therapy With Durvalumab or Cetuximab in Treating Patients With Locoregionally Advanced Head and Neck Cancer Who Cannot Take CisplatinStage III p16-positive OP/SCC of unknown head/neck primary cancer or stage III-IVB p16-negative laryngeal, HP, and oral cavity cancerAnti-PD-L1 DurvalumabConcurrent and adjuvant49331/12/2025NCT02999087Randomized Trial of Avelumab-cetuximab-radiotherapy Versus SOCs in LA SCCHN (REACH)Stage III/IVA/IVB oral cavity, OP, HP or larynx cancerAnti-PD-1 AvelumabConcurrent and adjuvant70701/12/2027NCT03427827PD-1 Antibody Versus Best Supportive Care After Chemoradiation in Locoregionally Advanced Nasopharyngeal Carcinoma (PACIFIC-NPC)Stage III/IVA nasopharyngeal cancerAnti-PD-1 CamrelizumabAdjuvant44201/02/2026NCT03452137A Study of Atezolizumab (Anti-Pd-L1 Antibody) as Adjuvant Therapy After Definitive Local Therapy in Patients With High-Risk Locally Advanced Squamous Cell Carcinoma of the Head and NeckSquamous cell carcinoma of the head and neck, not nasopharynx or paranasal sinusesAnti-PD-L1 AtezolizumabAdjuvant40601/06/2027NCT03700905Study of Nivolumab Alone or in Combination With Ipilimumab as Immunotherapy vs Standard Follow-up in Surgical Resectable HNSCC After Adjuvant Therapy (IMSTAR-HN)Stage III-IVB HPV-negative OP, oral cavity, HP and larynx cancerAnti-PD-1 Nivolumab, Anti-CTLA4 IpilumumabAdjuvant27601/05/2024NCT03811015Testing Immunotherapy Versus Observation in Patients With HPV Throat Cancerp16-positive OP cancerAnti-PD-1 NivolumabAdjuvant63601/01/2027HP, hypopharynx; OP, oropharynx. Open table in a new tab HP, hypopharynx; OP, oropharynx. The generation of T-cell anti-tumour responses to cancer is a cyclic process that can be enhanced with radiotherapy (Figure 1) that might be amplified by immunotherapeutic drugs and in theory produce synergistic efficacy [[18]Chen D.S. Mellman I. Oncology meets immunology: the cancer-immunity cycle.Immunity. 2013; 39 (PMID: 23890059): 1-10https://doi.org/10.1016/j.immuni.2013.07.012Abstract Full Text Full Text PDF PubMed Scopus (4230) Google Scholar]. For T-cells to be primed against cancer antigens, functional draining lymph nodes are important. Preclinical models suggest that radiotherapy to the draining lymph node dampens this adaptive immune response, reducing cytotoxic T-cell and dendritic cell signalling [[19]Marciscano A.E. Ghasemzadeh A. Nirschl T.R. Theodros D. Kochel C.M. Francica B.J. et al.Elective nodal irradiation attenuates the combinatorial efficacy of stereotactic radiation therapy and immunotherapy.Clin Cancer Res. 2018; 24: 5058-5071Crossref PubMed Scopus (183) Google Scholar,[20]Saddawi-Konefka R. O'Farrell A. Faraji F. Clubb L. Allevato M.M. Jensen S.M. et al.Lymphatic-preserving treatment sequencing with immune checkpoint inhibition unleashes cDC1-dependent antitumor immunity in HNSCC.Nat Commun. 2022; 13: 4298Crossref PubMed Scopus (30) Google Scholar]. Treatment of mucosal SCCs typically includes elective doses to uninvolved locoregional lymph nodes and lymphatic drainage. Elective doses may be as high as 60 Gy/30 fractions for HNSCC in ‘intermediate risk’ areas, which could impact anti-tumour T-cell priming. In contrast, lung and oesophageal treatment guidelines do not involve elective doses to local lymph nodes to the same extent. Volume and length of treatment may also impact the efficacy of ICI. Radiotherapy volumes in the pelvis can be large, in some instances including para-aortic nodes and metabolically active bone marrow. The standard fractionation regimen for mucosal SCCs produces ongoing lymphopenia during and immediately after a 5–7-week treatment regimen. Given the inherent sensitivity of leukocytes to radiotherapy and the significant neutropenia and lymphopenia associated with pelvic irradiation, a careful re-analysis of the benefits and drawbacks of pelvic treatment volumes is required in the age of immunotherapy. These issues are addressed in the INTERACT-ION study (NCT04719988), where a reduced radiotherapy field is prescribed following an objective complete response to chemoimmunotherapy in patients with locally advanced ASCC. Any future studies in this area will require rigorous radiotherapy quality assurance to ensure lymph node doses are prescribed and recorded. Retrospective review of reported mucosal SCC trials with high-quality radiotherapy quality assurance, such as JAVELIN, may allow us to see if elective dose volumes have impacted immunotherapy efficacy. Before testing reduced elective volumes in the curative setting, with the attendant risks of reduced rates of cure, these concepts could initially be explored in fractionated palliative radiotherapy, where lower doses and volumes are frequently utilised and could be combined with the (relatively) modest ICI toxicities. Although survival stratified by PD-L1 expression was investigated in CALLA (secondary endpoint), Keynote 412 and JAVELIN (both exploratory), none of these trials used any biomarker to select or stratify patient selection. Furthermore, PD-L1 positive definitions varied across all studies, making comparison even within HNSCC difficult (≥25% tumour proportion score in JAVELIN, ≥1% combined positive score in Keynote 412, ≥1% tumour proportion score in CALLA). There are many other potential biomarkers that could be investigated using existing samples from trials and compared with standard of care biobank samples. Simplistically, tumour infiltrating lymphocytes at diagnosis are prognostic in cervical, ASCC and HNSCC. Although outcomes vary for radical CRT across these cancers, there are certain groups of patients with locally advanced disease who do well. Five-year locoregional failure rates for locally advanced ASCC are 20–30% – three-quarters of unselected patients would get no benefit from immunotherapy while exposed to potential side-effects of additional treatment. The timing of immunotherapy in relation to CRT is another barrier to success, with discordant approaches across different preclinical models and clinical trials. Many of the mucosal SCC trials discussed reference the same preclinical papers showing that concurrent or sequential immunotherapy (starting within 7 days of finishing radiotherapy) was superior to adjuvant immunotherapy [[21]Dovedi S.J. Cheadle E.J. Popple A.L. Poon E. Morrow M. Stewart R. et al.Fractionated radiation therapy stimulates antitumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD-1 blockade.Clin Cancer Res. 2017; 23: 5514-5526Crossref PubMed Scopus (254) Google Scholar,[22]Dovedi S.J. Adlard A.L. Lipowska-Bhalla G. McKenna C. Jones S. Cheadle E.J. et al.Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade.Cancer Res. 2014; 74: 5458-5468Crossref PubMed Scopus (912) Google Scholar]. However, many of these trials investigated combinations of neoadjuvant, concurrent and adjuvant regimens together and teach us little about the scheduling of ICIs. Scheduling should consider different immunotherapeutic drug targets; PD-1 inhibitors have a different mechanism of action to drugs targeting CTLA-4 and it is likely optimal scheduling may differ too [[23]Demaria S. Guha C. Schoenfeld J. Morris Z. Monjazeb A. Sikora A. et al.Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose?.J Immunother Cancer. 2021; 9e002038Crossref Scopus (110) Google Scholar]. Preclinical data most relevant to mucosal SCCs should inform future trials. Many preclinical models use radiotherapy alone rather than CRT or have fractionation regimens completely different to those used in mucosal SCCs. While we await outcomes from the ongoing trials in anal cancer, the promise of ICI/CRT combinations for mucosal cancers remains unfulfilled. With many unknowns, it should be a fertile time for exploration of the underlying immunobiology of the CRT response. Importantly, these findings should inform future trials across the mucosal SCCs – also incorporating studies that include the rarer subtypes with the appropriate biological rationale (e.g. basket protocols that might incorporate Bayesian designs). In short, better science, better biomarkers and better radiotherapy are needed to improve outcomes for these patients. The authors declare no conflicts of interest.