Hyperprogression Emerges in a Subset of Patients Treated With Immunotherapy

The extent of hyperprogressive disease (HPD) after immunotherapy treatment has not been fully characterized, but evidence continues to build that it may not be as rare of a phenomenon as previously thought. Results from a recent multicenter, retrospective analysis of 242 patients with advanced non—small cell lung cancer (NSCLC) found that 16% developed hyperprogression during anti–PD-1/PD-L1 treatment.¹ The study, which was presented at the 2017 ESMO Annual Congress, is among the latest to highlight the risk of hyperprogression.

Awareness of hyperprogression—a rapid increase in tumor growth after initiation of immunotherapy—has been increasing since a 2016 French study first defined hyperprogression in a population of patients receiving anti—PD-1/PD-L1 therapy for melanoma, lung, renal, colorectal, head and neck, breast, brain, cervical, endometrial, and other cancers.² That study, which was published in Clinical Cancer Research, identified hyperprogression in 12 of 131 patients, for an incidence of 9%. Additional research studies suggest that rapid tumor growth during immunotherapy is likely more common than that, particularly in certain patient populations.

Hyperprogression Defined

Understanding the definition, incidence, and pathogenesis of hyperprogression will ultimately help clinicians provide better care to patients with cancer. “We know that immunotherapy doesn’t work for everyone. We need to do better,” said Charu Aggarwal, MD, MPH, an assistant professor of hematology/oncology in the Perelman School of Medicine at the University of Pennsylvania, who was instrumental in opening phase I clinical trials of pembrolizumab (Keytruda) in lung cancer at her institution. A key part of “doing better,” she said, will be learning how to accurately identify which patients are likely to benefit from immunotherapy, and which are not.The French study described HPD as a Response Evaluation Criteria in Solid Tumors (RECIST) progression at the first evaluation and a 2-fold or greater increase in tumor growth rate from baseline (before treatment with immunotherapy).² Similarly, an Annals of Oncology article from April 2017 about hyperprogression during anti— PD-1/PD-L1 therapy in patients with head and neck cancer defined hyperprogression as a tumor growth kinetics ratio equal to or greater than 2 (Figure).³

Figure. Tumor Growth Kinetics of Hyperprogressors Following Immunotherapy

And an August 2017 study by Shumei Kato, MD; Razelle Kurzrock, MD; and colleagues, used a 3-point definition of hyperprogression4 :

1. Time-to-treatment failure (TTF) of less than 2 months
2. Greater than 50% increase in tumor burden compared with preimmunotherapy imaging
3. Greater than or equal to a 2-fold increase in progression pace

“It’s important to not only compare imaging from right before immunotherapy and after immunotherapy, but to also compare with scans taken about 2 to 3 months before, to look at the pace of progression,” said Kato, an assistant clinical professor of medicine at the University of California, San Diego (UCSD) School of Medicine. Kurzrock is the chief of the Division of Hematology and Oncology, senior deputy director of clinical science, and director of the Center for Personalized Cancer Therapy and Clinical Trials Office at UCSD. Patients who exhibit hyperprogression may have relatively slow or stable tumor growth prior to immunotherapy treatment, followed by a rapid increase in tumor ^© BIOLOGY PICS / SCIENCE SOURCE. size after initiation of immunotherapy.

Incidence of Hyperprogression

Although researchers and clinicians haven’t yet agreed upon a universally accepted definition of hyperprogression, evidence of its existence has been established via a handful of studies from around the world. “A name has been given to an entity that was previously undescribed,” Aggarwal said in an interview with OncologyLive^®.Although the first published study of hyperprogression reported an incidence of 9% in a population of patients receiving anti—PD-1 or anti–PD-L1 monotherapy for a variety of cancers,² researchers speculated that the actual rate of hyperprogression could be higher, as 18 patients were excluded from evaluation because they exhibited clinical progression before tumor evaluation. This study found a significant difference between HPD status and age. Patients who experienced hyperprogression were older than patients who did not (66 vs 55 years; P = .007), and 19% of patients (7 of 36) older than 65 presented with HPD compared with 5% of patients (5 of 95) younger than 64 years (P = .018).

A hyperprogression rate of 29% was identified in a study of hyperprogression in patients receiving immunotherapy for recurrent and/or metastatic head and neck squamous cell carcinoma.³ That incidence rate was based on an analysis of the medical records of 34 patients, of which 10 exhibited hyperprogression. The median age was 63 years, and researchers noted that “previous irradiation might play a role, since almost all cases of hyperprogression occurred in patients who had at least a locoregional recurrence in an irradiated field.

Mechanisms behind this hypothesis are unknown.” The multicenter study of 242 patients with advanced NSCLC found a 16% rate of hyperprogression during anti−PD-1/PD-L1 treatment.1 Compared with the non-HPD population, patients with HPD had significantly lower median progression-free survival (1.4 vs 4.9 months; P <.001) and median overall survival (3.4 vs 17 months; P <.001).

Biomarkers May Indicate Increased Risk of Hyperprogression

Recent research suggests that the prevalence of hyperprogression may be related to the underlying genomic make up of tumor cells. A single-center retrospective analysis of hyperprogression after immunotherapy treatments of a variety of cancers found hyperprogression rates as high as 67% in patients with MDM2 amplification, and in 20% of patients with EGFR alterations.⁴The link between MDM2 amplification, EGFR alterations, and hyperprogression on immunotherapy treatment was revealed after Kato and Kurzrock noticed that several of their patients experienced rapid disease progression after initiation of immunotherapy. One was a 65-year-old woman with endometrial stromal sarcoma; she had undergone “several lines of treatment but was having slow-growing disease,” Kato said, including progression of liver metastases over 6 months with targeted therapy. She wanted to try immunotherapy and was switched to nivolumab (Opdivo) and stereotactic body radiation therapy. Within 2 weeks, she was complaining of increased abdominal pain and swelling, Kato said.

A CT scan revealed growth of the existing liver masses, and a grapefruit-sized mass in the abdomen. “We were scratching our heads, wondering if this was some kind of pseudoprogression,” Kato said. “We did a biopsy, and it was full of cancer.”

After a second patient exhibited an increase in clinical symptoms and liver metastases after initiation of atezolizumab (Tecentriq), despite the fact that his tumor had a high mutational burden and therefore was expected to respond well to immunotherapy, Kato and Kurzrock decided to look at genomic data.

“What we found is that, among the multiple genome alterations those 2 patients had, they had one in common: MDM2 amplification,” Kato said. Intrigued, they analyzed the medical records of all patients with stage IV cancers who received CTLA-4, PD-1/PD-L1 inhibitors and other investigational immunotherapy agents, and had comprehensive genomic analyses (n = 155) completed at their center between March 2011 and July 2016.

“Because we do genomics routinely here at UCSD, we looked at all patients who received some type of immunotherapy and also had a genomic analysis,” Kato said. They discovered that alterations in several genes—namely, TERT, PTEN, NF1, and NOTCH1—were associated with favorable clinical outcomes, while others (notably, EGFR, MDM2/4, and DNMT3A) were associated with a TTF of less than 2 months (Table).4 After multivariate analysis, only EGFR and DNMT3A alterations and MDM2 amplifications were significantly correlated with a TTF of less than 2 months.4 Evidence of hyperprogression was apparent in 4 of 6 patients (67%) with MDM2 family amplifications. Increases in tumor lesion size, compared with preimmunotherapy treatment, ranged from 55% to 258%. Hyperprogression was also noted in 2 of 10 patients (20%) with EGFR alterations, with lesions increasing by between 53.6% and 125%. Of note, all the patients who experienced hyperprogression were treated with anti—PD-1/ PD-L1 monotherapy.⁴

Table. Select Genomic Alterations and Associations With Hyperprogression⁴

The apparent connection between EGFR alterations and hyperprogression during immunotherapy treatment is interesting, given that previous research and clinical experience have already demonstrated that lung tumors featuring EGFR mutations are more likely to shrink in response to targeted therapy than immunotherapy. EGFR activation is also known to be associated with upregulation of PD-1, PD-L1, and CTLA-4.

Clinical Implications of Hyperprogression

Both MDM2 and MDM4 inhibit the p53 tumor suppressor; yet, to date, no one knows exactly how MDM2 family alternations might trigger hyperprogression. The researchers noted that immune checkpoint inhibitors can lead to elevated levels of interferon-gamma, which activates JAK-STAT signaling. This results in an increase in interferon regulatory factor-8 expression, which induces MDM2 expression. “It is conceivable that this cascade may not have significant impact when MDM2 is not amplified; however, in the presence of MDM2 amplification, hyperexpression could occur. Other hypotheses are also plausible, including the involvement of a gene that sits on the MDM2 amplicon and is coamplified with it,” the authors wrote in the study. Aggarwal called the link between MDM2 and hyperprogression “an interesting observation and a very novel discovery.”Though much remains to be learned about hyperprogression, the available research suggests that caution is warranted when using immunotherapy to treat patients with MDM2 amplification or EGFR mutations. “I don’t think we can strongly say that we should avoid putting patients on immune checkpoint inhibitors if they have an MDM2 amplification,” Kato said. “At the University of California, San Diego, we are definitely careful when we use immune checkpoint inhibitors for these patients. We may recommend combination treatment. But we don’t have the data that show us how to prevent a patient from having a quick progression.”

Of course, it’s not yet standard protocol to perform genomic sequencing on patients before initiating immunotherapy. “We do it standardly for all of our patients with nonsquamous non— small cell lung cancer, but for patients with squamous cell lung cancer, it’s not standard to do it,” Aggarwal noted. That may change, though, as researchers learn more about genetic alterations and responses to immunotherapy.

It’s also not current practice to measure the pace of tumor progression prior to initiation of immunotherapy, or to measure progression or regression via serial CT scans. Although serial CT scans provide evidence of hyperprogression in research studies, there’s no need to increase radiographic monitoring of patients receiving immunotherapy. “If you look at the literature of hyperprogressors, they all clinically manifested before they were radiographically picked up,” Aggarwal said. “Clinical symptoms should precipitate the need for scans. I don’t think the rates of hyperprogression justify the use of radiographic analysis for all patients at specified time points.”

Seeking a Better Understanding of Hyperprogression

If hyperprogression is evident, immunotherapy treatment should be stopped. However, management of hyperprogression will likely evolve as more is learned. For instance, MDM2 inhibitors are currently in clinical development; in the future, combination treatment with an MDM2 inhibitor and immunotherapy could possibly limit hyperprogression.To date, it is unclear whether the various reported rates of hyperprogression are the result of small study sizes, differing responses to immunotherapy based on cancer histology or immunotherapy medication, or something else. Researchers and clinicians are continuing to work toward an understanding of why some patients experience full regression with immunotherapy therapy treatment, while other see rapid advancement of their underlying disease.

Kato and Kurzrock are currently working with laboratory collaborators to better understand the mechanisms by which MDM2 amplification may cause hyperprogression. That kind of work will help to elucidate the link between MDM2 amplification and hyperprogression, and may point the way toward more effective treatments. “To move forward, we need to understand how exactly it leads to this rapid progression,” Kato said. “By understanding this, we may be able to overcome hyperprogression.”

Aggarwal and colleagues are currently working on a clinical trial to correlate prospective gene sequencing monitoring with either response or progression to single-agent pembrolizumab, she said. Such work will add to the body of knowledge regarding immunotherapy, and may point to important biomarkers clinicians can use to guide treatment.

Additional research is urgently needed, though. “We have a lot to do in terms of understanding and picking out which patients are predisposed to hyperprogression,” Aggarwal said.

References

1. Ferrara R, Caramella C, Texier M, et al. Hyperprogressive disease (HPD) is frequent in non-small cell lung cancer (NSCLC) patients (pts) treated with anti PD1/PD-L1 monoclonal antibodies (IO). Presented at: 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 1306PD.
2. Campiat S, Dercle L, Ammari S, et al. Hyperprogressive disease (HPD) is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res. 2016;23(8):1920-1928. doi: 10.1158/1078-0432.ccr-16-1741.
3. Saâda-Bouzid E, Defaucheux C, Karabajakian A, et al. Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol. 2017;28(7):1605-1611. doi: 10.1093/ annonc/mdx178.
4. Kato S, Goodman A, Walavalkar V, et al. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017;23(15):4242-4250. doi: 10.1158/1078-0432.ccr-16-3133.